ORCID Profile
0000-0002-8910-9787
Current Organisations
St George Hospital, SESLHD
,
UNSW Sydney
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Publisher: American Association for Cancer Research (AACR)
Date: 08-2015
DOI: 10.1158/1538-7445.AM2015-2001
Abstract: Introduction: Radiation therapy (RT) is an important treatment option for prostate cancer (CaP) patients at both early and advanced-stage disease. Many CaP patients suffer from relapse and metastasis due to radio-resistance. In this study, we aimed to develop a radio-resistant CaP (CaP-RR) xenograft model, to identify potential protein markers associated with radio-resistance using proteomic approach, and to validate the identified biomarkers in CaP cell lines and animal xenografts. Methods: Subcutaneous (s.c) CaP animal model was established using PC3-RR and PC3-control CaP cells in NODSCID mice. Tumor xenografts were harvested 5 weeks post cell inoculation and the proteins were extracted. Using LC-MS/MS expression protein profiles from the two groups were created. Statistical analysis was performed using one-way ANOVA for all features. Mascot was employed for peptide identification. Differential protein expressions were identified by re-importing the Mascot data to Progenesis software. The protein pathways and the top KEGG terms were searched against KEGG database using ingenuity software. Selected pathway markers or modulators were validated in CaP-RR cell lines and xenograft tumors using western blotting and immunohistochemistry, respectively. Lactate dehydrogenase A (LDHA) was selected for functional studies including radio-sensitivity, apoptosis and autophagy assays. Results: We found for the first time that higher levels of vascularity, proliferation, and proteins from the glycolysis pathway are associated with CaP-RR xenograft tumors and that more than two hundred proteins were differentially expressed between CaP-RR and CaP naïve tumor xenografts. In addition, we demonstrated that the increased expressions of glycolysis markers, including LDHA, were certified in both CaP- CaP-RR cell lines and xenograft tumors. Knock-down or inhibition of LDHA combined with RT increase the radiosensitivity in PC3-RR cells, induce more apoptosis and autophagy compared to each single treatment alone. Conclusions: We have successfully identified protein signatures using a CaP-RR xenograft animal model. The glycolysis pathway protein LDHA is a promising candidate to develop combination therapy to overcome CaP radioresistance. Citation Format: Jingli Hao, Peter H. Graham, Lei Chang, Jie Ni, Valerie Wasinger, Julia Beretov, Joseph Bucci, Paul Cozzi, Yong Li. Identification of lactate dehydrogenase A (LDHA) as a potential therapeutic target for prostate cancer radiotherapy. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research 2015 Apr 18-22 Philadelphia, PA. Philadelphia (PA): AACR Cancer Res 2015 (15 Suppl):Abstract nr 2001. doi:10.1158/1538-7445.AM2015-2001
Publisher: Ivyspring International Publisher
Date: 2019
DOI: 10.7150/THNO.34692
Publisher: Wiley
Date: 12-02-2014
DOI: 10.1002/PROS.22775
Abstract: Prostate cancer (CaP) is the second leading malignancy in older men in Western countries. The role of CD44 variant 6 (CD44v6) in CaP progression and therapeutic resistance is still uncertain. Here, we investigated the roles of CD44v6 in CaP metastasis and chemo/radioresistance. Expression of CD44v6 in metastatic CaP cell lines, human primary CaP tissues and lymph node metastases was assessed using immunofluorescence and immunohistochemistry, respectively. Knock down (KD) of CD44v6 was performed in PC-3M, DU145, and LNCaP cells using small interfering RNA (siRNA), and confirmed by confocal microscope, Western blot and quantitative real time polymerase chain reaction (qRT-PCR). Cell growth was evaluated by proliferation and colony formation assays. The adhesive ability and invasive potential were assessed using a hyaluronic acid (HA) adhesion and a matrigel chamber assay, respectively. Tumorigenesis potential and chemo-/radiosensitivity were measured by a sphere formation assay and a colony assay, respectively. Over-expression of CD44v6 was found in primary CaP tissues and lymph node metastases including cancer cells and surrounding stromal cells. KD of CD44v6 suppressed CaP proliferative, invasive and adhesive abilities, reduced sphere formation, enhanced chemo-/radiosensitivity, and down-regulated epithelial-mesenchymal transition (EMT), PI3K/Akt/mTOR, and Wnt/β-catenin signaling pathway proteins in vitro. Our findings demonstrate that CD44v6 is an important cancer stem cell-like marker associated with CaP proliferation, invasion, adhesion, metastasis, chemo-/radioresistance, and the induction of EMT as well as the activation PI3K/Akt/mTOR and Wnt signaling pathways, suggesting that CD44v6 is a novel therapeutic target to sensitize CaP cells to chemo/radiotherapy.
Publisher: Bentham Science Publishers Ltd.
Date: 31-12-2010
DOI: 10.2174/1875318301003010026
Abstract: Prostate cancer (CaP) continues to be the second leading cause of cancer-specific death in men in Western countries. The marker currently used for CaP detection is an increase in serum prostate specific antigen (PSA). However, the PSA test may give false positive or negative information and does not allow the differentiation of benign prostate hyperplasia (BPH), non-aggressive CaP and aggressive CaP. Tears are a unique source of body fluid and contain proteins, peptides, mucins and lipids, which is useful for studying clinical proteomics. Advances in the field of proteomics have greatly enhanced the study of tears, with a greater number of proteins now being identified in tears. Identification of novel biomarkers in tear is a new area of development. Modern advances in the field of proteomic techniques hold the promise of providing the clinical oncologists with new tools to find novel CaP biomarkers for early diagnosis and prognosis.
Publisher: Impact Journals, LLC
Date: 30-09-2016
Publisher: Public Library of Science (PLoS)
Date: 26-08-2013
Publisher: Informa UK Limited
Date: 12-07-2013
DOI: 10.3109/01902148.2013.808285
Abstract: Despite the critical role of microRNA in inflammatory response, little is known about its function in inflammation-induced Acute Lung Injury (ALI)/Acute Respiratory Distress Syndrome (ARDS). To investigate the potential role of microRNA146a (miR-146a) in ALI, we used lipopolysaccharide (LPS)-induced ALI rat model. Our data revealed that LPS-induced lung injury in rats resulted in significant upregulation of proinflammatory cytokine tumor necrosis factor-alpha (TNF-α), IL-6, IL-1β, and miR-146a expression. LPS treatment also leads to higher expression of miR-146a as well as increase in secretion of TNF-α, IL-6, and IL-1β in alveolar macrophage (AM) NR8383 cells in a time-dependent manner. Manipulation with miR146a mimic significantly suppressed LPS-mediated TNF-α, IL-6, and IL-1β induction in NR8383 cells by repressing expression of IRAK-1 and TRAF-6. These data clearly indicate that the upregulation of miR146a suppresses inflammatory mediators in LPS induced-ALI model. Therefore, miR-146a may be therapeutically targeted as a mean to repress inflammatory response following ALI.
Publisher: Frontiers Media SA
Date: 06-09-2019
Publisher: Ivyspring International Publisher
Date: 2017
DOI: 10.7150/THNO.20168
Publisher: Wiley
Date: 28-01-2005
DOI: 10.1111/J.1440-1746.2004.03531.X
Abstract: Overexpression of urokinase-type plasminogen activator (uPA) has been shown to be strongly associated with an increased metastatic potential and poor prognosis in a variety of human malignancies. It was hypothesized that uPA would be overexpressed in highly metastatic pancreatic cancer. The aims of this study were to analyze uPA mRNA expression in pancreatic cancer and to correlate this to the expression of uPA protein and to the stage of the disease. Twenty-one pancreatic adenocarcinoma, six ullary carcinoma and 10 benign mucinous cystadenoma s les, all with adjacent normal tissue, were collected. uPA mRNA was measured using real-time quantitative reverse transcription polymerase chain reaction. Localization of uPA within normal and pancreatic tumor sections was subsequently confirmed using immunohistochemistry. The median and range of the ratios of uPA mRNA measures between tumor tissue and non-involved pancreatic tissue was 17.1 (1.4-653.6) for pancreatic adenocarcinoma (P < 0.001), 3.9 (0.7-7.7) for ullary carcinoma (P = 0.055) and 1.9 (0.6-5.9) for mucinous cystadenoma tissue (P = 0.052). uPA low tumors were associated with an exuberant stromal reaction, whereas uPA high tumors showed little stromal response. Immunohistochemistry confirmed that uPA protein was more prevalent in pancreatic adenocarcinoma tissue than in normal tissue and that it was membrane-bound. uPA mRNA expression was significantly associated with poorly differentiated pancreatic cancers (P < 0.05) and positively associated with tumor stage. These observations suggest that significant overexpression of uPA correlates closely to the rapid progression and invasiveness of pancreatic cancer and that uPA may provide a future therapeutic target for pancreatic cancer treatment.
Publisher: Elsevier
Date: 2014
DOI: 10.1016/B978-0-12-800094-6.00004-2
Abstract: Although the survival of breast cancer (BC) patients has increased over the last two decades due to improved screening programs and postoperative adjuvant systemic therapies, many patients die from metastatic relapse. Current biomarkers used in the clinic are not useful for the early detection of BC, or monitoring its progression, and have limited value in predicting response to treatment. The development of proteomic techniques has sparked new searches for novel protein markers for many diseases including BC. Proteomic techniques allow for a high-throughput analysis of s les with the visualization and quantification of thousands of potential protein and peptide markers. Human urine is one of the most interesting and useful biofluids for routine testing and provides an excellent resource for the discovery of novel biomarkers, with the advantage over tissue biopsy s les due to the ease and less invasive nature of collection. In this review, we summarize the results from studies where urine was used as a source for BC biomarker research and discuss urine s le preparation, its advantage, challenges, and limitation. We focus on the gel-based proteomic approaches as well as the recent development of quantitative techniques in BC urine biomarker detection. Finally, the future use of modern proteomic techniques in BC biomarker identification will be discussed.
Publisher: SAGE Publications
Date: 2014
DOI: 10.4137/BIC.S17991
Abstract: A suitable and standardized protein purification technique is essential to maintain consistency and to allow data comparison between proteomic studies for urine biomarker discovery. Ultimately, efforts should be made to standardize urine preparation protocols. The aim of this study was to develop an optimal analytical protocol to achieve maximal protein yield and to ensure that this method was applicable to examine urine protein patterns that distinguish disease and disease-free states. In this pilot study, we compared seven different urine s le preparation methods to remove salts, and to precipitate and isolate urinary proteins. Sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE) profiles showed that the sequential preparation of urinary proteins by combining acetone and trichloroacetic acid (TCA) alongside high speed centrifugation (HSC) provided the best separation, and retained the most urinary proteins. Therefore, this approach is the preferred method for all further urine protein analysis.
Publisher: Springer Science and Business Media LLC
Date: 24-08-2010
Publisher: Springer Science and Business Media LLC
Date: 22-02-2017
DOI: 10.1038/SREP41834
Abstract: Identifying biomarkers and signaling pathways are important for the management of prostate cancer (CaP) radioresistance. In this study, we identified differential proteins and signaling pathways from parental CaP cell lines and CaP radioresistant (RR) sublines using a label-free LC-MS/MS proteomics approach. A total of 309 signaling pathway proteins were identified to be significantly altered between CaP and CaP-RR cells ( p ≤ 0.05, fold differences .5, ≥80% power). Among these proteins, nineteen are common among three paired CaP cell lines and associated with metastasis, progression and radioresistance. The PI3K/Akt, VEGF and glucose metabolism pathways were identified as the main pathways associated with CaP radioresistance. In addition, the identified potential protein markers were further validated in CaP-RR cell lines and subcutaneous (s.c) animal xenografts by western blotting and immunohistochemistry, respectively and protein aldolase A (ALDOA) was selected for a radiosensitivity study. We found the depletion of ALDOA combined with radiotherapy effectively reduced colony formation, induced more apoptosis and increased radiosensitivity in CaP-RR cells. Our findings indicate that CaP radioresistance is caused by multifactorial traits and downregulation of ALDOA increases radiosensitivity in CaP-RR cells, suggesting that controlling these identified proteins or signaling pathways in combination with radiotherapy may hold promise to overcome CaP radioresistance.
Publisher: Wiley
Date: 18-07-2011
DOI: 10.1111/J.1740-0929.2011.00901.X
Abstract: Studies of uterine capacity and litter size in swine have suggested that erythropoietin receptor (EPOR) plays an important role in fetal survival through maturation of red blood cells. In this study, we screened the porcine EPOR gene for mutations and identified three single nucleotide polymorphisms (SNPs): two missense mutations and one synonymous mutation. We then genotyped 272 Beijing Black sows, Sus scrofa, and compared this data with litter sizes from a total of 1523 parities among the sows. The G allele of the nonsynonymous SNP, EPOR c.434A>G, was associated with greater litter size at both first parity (P < 0.05) and at later parities (P G could be a useful genetic marker to improve litter size in swine.
Publisher: Springer Science and Business Media LLC
Date: 03-2003
Publisher: Future Science Ltd
Date: 02-2012
DOI: 10.4155/TDE.11.148
Abstract: Cancer stem cells (CSCs) have the capacity to generate the heterogeneous lineages of all cancer cells comprising a tumor and these populations of cells are likely to be more relevant in determining prognosis. However, these cells do not operate in isolation, but instead rely upon signals co-opted from their microenvironment, making the targeting and imaging of CSCs within a cancer mass a daunting task. A better understanding of the molecular cell biology underlying CSC pathology will facilitate the development of new therapeutic targets and novel strategies for the successful eradication of cancer. In addition, the continued investigation of sensitive molecular-imaging modalities will enable more accurate staging, treatment planning and the ability to monitor the effectiveness of CSC-targeted therapies in vivo. In this review, we explore the possibilities and limitations of CSC-directed therapies and molecular imaging modalities.
Publisher: American Association for Cancer Research (AACR)
Date: 10-2014
DOI: 10.1158/1538-7445.AM2014-4005
Abstract: Aim: The role of CD44 variant 6 (CD44v6) in prostate cancer (CaP) metastasis and progression remains unclear. The aim of this study was 1) to examine the expression of CD44v6 in metastatic CaP cell lines, and normal, benign hyperplastic, and CaP tissues in different stages and lymph node metastases 2) to investigate the role of CD44v6 in CaP progression, metastasis and therapy resistance as well as underlying pathways in vitro for a potential therapeutic target. Methods: Immunohistochemical/immunocytochemical analysis using an anti-CD44V6 monoclonal antibody (MAb) was performed on metastatic CaP cell lines and paraffin embedded specimens from patients (n=10) who underwent radical prostatectomy (RP), lymph node metastases (n=10), benign prostatic hyperplasia (BPH) (n=10), and normal prostate tissues (n=10). The immunostaining results from CaP cell lines were further confirmed by Western blot. The functional roles of CD44v6 in CaP metastasis and chemo- and radio-sensitivity were examined by knocking down (KD) CD44v6 gene using siRNAs in PC-3M, DU145 and LNCaP CaP cells, respectively and then performing cell invasion, colony formation, proliferation rate, sphere formation, chemo- and radio-sensitivity assays. Results: The expression of CD44v6 was found moderately to strongly positive in androgen-responsive (LNCaP, LNCaP-LN3) and androgen-nonresponsive (PC-3, PC-3M, DU145 and LNCaP-C4B2) metastatic CaP cell lines. The expression of CD44v6 was found negative in normal prostate and BPH tissues, and moderately to strongly positive primary CaP tissues and lymph node metastases. Three CD44v6-KD cell lines showed notable decreases in functions of invasion, colony formation, proliferation, sphere formation, and an increase in chemodrug and radiation sensitivity, compared to the parental cell lines, respectively. Obvious down-regulation of PI3K/Akt/mTOR and Wnt/β-catenin signaling pathways were observed in three CD44v6-KD cell lines by Western Blot. Conclusions: CD44v6 is a biomarker involved in CaP progression and metastasis, associated with CaP chemo-/radio-resistance via PI3K/Akt/mTOR and Wnt/β-catenin signaling pathways and could be an ideal potential therapeutic target for the treatment of castrate-resistant prostate cancer (CRPC). The in vivo study of CD44v6 functions in CaP animal models is ongoing in our laboratory. Citation Format: Jie Ni, Paul Cozzi, Jingli Hao, Julia Beretov, Lei Chang, Wei Duan, Warick Delprado, Peter Graham, Joseph Bucci, John Kearsley, Yong Li. CD44 isoform variant 6 is associated with prostate cancer progression, metastasis and chemo-/radio-resistance via PI3K/Akt/mTOR and Wnt/β-catenin signaling pathways in vitro. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research 2014 Apr 5-9 San Diego, CA. Philadelphia (PA): AACR Cancer Res 2014 (19 Suppl):Abstract nr 4005. doi:10.1158/1538-7445.AM2014-4005
Publisher: Impact Journals, LLC
Date: 09-06-2016
Publisher: Elsevier BV
Date: 12-2015
DOI: 10.1016/J.CANLET.2015.09.013
Abstract: Radiotherapy (RT) is one of the most important strategies in cancer treatment. Radioresistance is a major challenge to RT and results in locoregional recurrence and metastasis. Thus, there is a great interest in investigating biomarkers to distinguish radiosensitive from radioresistant (RR) cancer patients. The development of proteomic techniques has sparked new searches for novel proteins for cancer biomarker discovery. Modern proteomic techniques allow for a high-throughput analysis of s les with the visualization and quantification of thousands of potential protein and peptide markers. The discovery of RR biomarkers can provide a clue for predicting RT response and discover therapeutic targets for developing personalised medicine of in idual patients. In the past decade, emerging advanced proteomic technologies have been performed to identify radiation-related biomarkers in human cancers. This review discusses the mass spectrometry (MS)-based proteomic techniques in RR cancer biomarker discovery, summarises RR biomarkers identified in cancers from proteomics-based findings and explores potential values of RR biomarkers for future clinical trials.
Publisher: Springer Science and Business Media LLC
Date: 21-06-2012
DOI: 10.1007/S10555-012-9389-1
Abstract: Despite significant advances in surgery, radiotherapy and chemotherapy to treat prostate cancer (CaP), many patients die of secondary disease (metastases). Current therapeutic approaches are limited, and there is no cure for metastatic castration-resistant prostate cancer (CRPC). Epithelial cell adhesion molecule (EpCAM, also known as CD326) is a transmembrane glycoprotein that is highly expressed in rapidly proliferating carcinomas and plays an important role in the prevention of cell-cell adhesion, cell signalling, migration, proliferation and differentiation. Stably and highly expressed EpCAM has been found in primary CaP tissues, effusions and CaP metastases, making it an ideal candidate of tumour-associated antigen to detect metastasis of CaP cells in the circulation as well as a promising therapeutic target to control metastatic CRPC disease. In this review, we discuss the implications of the newly identified roles of EpCAM in terms of its diagnostic and metastatic relevance to CaP. We also summarize EpCAM expression in human CaP and EpCAM-mediated signalling pathways in cancer metastasis. Finally, emerging and innovative approaches to the management of the disease and expanding potential therapeutic applications of EpCAM for targeted strategies in future CaP therapy will be explored.
Publisher: Elsevier BV
Date: 02-2023
Publisher: Impact Journals, LLC
Date: 24-12-2016
Publisher: Public Library of Science (PLoS)
Date: 06-11-2015
Publisher: Elsevier BV
Date: 12-2014
Publisher: Elsevier BV
Date: 12-2013
DOI: 10.1016/J.BIOCEL.2013.09.008
Abstract: Prostate cancer (CaP) is the second leading malignancy in men. The role of epithelial cell adhesion molecule (EpCAM), also known as CD326, in CaP progression and therapeutic resistance is still uncertain. Here, we aimed to investigate the roles of EpCAM in CaP metastasis and chemo/radioresistance. Expression of EpCAM in CaP cell lines and human CaP tissues was assessed using immunofluorescence and immunohistochemistry, respectively. EpCAM was knocked down (KD) in PC-3, DU145 and LNCaP-C4-2B cells using small interfering RNA (siRNA), and KD results were confirmed by confocal microscope, Western blotting and quantitative real time polymerase chain reaction (qRT-PCR). Cell growth was evaluated by proliferation and colony formation assays. The invasive potential was assessed using a matrigel chamber assay. Tumorigenesis potential was measured by a sphere formation assay. Chemo-/radiosensitivity were measured using a colony formation assay. Over-expression of EpCAM was found in primary CaP tissues and lymph node metastases including cancer cells and surrounding stromal cells. KD of EpCAM suppressed CaP proliferation and invasive ability, reduced sphere formation, enhanced chemo-/radiosensitivity, and down-regulated E-cadherin, p-Akt, p-mTOR, p-4EBP1 and p-S6K expression in CaP cells. Our findings suggest that EpCAM plays an important role in CaP proliferation, invasion, metastasis and chemo-/radioresistance associated with the activation of the PI3K/Akt/mTOR signaling pathway and is a novel therapeutic target to sensitize CaP cells to chemo-/radiotherapy.
Publisher: Ivyspring International Publisher
Date: 2015
DOI: 10.7150/THNO.11711
Publisher: Elsevier BV
Date: 10-2017
DOI: 10.1016/J.CRITREVONC.2017.08.002
Abstract: Prostate cancer (CaP) is the most common cancer in men and the second leading cause of cancer deaths in males in Australia. Although serum prostate-specific antigen (PSA) has been the most widely used biomarker in CaP detection for decades, PSA screening has limitations such as low specificity and potential association with over-diagnosis. Current biomarkers used in the clinic are not useful for the early detection of CaP, or monitoring its progression, and have limited value in predicting response to treatment. Urine is an ideal body fluid for the detection of protein markers of CaP and is emerging as a potential source for biomarker discovery. Gene-based biomarkers in urine such as prostate cancer antigen-3 (PCA3), and genes for transmembrane protease serine-2 (TMPRSS2), and glutathione S-transferase P (GSTP1) have been developed and evaluated in the past decades. Among these biomarkers, urinary PCA3 is the only one approved by the FDA in the USA for clinical use. The study of urine microRNAs (miRNAs) is another burgeoning area for investigating biomarkers to achieve a pre-biopsy prediction of CaP to contribute to early detection. The development of mass spectrometry (MS)-based proteomic techniques has sparked new searches for novel protein markers for many diseases including CaP. Urinary biomarkers for CaP represent a promising alternative or an addition to traditional biomarkers. Future success in biomarker discovery will rely on collaboration between clinics and laboratories. In addition, research efforts need to be moved from biomarker discovery to validation in a large cohort or separate population of patients and translation of these findings to clinical practice. In this review, we discuss urine as a potential source for CaP biomarker discovery, summarise important genetic urine biomarkers in CaP and focus on MS-based proteomic approaches as well as other recent developments in quantitative techniques for CaP urine biomarker discovery.
Publisher: Wiley
Date: 08-2005
DOI: 10.1002/JGM.808
Publisher: Public Library of Science (PLoS)
Date: 27-02-2013
Publisher: American Scientific Publishers
Date: 04-2013
Publisher: Elsevier BV
Date: 2010
DOI: 10.1016/J.CRITREVONC.2009.02.007
Abstract: The marker currently used for prostate cancer (CaP) detection is an increase in serum prostate-specific antigen (PSA). However, the PSA test which may give false positive or negative information, is not reliable and does not allow the differentiation of benign prostate hyperplasia (BPH), non-aggressive CaP and aggressive CaP. There is thus an urgent need to search for novel CaP biomarkers to improve the early detection and accuracy of diagnosis, determine the aggressiveness of CaP and to monitor the efficacy of treatment. Proteomic techniques allow for a high-throughput analysis of bio-fluids with the visualization and quantification of thousands of potential protein markers and represent very promising tools in the search for new, improved molecular markers of CaP. In this review, we will summarize conventional CaP biomarkers and focus on novel identified biomarkers for CaP early diagnosis and progression that might be used in the future.
Publisher: Springer Science and Business Media LLC
Date: 2011
Publisher: American Association for Cancer Research (AACR)
Date: 07-2018
DOI: 10.1158/1538-7445.AM2018-1999
Abstract: Background: Chemo-/radio-resistance is an important reason for prostate cancer (CaP) progression and metastasis. CD44 is a well-documented cancer stem cell (CSC) biomarker, and one of its variants, CD44 variant 6 (CD44v6) is closely associated with aggressive behaviour and correlates with poor prognosis in a variety of human cancers. Our previous study has demonstrated increased expressions of CD44v6 in metastatic CaP cell lines and human CaP tissues, which was associated with CaP progression and chemo-/radio-resistance in vitro. However, the role of CD44v6 in CaP progression and therapeutic resistance in vivo is still uncertain. Aim: The aim of this study was to investigate the role of CD44v6 in CaP development and chemo-/radioresistance as well as underlying pathways in vivo, and find whether it is a suitable therapeutic target for CaP therapy. Methods: CD44v6 gene was knocked down (KD) in PC-3M CaP cell line using short hairpin RNA (shRNA). Subcutaneous (s.c.) and orthotopic CaP animal models were established using PC-3M-CD44v6-KD and PC-3M-CD44v6-scramble (scr) control cells, to assess the effect of CD44v6 on CaP tumourigenesis, chemotherapy (docetaxel) response and radiation response. Signal transduction proteins in PI3K/Akt/mTOR pathway (Akt, p-Akt, mTOR and p-mTOR) as well as proliferation and apoptosis makers were assessed by immunohistochemistry in xenografts from both animal models. Results: Both s.c. and orthotopic xenografts from PC-3M-CD44v6-KD cells displayed supressed tumour growth and increased responsiveness to docetaxel (40mg/kg) and radiation (2Gy/day for 4 consecutive days) compared to control xenografts from PC-3M-CD44v6-scr cells in NOD/SCID male mice. Down-regulation of the PI3K/Akt/mTOR pathway proteins (p-Akt and p-mTOR), proliferation marker (Ki-67) and angiogenesis marker (CD31), as well as up-regulation of apoptotic responses (cleaved Caspase-3) to chemotherapy, DNA damage responses (γ-H2AX) to radiation were found in PC-3M-CD44v6-KD s.c. xenografts, respectively. Conclusions: CD44v6 is actively involved in CaP tumorigenesis and treatment responses to chemo-/radio-therapy via PI3K/Akt/mTOR signalling pathway in in vivo mouse models and holds promise as a therapeutic target for the treatment of CaP. Key words: CD44v6, prostate cancer, chemo-/radio-resistance, animal model, metastasis Citation Format: Jie Ni, Paul Cozzi, Julia Beretov, Joseph Bucci, Peter Graham, Yong Li. Study of CD44 variant 6 (CD44v6) in prostate cancer chemo-/radio resistance in vivo [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018 2018 Apr 14-18 Chicago, IL. Philadelphia (PA): AACR Cancer Res 2018 (13 Suppl):Abstract nr 1999.
Publisher: Public Library of Science (PLoS)
Date: 23-07-2012
Publisher: Elsevier BV
Date: 03-2014
DOI: 10.1016/J.CANLET.2013.11.012
Abstract: Cancer stem cells are a progressive concept to account for the cell biological nature of cancer. Despite the controversies regarding the cancer stem cell model, it has the potential to provide a foundation for new innovative treatment targeting the roots of cancer. The last two years have witnessed exceptional progress in cancer stem cell research, in particular on solid tumours, which holds promise for improved treatment outcomes. Here, we review recent advances in cancer stem cell research, discuss challenges in the field and explore future strategies and opportunities in cancer stem cell studies to overcome resistance to chemotherapy.
Publisher: Springer Science and Business Media LLC
Date: 28-09-2011
DOI: 10.1007/S10585-011-9423-7
Abstract: CD44 plays an important role in cancer metastasis, chemotherapy, and radiation resistance. The present study investigated the relationship of CD44 expression and radioresistance, and the potential mechanisms of CD44 in radiosensitivity using prostate cancer (CaP) cell lines. CD44 was knocked down in three CaP cell lines (PC-3, PC-3M-luc, and LNCaP) using small interfering RNA (siRNA) and clonogenic survival fractions after single dose irradiation were compared before and after CD44 knocking down (KD). The effect of radiation on cell cycle distribution was examined by flow cytometry and the cell cycle-related protein levels of phospho-Chk1 and phospho-Chk2 were ascertained by Western blotting. The expression of the DNA double strand break (DSB) marker-γH2AX was also quantified by immunofluorescence staining. Our results indicate that the down-regulation of CD44 enhanced radiosensitivity in PC-3, PC-3M-luc, and LNCaP CaP cells, the sensitizing enhancement ratio for these cell lines was 2.3, 1.3, and 1.5, respectively and that the delay of DNA DSB repair in low CD44-expressing KD CaP cells correlated with ineffective cell cycle arrest and the delayed phosphorylation of Chk1 and Chk2. These findings suggest that CD44 may be a valuable biomarker and a predictor of radiosensitivity in CaP treatment.
Publisher: Impact Journals, LLC
Date: 19-10-2015
Publisher: IEEE
Date: 07-2008
Publisher: Medwell Publications
Date: 12-2010
Publisher: Springer Science and Business Media LLC
Date: 03-2002
Publisher: Impact Journals, LLC
Date: 25-07-2016
Publisher: American Association for Cancer Research (AACR)
Date: 02-2009
DOI: 10.1158/1078-0432.CCR-08-1203
Abstract: Purpose: To investigate the therapeutic potential of 213Bilabeled multiple targeted α-radioimmunoconjugates for treating prostate cancer (CaP) micrometastases in mouse models. Experimental Design: PC-3 CaP cells were implanted s.c., in the prostate, and intratibially in NODSCID mice. The expression of multiple tumor–associated antigens on tumor xenografts and micrometastases was detected by immunohistochemistry. Targeting vectors were two monoclonal antibodies, and a plasminogen activator inhibitor type 2 that binds to cell surface urokinase plasminogen activator, labeled with 213Bi using standard methodology. In vivo efficacy of multiple α conjugates (MTAT) at different activities was evaluated in these mouse models. Tumor growth was monitored during observations and local regional lymph node metastases were assessed at the end of experiments. Results: The take rate of PC-3 cells was 100% for each route of injection. The tumor-associated antigens (MUC1, urokinase plasminogen activator, and BLCA-38) were heterogeneously expressed on primary tumors and metastatic cancer clusters at transit. A single i.p. injection of MTAT (test) at high and low doses caused regression of the growth of primary tumors and prevented local lymph node metastases in a concentration-dependent fashion it also caused cancer cells to undergo necrosis and apoptosis. Conclusions: Our results suggest that MTAT can impede primary PC-3 CaP growth at three different sites in vivo through induction of apoptosis, and can prevent the spread of cancer cells and target lymph node micrometastases in a concentration-dependent manner. MTAT, by targeting multiple antigens, can overcome heterogeneous antigen expression to kill small CaP cell clusters, thus providing a potent therapy for micrometastases.
Publisher: Informa UK Limited
Date: 08-2005
DOI: 10.4161/CBT.4.8.1892
Abstract: The aim of this study was to investigate the effect of targeted alpha therapy for the control of in vitro pancreatic cancer cell clusters and micrometastatic cancer lesions in vivo. The expression of tumor-associated antigen MUC-1 on three pancreatic cancer cell clusters and animal xenografts was detected by indirect immmunostaining. Monoclonal antibodies C595 (test) and A2 (non-specific control) were labeled with 213Bi using the chelator CHX.A" to form the alpha-immunoconjugate (AIC). Cell clusters were incubated with AIC and examined at 48 h. Apoptosis was documented using the TUNEL assay. In vivo, an antiproliferative effect for tumors was tested at two days post-subcutaneous cell inoculation. Mice were injected with different concentrations of AIC by regional or systemic administration. Changes in tumor progression were assessed by tumor size. MUC-1 is strongly expressed on CFPAC-1, PANC-1 and moderate expression was found CAPAN-1 cell clusters and tumor xenografts. The AICs can target and kill cancer cell clusters (100 mm) in vitro. Some 73-81 % of cells were TUNEL positive cells in the clusters after incubation with AIC. At two days post- cell inoculation in mice, a single local injection of 74 and 148 MBq/kg of AIC causes complete inhibition of tumor growth. Systemic injections of 111, 222 and 333 MBq/kg of AIC cause significant tumor growth delay after 16 weeks, compared with the nonspecific control providing 333 MBq/kg after 16 weeks. CFPAC-1, PANC-1 and CAPAN-1 pancreatic cancer cell clusters and pancreatic tumor xenografts show high expression of the MUC-1 target antigen. 213Bi-C595 can specifically target and regress pancreatic cancer cell clusters in vitro, and delay and inhibit tumor growth in vivo. 213Bi-C595 may be a useful agent for the treatment of micrometastatic pancreatic cancer with overexpression of MUC 1 antigen in post-surgical patients with minimal residual disease.
Publisher: Elsevier BV
Date: 12-2015
DOI: 10.1016/J.CRITREVONC.2015.07.005
Abstract: The phosphatidylinositol-3-kinase/Akt and the mammalian target of rapamycin (PI3K/Akt/mTOR) pathway is one of the most frequently activated signaling pathways in prostate cancer (CaP) and other cancers, and responsible for the survival, metastasis and therapeutic resistance. Recent advances in radiation therapy indicate that activation of this pathway is closely associated with cancer radioresistance, which is a major challenge for the current CaP radiation treatment. Therefore, targeting this pathway by inhibitors to enhance radiosensitivity has great potential for clinical benefits of CaP patients. In this review, we summarize the recent findings in the PI3K/Akt/mTOR pathway in CaP radiotherapy research and discuss the potential use of the PI3K/Akt/mTOR pathway inhibitors as radiosensitizers in the treatment of CaP radioresistance in preclinical studies to explore novel approaches for future clinical trials.
Publisher: Elsevier BV
Date: 02-2016
Publisher: SAGE Publications
Date: 2019
Abstract: Prostate cancer (CaP) is the most commonly diagnosed cancer in males in western countries. Orthotopic implantation is considered as an ideal xenograft model for CaP study, and noninvasive measurement of tumor volume changes is important for monitoring responses to anticancer therapies. In this study, the T2-weighted fast spin echo sequence magnetic resonance imaging (MRI) was performed on a CaP orthotopic non-obese diabetic/severe combined immunodeficiency (NOD/SCID) mouse model weekly for 6 weeks post PC-3 CaP cell inoculation, and the fat signal was suppressed using a chemical shift-selective pulse. Subsequently, the MRI data were imported into the image processing software Avizo Standard and stacked into three-dimensional (3D) volumes. Our results demonstrate that MRI, combined with 3D reconstruction, is a feasible and sensitive method to assess tumor growth in a PC-3 orthotopic CaP mouse model and this established monitoring approach is promising for longitudinal observation of CaP xenograft development after anticancer therapy in vivo. Further investigation is needed to validate this protocol in a larger cohort of mice to generate enough statistical power.
Publisher: Ivyspring International Publisher
Date: 2012
DOI: 10.7150/IJBS.4027
Publisher: Elsevier BV
Date: 06-2011
Publisher: Frontiers Media SA
Date: 27-06-2019
Publisher: Ivyspring International Publisher
Date: 2012
DOI: 10.7150/IJBS.3614
Publisher: Springer Science and Business Media LLC
Date: 19-07-2017
DOI: 10.1038/S41598-017-05859-Z
Abstract: The development of chemoresistance and inability in elimination of cancer stem cells are among the key limitations of cancer chemotherapy. Novel molecular therapeutic strategies able to overcome such limitations are urgently needed for future effective management of cancer. In this report, we show that EpCAM-aptamer-guided survivin RNAi effectively downregulated survivin both in colorectal cancer cells in vitro and in a mouse xenograft model for colorectal cancer. When combined with the conventional chemotherapeutic agents, the aptamer-guided survivin RNAi was able to enhance the sensitivity towards 5-FU or oxaliplatin in colorectal cancer stem cells, increase apoptosis, inhibit tumour growth and improve the overall survival of mice bearing xenograft colorectal cancer. Our results indicate that survivin is one of the key players responsible for the innate chemoresistance of colorectal cancer stem cells. Thus, aptamer-mediated targeting of survivin in cancer stem cells in combination with chemotherapeutic drugs constitutes a new avenue to improve treatment outcome in oncologic clinics.
Publisher: Springer Science and Business Media LLC
Date: 17-11-2020
DOI: 10.1038/S41419-020-03189-Z
Abstract: Drug resistance is a daunting challenge in the treatment of breast cancer (BC). Exosomes, as intercellular communicative vectors in the tumor microenvironment, play an important role in BC progression. With the in-depth understanding of tumor heterogeneity, an emerging role of exosomes in drug resistance has attracted extensive attention. The functional proteins or non-coding RNAs contained in exosomes secreted from tumor and stromal cells mediate drug resistance by regulating drug efflux and metabolism, pro-survival signaling, epithelial–mesenchymal transition, stem-like property, and tumor microenvironmental remodeling. In this review, we summarize the underlying associations between exosomes and drug resistance of BC and discuss the unique biogenesis of exosomes, the change of exosome cargo, and the pattern of release by BC cells in response to drug treatment. Moreover, we propose exosome as a candidate biomarker in predicting and monitoring the therapeutic drug response of BC and as a potential target or carrier to reverse the drug resistance of BC.
Publisher: Bentham Science Publishers Ltd.
Date: 09-03-2015
DOI: 10.2174/1566523214666141224095105
Abstract: Cancer as a genetic disorder is one of the leading causes of death worldwide. Conventional anticancer options such as chemo- and/or radio-therapy have their own drawbacks and could not provide a cure in most cases at present. More effective therapeutic strategies with less side effects are urgently needed. Aptamers, also known as chemical antibodies, are single strand DNA or RNA molecules that can bind to their target molecules with high affinity and specificity. Such site-specific binding ability of aptamers facilitates the delivery and interaction of exogenous nucleic acids with diseased genes. Thus, aptamer-guided gene therapy has emerged as a promising anticancer strategy in addition to the classic treatment regimen. Aptamers can directly deliver anti-cancer nucleic acids, e.g. small interfering RNA, micro RNA, antimicroRNA and small hairpin RNA, to cancer cells or function as a targeting ligand to guide nanoparticles containing therapeutic nucleic acids. This review focuses on recent progress in aptamer-mediated gene therapy for the treatment of hepatocellular carcinoma and other types of cancers, shedding light on the potential of this novel approach of targeted cancer gene therapy.
Publisher: Elsevier BV
Date: 03-2020
DOI: 10.1016/J.YEXCR.2020.111850
Abstract: We have previously demonstrated that CD44 variant 6 (CD44v6) is associated with prostate cancer (CaP) growth and therapeutic resistance in vitro, however, the role of CD44v6 in CaP in vivo is not fully understood. The purpose of this study is to investigate the effect of CD44v6 on CaP growth and chemo-/radiotherapy response in NOD/SCID mouse models in vivo and to validate its role as a therapeutic target for CaP therapy. CD44v6 was knocked down in PC-3M CaP cell line using short hairpin RNA. Subcutaneous (s.c.) and orthotopic CaP mouse xenografts were established. The effect of CD44v6 knockdown (KD) on tumour growth was evaluated in both s.c. and orthotopic models. Chemo-/radiotherapy response was evaluated in the s.c. model. Association of CD44v6 with PI3K/Akt pathway was validated using immunohistochemistry staining. We found that KD of CD44v6 significantly reduced tumour growth in both models, and enhanced the sensitivity of tumours to chemotherapy and radiotherapy in the s.c. model. In addition, we demonstrated that KD of CD44v6 is associated with downregulation of the PI3K/Akt/mTOR pathway. Our data confirm that CaP growth and chemo-/radiosensitivity in vivo is associated with CD44v6, which holds great promises as a therapeutic target in the treatment of CaP.
Publisher: Springer Science and Business Media LLC
Date: 24-06-2019
Publisher: JMIR Publications Inc.
Date: 27-09-2023
DOI: 10.2196/45216
Publisher: Wiley
Date: 18-09-2019
Abstract: Targeted exosomal delivery systems for precision nanomedicine attract wide interest across areas of molecular cell biology, pharmaceutical sciences, and nanoengineering. Exosomes are naturally derived 50-150 nm nanovesicles that play important roles in cell-to-cell and/or cell-to-tissue communications and cross-species communication. Exosomes are also a promising class of novel drug delivery vehicles owing to their ability to shield their payload from chemical and enzymatic degradations as well as to evade recognition by and subsequent removal by the immune system. Combined with a new class of affinity ligands known as aptamers or chemical antibodies, molecularly targeted exosomes are poised to become the next generation of smartly engineered nanovesicles for precision medicine. Here, recent advances in targeted exosomal delivery systems engineered by aptamer for future strategies to promote human health using this class of human-derived nanovesicles are summarized.
Publisher: Ivyspring International Publisher
Date: 2015
DOI: 10.7150/THNO.10202
Publisher: Ivyspring International Publisher
Date: 2020
DOI: 10.7150/THNO.39706
Publisher: Elsevier BV
Date: 11-2019
DOI: 10.1016/J.CANLET.2019.08.020
Abstract: Cancer stem cells (CSCs) in prostate cancer (CaP) are regarded as major contributors to radioresistance due to complex mechanisms including enhanced DNA repair, increased intracellular reactive oxygen species scavenging, activation of anti-apoptotic pathways, microenvironment hypoxia, epithelial-to-mesenchymal transition (EMT) and autophagy. They are also believed to cause tumour recurrence and metastasis due to their unique capability to survive and replicate the heterogeneity of the original tumour. Finding markers of prostate CSCs (PCSC) for identification, prognostication and targeting is key in enhancing therapeutic and clinical outcomes. Markers such as aldehyde dehydrogenase, CD44, integrins and EMT markers have been proved to show great potential in being sensitive and specific to the presence of PCSCs. Novel therapies such as Hedgehog and Wnt pathway inhibitors, angiogenesis inhibitors and metformin show potential in eliminating PCSCs to improve therapeutic outcomes. Here, we review the current state of the literature regarding mechanisms of PCSC radioresistance, promising PCSC markers and novel PCSC-specific therapeutic approaches and their implications in CaP treatment and prognosis.
Publisher: Genetics and Molecular Research
Date: 2012
Publisher: Elsevier BV
Date: 09-2018
DOI: 10.1016/J.CTRV.2018.07.004
Abstract: Development of therapeutic resistance and metastasis is a major challenge with current breast cancer (BC) therapy. Mounting evidence suggests that a subpopulation of cancer stem cells (CSCs) contribute to the cancer therapeutic resistance and metastasis, leading to the recurrence and death in patients. Breast cancer stem cells (BCSCs) are not only a consequence of mutations that overactivate the self-renewal ability of normal stem cells or committed progenitors but also a result of the de-differentiation of cancer cells induced by somatic mutations or microenvironmental components under treatment. Eradication of BCSCs may bring hope and relief to patients whose lives are threatened by recurrent BCs. Therefore, a better understanding of the generation, regulatory mechanisms, and identification of CSCs in BC therapeutic resistance and metastasis will be imperative for developing BCSC-targeted strategies. Here we summarize the latest studies about cell surface markers and signalling pathways that sustain the stemness of BCSC and discuss the associations of mechanisms behind these traits with phenotype and behavior changes in BCSCs. More importantly, their implications for future study are also evaluated and potential BCSC-targeted strategies are proposed to break through the limitation of current therapies.
Publisher: Elsevier BV
Date: 03-2016
Abstract: The mass spectrometry technique of multiple reaction monitoring (MRM) was used to quantify and compare the expression level of lactoferrin in tear films among control, prostate cancer (CaP), and benign prostate hyperplasia (BPH) groups. Tear s les from 14 men with CaP, 15 men with BPH, and 14 controls were analyzed in the study. Collected tears (2 μl) of each s le were digested with trypsin overnight at 37 °C without any pretreatment, and tear lactoferrin was quantified using a lactoferrin-specific peptide, VPSHAVVAR, both using natural/light and isotopic-labeled/heavy peptides with MRM. The average tear lactoferrin concentration was 1.01 ± 0.07 μg/μl in control s les, 0.96 ± 0.07 μg/μl in the BPH group, and 0.98 ± 0.07 μg/μl in the CaP group. Our study is the first to quantify tear proteins using a total of 43 in idual (non-pooled) tear s les and showed that direct digestion of tear s les is suitable for MRM studies. The calculated average lactoferrin concentration in the control group matched that in the published range of human tear lactoferrin concentration measured by enzyme-linked immunosorbent assay (ELISA). Moreover, the lactoferrin was stably expressed across all of the s les, with no significant differences being observed among the control, BPH, and CaP groups.
Publisher: Ivyspring International Publisher
Date: 2017
DOI: 10.7150/THNO.19934
Publisher: Public Library of Science (PLoS)
Date: 03-08-2012
Publisher: Elsevier BV
Date: 03-2013
DOI: 10.1016/J.CANLET.2012.11.032
Abstract: The monoclonal antibody against the AC133 epitope of CD133 has been widely used as a cell surface marker of cancer stem cells in several different cancer types. Here, we describe the isolation and characterisation of two RNA aptamers, including the smallest described 15 nucleotide RNA aptamer, which specifically recognise the AC133 epitope and the CD133 protein with high sensitivity. As well, both these aptamers show superior tumour penetration and retention when compared to the AC133 antibody in a 3-D tumour sphere model. These novel CD133 aptamers will aid future development of cancer stem cell targeted therapeutics and molecular imaging.
Publisher: Springer Science and Business Media LLC
Date: 24-07-2010
DOI: 10.1007/S10585-010-9345-9
Abstract: Cancer metastasis and anti-cancer drug resistance are the major reason for the failure of clinical cancer treatment. We evaluated CD147, monocarboxylate transporters (MCT1 and MCT4), and multidrug resistance (MDR) markers (MDR1 and MRP2) in 4 epithelial ovarian cancer (EOC) cell lines and primary tumors (n = 120) along with the matched metastatic lesions (n = 40) with immunofluorescence labeling. We correlated CD147 with MCT1, MCT4, MDR1 and MRP2 markers in primary and metastatic cells in cell lines and tissues using confocal microscopy. We also investigated the relationship of expression of CD147, MCT1 and MCT4 with various progression parameters. Our results indicate that the co-expression of CD147 with MCTs or MDR markers was found in primary and metastatic EOC cells and stromal cells the over-expression of CD147, MCT1 and MCT4 was found in most primary and the matched metastatic lesions of EOC, and was significantly associated with tumor stage, grade, residual disease status and presence of ascites (P 0.05). These results suggest that over-expression of CD147, MCT1 and MCT4 is correlated with EOC progression, and co-expression of CD147 and MCT1/MCT4 is related to drug resistance during EOC metastasis and could be useful therapeutic targets to prevent the development of incurable, recurrent and drug resistance EOC.
Publisher: Springer Science and Business Media LLC
Date: 12-11-2018
Publisher: Elsevier
Date: 2013
DOI: 10.1016/B978-0-12-800096-0.00004-4
Abstract: The tear film covers and protects the ocular surface. It contains various molecules including a large variety of proteins. The protein composition of the tear fluid can change with respect to various local and systemic diseases. Prior to the advent of the proteomic era, tear protein analysis was limited to a few analytical techniques, the most common of which was immunoelectrophoresis, an approach dependent on antibody availability. Using proteomics, hundreds of tear proteins could potentially be identified and subsequently studied. Although detection of low-abundance proteins in the complex tear proteome remains a challenge, advances in s le fractionation and mass spectrometry have greatly enhanced our ability to detect these proteins. With increasing proteomic applications, tears show great potential as biomarkers in the development of clinical assays for various human diseases. In this chapter, we discuss the structure and functions of the tear film and methods for its collection. We also summarize potential tear protein biomarkers identified using proteomic techniques for both ocular and systemic diseases. Finally, modern proteomic techniques for tear biomarker research and future challenges are explored.
Publisher: Springer Science and Business Media LLC
Date: 21-01-2014
DOI: 10.1007/S10555-014-9493-5
Abstract: Radiation therapy (RT) continues to be one of the most popular treatment options for localized prostate cancer (CaP). Local CaP recurrence after RT is a pattern of treatment failure attributable to radioresistance of cancer cells. One major obstacle to RT is that there is a limit to the amount of radiation that can be safely delivered to the target organ. Recent results indicate that phosphoinositide 3-kinase (PI3K)/Akt hosphatase and tensin homolog (PTEN)/mammalian target of rapamycin (mTOR) signaling pathway, autophagy, epithelial-mesenchymal transition (EMT) and cancer stem cells (CSCs) are involved in CaP metastasis and radioresistance. Emerging evidence also suggests that combining a radiosensitizer with RT increases the efficacy of CaP treatment. Understanding the mechanisms of radioresistance will help to overcome recurrence after RT in CaP patients and prevent metastasis. In this review, we discuss the novel findings of PI3K/Akt/PTEN/mTOR signaling pathway, autophagy, EMT and CSCs in the regulation of CaP metastasis and radioresistance, and focus on combination of radiosensitizers with RT in the treatment of CaP in preclinical studies to explore novel approaches for future clinical trials.
Publisher: MDPI AG
Date: 23-10-2023
Publisher: Elsevier BV
Date: 08-2001
DOI: 10.1016/S1040-8428(01)00113-5
Abstract: Targeted alpha therapy (TAT) can inhibit the growth of micrometastases by selectively killing isolated and preangiogenic clusters of cancer cells. The alpha emitting radioisotopes Tb-149 and Bi-213 were chelated to cancer specific monoclonal antibodies to form alpha-immunoconjugates (AIC) against melanoma, leukaemia, prostate and colorectal cancer, and to the plasminogen activator inhibitor type-2 (PAI2) to form alpha-PAI2 (API) against breast and prostate cancer. These conjugates were found to be highly stable, specific and cytotoxic in vitro. Melanoma and breast cancer tumour growth was observed in nude mouse models for untreated controls and non-specific AIC/API at 2 days post-subcutaneous inoculation of cancer cells. Complete inhibition of melanoma and breast cancer growth was found for local injections of AIC and API, respectively. Intra-lesional TAT of established melanoma showed that all melanomas regressed with 100 microCi injections of AIC. These results point to the potential application of local and systemic TAT in the management of metastatic cancer.
Publisher: Springer Science and Business Media LLC
Date: 24-10-2013
Publisher: Elsevier BV
Date: 05-2006
Publisher: American Association for Cancer Research (AACR)
Date: 11-2013
DOI: 10.1158/1535-7163.TARG-13-A283
Abstract: Purpose: Radioresistance is a major problem in prostate cancer (CaP) radiotherapy (RT). The phosphatidylinositol-3-kinase (PI3K)/Akt/mTOR signaling pathway plays a central role in cancer metastasis and radioresistance. This study aimed to evaluate the effects of combination of dual or single inhibitors targeting PI3K/Akt/mTOR pathway proteins with RT in CaP radioresistant (RR) cells in vitro. Experimental Design: Three CaP-RR cell lines (PC-3RR, DU145RR, and LNCaPRR) were established in our laboratory by radiation treatment and their radioresistance was confirmed by colony assay. The half maximal inhibitory concentration (IC50) values of four inhibitors including two dual inhibitors (BEZ235 and PI103) and two single inhibitors (BKM120 and Rapamycin) were tested by 3-(4,5-Dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) assay in CaP RR cells. Combination of 1/2 IC50 doses of each inhibitor with RT was examined to decide which inhibitor has a better capability to improve radiosensitivity of CaP-RR cells by cologenic assay and apoptosis assays. Results: We found that CaP-RR cells are associated with epithelial-mesenchymal transition (EMT) and enhanced cancer stem cell phenotypes, and the activation of PI3K/Akt/mTOR signaling pathway. We also found that the combination of single inhibitor either BKM120 (targeting PI3k) or rapamycin (Targeting mTOR) with RT had limited capability to improve radiosensitivity, including less regression of colony formation and inducing less apoptosis in CaP RR cells, whereas dual inhibitor BEZ235 or PI103 combined with RT could effectively improve radiosensitivity, obviously inhibit CaP RR cells in colony ability (P& .05), and induce more apoptosis (P& .05). Conclusions: Our findings suggest that PI3K/Akt/mTOR pathway is actively involved in CaP radioresistance and the dual PI3K/Akt/mTOR inhibitors (BEZ235 and PI103) have obvious advantages over single inhibitors in sensitizing radiation therapy and overcome CaP radioresistance. Using a PI3K/mTOR dual inhibitor with RT is a promising modality for the treatment of CaP to overcome radioresistance and this combination approach is worthwhile for future animal study and clinical trials. Citation Information: Mol Cancer Ther 2013 (11 Suppl):A283. Citation Format: Lei Chang, Peter Graham, Jingli Hao, Jie Ni, Joseph Bucci, Paul Cozzi, John Kearseley, Yong Li. PI3K/Akt/mTOR dual inhibitors have an advantage over single inhibitors in overcoming prostate cancer radioresistance. [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference: Molecular Targets and Cancer Therapeutics 2013 Oct 19-23 Boston, MA. Philadelphia (PA): AACR Mol Cancer Ther 2013 (11 Suppl):Abstract nr A283.
Publisher: Mary Ann Liebert Inc
Date: 02-2019
Abstract: As a nucleic acid alternative to traditional antibody, aptamer holds great potential in various fields of biology and medicine such as targeted gene therapy, drug delivery, bio-sensing, and laboratory medicine. Over the past decades, the conventional Systematic Evolution of Ligands by Exponential Enrichment (SELEX) method has undergone dramatic modifications and improvements owing to developments in material sciences and analytical techniques. However, many of the recently developed strategies either require complex materials and instruments or suffer from low efficiency and high failure rates in the selection of desired aptamers. Accordingly, the development of aptamers against new or novel targets is still a major obstacle for aptamer-based research and application. Here, an improved protein-SELEX procedure is presented for simplified and highly efficient isolation of aptamers against protein targets. Approaches are described that ensure a high success rate in aptamer selection by simplifying polymerase chain reaction procedures, introducing denature gel, utilizing an electro-elution-based single-stranded DNA separation strategy, as well as an enzyme-linked immunosorbent assay-based highly sensitive binding assay. In addition, a simplified s le preparation method for MiSeq-based next-generation sequencing is also introduced. While a recombinant protein as a bait protein for SELEX is discussed here, this protocol will also be invaluable for researchers wishing to develop aptamers against targets other than proteins such as small molecules, lipids, carbohydrates, cells, and micro-organisms for future gene therapy and/or diagnostics.
Publisher: Springer Science and Business Media LLC
Date: 29-09-2011
DOI: 10.1007/S11604-011-0603-9
Abstract: The aim was to study the effect of vascular endothelial growth factor (VEGF) down-regulation by small interfering (si)RNA-mediated interference (RNAi) on the biological features of nasopharyngeal carcinoma cell line CNE-2. The combined plasmids pU-siVEGF and pU-siCONT were transfected into CNE-2 cells with lipofectamine. The transfected cells were placed in fresh medium containing G418. Expression of VEGF mRNA and protein were measured by reverse transcriptase-polymerase chain reaction and Western blot, respectively. The transwell chamber model was employed to test the ability of cell invasion in vitro. The distribution of cell cycle phases was determined by flow cytometry. Cell survival was assessed by clonogenic assays. Both VEGF mRNA and protein expression were significantly decreased in the pU-siVEGF group compared with controls (P < 0.05). The cell cycle was arrested in the G(1) phase (P < 0.05). A higher apoptotic ratio and lower invasion ability were seen in the pU-siVEGF group. The D(0) (mean lethal dose) and SF(2) values were significantly lower than those in the control group (P < 0.05). Delivery of siRNA targeting VEGF seems efficient in down-regulating VEGF expression and diminishing the growth, proliferation, and invasiveness of CNE-2 cells. It also enhanced the sensitivity of CNE-2 cells to radiation.
Publisher: American Association for Cancer Research (AACR)
Date: 07-2017
DOI: 10.1158/1538-7445.AM2017-2833
Abstract: Aims: Prostate cancer (CaP) is the most common cancer in males in Australia which caused more than 3000 deaths in 2015. EpCAM is a transmembrane protein that is expressed at low levels in a variety of human epithelial tissues, but overexpressed in most solid tumors. Our previous study indicated that EpCAM was strongly expressed in metastatic CaP cell lines, primary human CaP tissues and lymph node metastasis and is a biomarker involved in CaP progression, and chemo-/radio-resistance. However, the role of EpCAM in CaP progression and therapeutic resistance is still uncertain. The aim of this study was to investigate the role of EpCAM in CaP progression and chemo-/radio-resistance as well as underlying mechanisms in vitro and in vivo. Methods: EpCAM gene was knocked down (KD) in PC-3, DU145 and LNCaP CaP cell lines using shRNA. Proliferation assay, colony formation assay, docetaxel (DTX) and radiation dose-response assay were carried out to evaluate the effect of KD of EpCAM on proliferation and therapeutic response of CaP cells in vitro. Subcutaneous (s.c) and orthotopic CaP animal models were established using PC-3-EpCAM-KD and PC-3-EpCAM-scramble (scr) control cells in NOD/SCID mice, to assess the effect of EpCAM on CaP tumourigenecity, chemotherapy (DTX) and radiation response. Signal transduction proteins in PI3K/Akt/mTOR signaling pathway, as well as proliferation, apoptotic and radiation response markers were evaluated by immunohistochemistry in xenografts. Results: KD of EpCAM reduced CaP proliferative potential and enhanced DTX and radiation sensitivity in three CaP cell lines. Both s.c and orthotopic EpCAM-KD xenografts displayed suppressed tumor growth and increased DTX and radiation responsiveness compared to EpCAM-scr control xenografts in NOD/SCID mice. Marked down-regulation of PI3K/Akt/mTOR pathway proteins (p-Akt and p-mTOR) and proliferation marker (Ki-67) and significant up-regulation of apoptotic (Caspase-3) and radiation (γ-H2AX) responses to chemo-/radio-therapies were found in EpCAM-KD xenografts, compared with control xenografts. In addition, Kaplan-Meier curve analysis demonstrated that KD of EpCAM improved median survival (MS) of tumor-bearing mice by 21.5 days compared with the control group (HR=26.94, CI95% 4.317-168.1, p=0.0004) and that KD of EpCAM improved MS of tumor-bearing mice which received docetaxel (50mg/kg, single dose, i.p.) by 11 days (HR=20.95, CI95% 3.599-121.9, p=0.0007), and radiotherapy (2Gy/day for 4 days) by 12 days (HR=11.00, CI95% 2.11-57.36, p=0.0044) compared with the control group, respectively. Conclusions: EpCAM plays an important role in CaP progression and chemo-/radio-resistance via PI3K/Akt/mTOR signaling pathway in vitro and in vivo and it is a promising therapeutic target for the treatment of CaP. EpCAM targeted therapy combined with chemo-/radio-therapy could be a novel modality for treatment-resistant CaP. Citation Format: Jie Ni, Paul Cozzi, Julia Beretov, Junli Deng, Joseph Bucci, Peter Graham, Yong Li. Epithelial cell adhesion molecule (EpCAM) is associated with prostate cancer progression and chemo-/radio-resistance in vitro and in vivo [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017 2017 Apr 1-5 Washington, DC. Philadelphia (PA): AACR Cancer Res 2017 (13 Suppl):Abstract nr 2833. doi:10.1158/1538-7445.AM2017-2833
Publisher: IEEE
Date: 11-2014
Publisher: Elsevier BV
Date: 07-2021
Publisher: Elsevier BV
Date: 2020
DOI: 10.1016/J.CRITREVONC.2019.102860
Abstract: Prostate cancer (PCa) is the most commonly diagnosed solid-organ cancer in males. The PSA testing may cause overdiagnosis and overtreatment for PCa patients. There is an urgent need for new biomarkers with greater discriminative precision for diagnosis and risk-stratification, to select for prostate biopsy and treatment of PCa. Liquid biopsy is a promising field with the potential to provide comprehensive information on the genetic landscape at diagnosis and to track genomic evolution over time in order to tailor the therapeutic choices at all stages of PCa. Exosomes, containing RNAs, DNAs and proteins, have been shown to be involved in tumour progression and a rich potential source of tumour biomarkers, especially for profiling analysis of their miRNAs content. In this review, we summarise the exosomal miRNAs in PCa diagnosis, prognosis and management, and further discuss their possible technical challenges associated with isolating PCa-specific exosomes.
Publisher: Elsevier BV
Date: 11-2017
Publisher: Ivyspring International Publisher
Date: 2012
DOI: 10.7150/IJBS.4071
Publisher: Royal Society of Chemistry (RSC)
Date: 2012
DOI: 10.1039/C2MB25228G
Abstract: Microphthalmia-associated transcription factor (MITF) is a master regulator in melanocyte proliferation, development, survival and melanoma formation. In melanocyte dysfunction disease, it is observed that the expressions of MITF, tyrosinase (TYR), tyrosinase related protein 1 (TYRP1) and tyrosinase related protein 2 (TYRP2)/dopachrome tautomerase (DCT) are changed, the consequence of which remains unclear. In this study, we focused on the change of microRNA (miRNA) profiles and Tyrosinase Related Proteins (TRPs) in MITF knocked down melanocytes. For the first time, we assayed the MITF-KD miRNA profiles using a miRNA microarray and found that hsa-miR-1225-3p, hsa-miR-634, hsa-miR-197, hsa-miR-766, hsa-miR-574-5p and hsa-miR-328 were upregulated, and hsa-miR-720 and hsa-miR-1308 were downregulated in MITF knocked down melanocytes. These miRNAs were validated by miRNA real time qPCR. These miRNA potential targets, especially the TRPs, were analyzed according to the miRNA database (Sanger Center). By TargetScan prediction, the hsa-miR-634 and hsa-miR-328 have poorly conserved sites on TYR and hsa-miR-197 have poorly conserved sites on TYR1. Through qPCR and western blotting we found that the expression of TYR and TYRP1 were dramatically decreased and the expression of TYRP2 was increased in MITF knocked down melanocytes (MITF-KD). These results suggested that the miRNAs may be involved in MITF regulation of TYR, TYRP1 and TYRP2, which provides a new clue for understanding the role of miRNAs in melanocyte dysfunctional disease.
Publisher: Informa UK Limited
Date: 21-09-2016
DOI: 10.1080/14789450.2016.1233065
Abstract: Chemoresistance is a major challenge to current ovarian cancer chemotherapy. It is important to identify biomarkers to distinguish chemosensitive and chemoresistant patients. Areas covered: We review the medical literature, discuss MS-based technologies with respect to chemoresistant ovarian cancer and summarize the promising chemoresistant biomarkers identified. In addition, the challenges and future perspectives of biomarker discovery research are explored. With the employment of mass spectrometry-based (MS-based) proteomics, biomarker discovery of ovarian cancer has made great progress in the last decade. Many potential biomarkers were identified by MS-based proteomics technologies, some of which have been validated for further extensive studies in clinical settings. Expert commentary: The discovery of chemoresistant biomarkers is a newly developing area and may provide a clue for predicting chemotherapeutic response and discover therapeutic targets for paving the way of personalized medicine. Multiple complementary MS-based proteomics approaches hold promise for finding novel therapeutic targets in ovarian cancer treatment.
Publisher: Elsevier BV
Date: 04-2013
DOI: 10.1016/J.CANLET.2013.07.031
Abstract: Cancer stem cells are becoming recognised as being responsible for metastasis and treatment resistance. The complex cellular and molecular network that regulates cancer stem cells and the role that inflammation plays in cancer progression are slowly being elucidated. Cytokines, secreted by tumour associated immune cells, activate the necessary pathways required by cancer stem cells to facilitate cancer stem cells progressing through the epithelial-mesenchymal transition and migrating to distant sites. Once in situ, these cancer stem cells can secrete their own attractants, thus providing an environment whereby these cells can continue to propagate the tumour in a secondary niche.
Publisher: MDPI AG
Date: 03-11-2022
DOI: 10.3390/BIOM12111623
Abstract: Doxorubicin is the most frequently used chemotherapeutic agent for the treatment of hepatocellular carcinoma. However, one major obstacle to the effective management of liver cancer is the drug resistance derived from the cancer stem cells. Herein, we employed a CD133 aptamer for targeted delivery of doxorubicin into liver cancer stem cells to overcome chemoresistance. Furthermore, we explored the efficacy of autophagy inhibition to sensitize liver cancer stem cells to the treatment of CD133 aptamer-doxorubicin conjugates based on the previous observation that doxorubicin contributes to the survival of liver cancer stem cells by activating autophagy. The kinetics and thermodynamics of aptamer-doxorubicin binding, autophagy induction, cell apoptosis, and self-renewal of liver cancer stem cells were studied using isothermal titration calorimetry, Western blot analysis, annexin V assay, and tumorsphere formation assay. The aptamer-cell binding andintracellular accumulation of doxorubicin were quantified via flow cytometry. CD133 aptamer-guided delivery of doxorubicin resulted in a higher doxorubicin concentration in the liver cancer stem cells. The combinatorial treatment strategy of CD133 aptamer-doxorubicin conjugates and an autophagy inhibitor led to an over 10-fold higher elimination of liver cancer stem cells than that of free doxorubicin in vitro. Future exploration of cancer stem cell-targeted delivery of doxorubicin in conjunction with autophagy inhibition in vivo may well lead to improved outcomes in the treatment of hepatocellular carcinoma.
Publisher: Springer Science and Business Media LLC
Date: 18-01-2022
DOI: 10.1038/S41419-022-04510-8
Abstract: Chemoresistance and metastasis are the major challenges for the current ovarian cancer treatment. Understanding the mechanisms of ovarian cancer progression and metastasis is critically important for developing novel therapies. The advances in extracellular vesicles (EVs) research in recent years have attracted extensive attention. EVs contain a variety of proteins, RNAs, DNAs, and metabolites. Accumulating evidence indicates that ovarian cancer cells secrete a large amount of EVs, playing an important role in tumor progression and recurrence. In the microenvironment of ovarian tumor, EVs participate in the information transmission between stromal cells and immune cells, promoting the immune escape of ovarian cancer cells and facilitating cancer metastasis. Here, we review the recent advances of EVs in chemoresistance, mechanisms of metastasis, and immune evasion of ovarian cancer. Furthermore, we also discuss the challenges of EV research and future application of EVs as promising biomarker sources in response to therapy and in therapy-delivery approaches for ovarian cancer patients.
Publisher: Elsevier BV
Date: 2000
Publisher: Ovid Technologies (Wolters Kluwer Health)
Date: 11-2012
Publisher: Springer Science and Business Media LLC
Date: 02-10-2014
Abstract: The PI3K/Akt/mTOR pathway has a central role in cancer metastasis and radiotherapy. To develop effective therapeutics to improve radiosensitivity, understanding the possible pathways of radioresistance involved and the effects of a combination of the PI3K/Akt/mTOR inhibitors with radiotherapy on prostate cancer (CaP) radioresistant cells is needed. We found that compared with parent CaP cells, CaP-radioresistant cells demonstrated G0/G1 and S phase arrest, activation of cell cycle check point, autophagy and DNA repair pathway proteins, and inactivation of apoptotic proteins. We also demonstrated that compared with combination of single PI3K or mTOR inhibitors (BKM120 or Rapamycin) and radiation, low-dose of dual PI3K/mTOR inhibitors (BEZ235 or PI103) combined with radiation greatly improved treatment efficacy by repressing colony formation, inducing more apoptosis, leading to the arrest of the G2/M phase, increased double-strand break levels and less inactivation of cell cycle check point, autophagy and non-homologous end joining (NHEJ)/homologous recombination (HR) repair pathway proteins in CaP-radioresistant cells. This study describes the possible pathways associated with CaP radioresistance and demonstrates the putative mechanisms of the radiosensitization effect in CaP-resistant cells in the combination treatment. The findings from this study suggest that the combination of dual PI3K/Akt/mTOR inhibitors (BEZ235 or PI103) with radiotherapy is a promising modality for the treatment of CaP to overcome radioresistance.
Publisher: Bentham Science Publishers Ltd.
Date: 04-2014
DOI: 10.2174/1568009614666140328152459
Abstract: There is currently no cure for metastatic castration-resistant prostate cancer (CRPC). Chemoresistance and metastatic disease remain the main causes of treatment failure and mortality in CaP patients. Although several advances have been made in the control of CRPC with some newly developed drugs, there is still an urgent need to investigate the mechanisms and pathways of prostate cancer (CaP) metastasis and chemoresistance, identify useful therapeutic targets, develop novel treatment approaches, improve current therapeutic modalities and increase patients' survival. Cancer stem cells (CSCs), a minority population of cancer cells characterised by self-renewal and tumor initiation, have gained intense attention as they not only play a crucial role in cancer recurrence but also contribute substantially to chemoresistance. As such, a number of mechanisms in chemoresistance have been identified to be associated with CSCs. Therefore, a thorough and integral understanding of these mechanisms can identify novel biomarkers and develop innovative therapeutic strategies for CaP treatment. Our recent data have demonstrated CSCs are associated with CaP chemosensitivity. In this review, we discuss the roles of putative CSC markers in CaP chemoresistance and elucidate several CSC-associated signaling pathways such as PI3K/Akt/mTOR, Wnt/β-catenin and Notch pathways in the regulation of CaP chemoresistance. Moreover, we will summarize emerging and innovative approaches for the treatment of CRPC and address the challenging CRPC that is driven by CSCs. Understanding the link between CSCs and metastatic CRPC will facilitate the development of novel therapeutic approaches to overcome chemoresistance and improve the clinical outcomes of CaP patients.
Publisher: Wiley
Date: 18-06-2009
DOI: 10.1002/MED.20161
Abstract: It is becoming increasingly clear that angiogenesis plays a crucial role in prostate cancer (CaP) survival, progression, and metastasis. Tumor angiogenesis is a hallmark of advanced cancers and an attractive treatment target in multiple solid tumors. By understanding the molecular basis of resistance to androgen withdrawal and chemotherapy in CaP, the rational design of targeted therapeutics is possible. This review summarizes the recent advancements that have improved our understanding of the role of angiogenesis in CaP metastasis and the potential therapeutic efficacy of inhibiting angiogenesis in this disease. Current therapeutic options for patients with metastatic hormone-refractory CaP are very limited. Targeting vasculature is a developing area, which shows promise for the control of late stage and recurrent CaP disease and for overcoming drug resistance. We discuss angiogenesis and its postulated mechanisms and focus on the regulation of angiogenesis in CaP progression and the therapeutic beneficial effects associated with targeting of the CaP vasculature to overcome the resistance to current treatments and CaP recurrence.
Publisher: Elsevier BV
Date: 04-2011
DOI: 10.1016/J.INTIMP.2010.12.014
Abstract: This study investigated the efficacy of cord blood-derived cytokine-induced killer (CB-CIK) biotherapy combined with second-line chemotherapy in treating advanced solid malignancies after first-line chemotherapy failure. Forty patients with advanced solid malignancies after first-line chemotherapy failure were ided into two groups: CB-CIK cells transfusion plus second-line chemotherapy (CB-CIK+Chemotherapy) group and second-line chemotherapy alone (Chemotherapy) group. The ORR and DCR were 30% and 80% in CB-CIK + Chemotherapy group compared with 15% and 70% in Chemotherapy group (P = 0.451 for ORR and P = 0.716 for DCR) respectively. The time to progression and the median survival time were 3.45 months (95% CI 2.30-4.60 months) and 11.17 months (95% CI 9.05-13.28 months) in CB-CIK+Chemotherapy group compared with 2.03 months (95% CI 1.23-2.82 months) and 7.52 months (95% CI 5.97-9.06 months) in Chemotherapy group respectively. Compared with patients in Chemotherapy group, the patients in CB-CIK+Chemotherapy group had significantly longer PFS (P = 0.031) and overall survival (P = 0.048). In vitro studies further revealed that CB-CIK cells could overcome drug resistance in cisplatin-resistant lung adenocarcinoma cell line A549/CDDP through downregulating ABCG-2 and P-gp and induce cytotoxicity through the high level expression of CD3, CD56, FasL, and CD69. This could explain why CB-CIK could have synergistic effects with second-line chemotherapy shown in this clinical study. We concluded CB-CIK cells combined with second-line chemotherapy can significantly improve PFS and median survival compared with second-line chemotherapy alone in patients with advanced solid malignancies after first-line chemotherapy failure.
Publisher: Institution of Engineering and Technology (IET)
Date: 17-02-2011
Publisher: Wiley
Date: 26-05-2010
Abstract: This is the first 2-DE study using sequential dyes to analyse phospho-, glyco- and total tear protein profiles (Pro-Q Diamond for phosphoprotein, Pro-Q Emerald for glycoprotein and Sypro Ruby for total protein). This method minimised the gel-gel variations, allowing better comparisons among the three profiles and generated a whole map of PTM profiles of tear protein. A novel tear protein, dermcidin, was identified for the first time in this study. The identification of this antimicrobial protein suggests a new model of defence in tears. In addition, we are able to present the first experimental evidence of the presence of glycosylated lipocalin 1 and cystatin S. Nucleobindin 2 was only detected using phospho staining, suggesting it is only phosphorylated in tears. This study provides the groundwork for understanding the PTM of tear proteins and consequently these methods could be useful in the search for biomarkers in tears.
Publisher: Wiley
Date: 27-10-2021
Abstract: Triple‐negative breast cancer (TNBC) is the most aggressive subtype of breast cancer. Radioresistance and stemness are substantial obstacles to TNBC treatment. The THO complex (THOC) is a subunit of the TRanscription–EXport complex that functions in the coupling of transcription to nascent RNA splicing, elongation, and export. However, its role in regulating TNBC therapeutic resistance is not reported yet. In this study, the authors demonstrate that cancer stem cells are enriched in radioresistant TNBC cells and describe the role of the THOC in regulating TNBC radioresistance and stemness. The authors find that THOC2 and THOC5 are upregulated in radioresistant TNBC cells and associated with a poor prognosis in TNBC patients. Further investigation reveals that THOC2 promotes the stem‐like properties and radioresistance of TNBC cells in a THOC5‐dependent manner by facilitating the release of sex‐determining region Y (SRY)‐box transcription factor 2 (SOX2) and homeobox transcription factor (NANOG) transcripts from the nucleus. Silencing THOC2 or THOC5 expression decreases the protein expression of SOX2 and NANOG, depletes the stem‐like properties, and causes radiosensitization in these TNBC cells. Moreover, THOC2 or THOC5 depletion blocks the xenograft tumorigenesis and growth of radioresistant TNBC in vivo. These findings uncover the novel correlations of THOC with TNBC stemness and therapeutic resistance, proposing alternative therapeutic strategies against relapsed TNBC.
Publisher: IOP Publishing
Date: 28-12-2007
DOI: 10.1088/0031-9155/53/2/001
Abstract: Ionizing radiation causes structural chromosomal aberrations, a proportion of which give rise to chromosome fragments without spindle attachment organelles. When a cell ides, some of these fragments are excluded from the main daughter nuclei and form small nuclei within the cytoplasm. The cytokinesis-block micronucleus assay allows these micronuclei (MN) to be counted, providing an in situ biological dosimeter. In this study, we evaluated the micronucleus frequency in peripheral blood lymphocytes after in vitro incubation with the alpha conjugates (213)BiI(3) and (213)Bi-9.2.27 (AIC). Lymphocytes were inoculated in vitro AIC for 3 h. Further, we report the first MN measurements in melanoma patients after targeted alpha therapy (TAT) with (213)Bi-9.2.27. Patients were injected with 260-360 MBq of AIC, and blood s les taken at 3 h, 2 weeks and 4 weeks post-treatment. Absorbed dose (MIRD) and effective total body dose (PED) were calculated. The MN frequency in lymphocytes was similar for equal in vitro incubation activities of (213)BiI(3) and (213)Bi-9.2.27 (P=0.5), indicating that there is no selective targeting of lymphocytes by the alpha conjugates. After inoculation with 10-1200 kBq mL-1 of AIC, there was a substantial activity-related increase in MN. The number of MN in the blood of treated patients peaked at 3 h post-TAT, slowly returning to baseline levels by 4 weeks. The mean photon equivalent dose (PED) is 0.43 Gy (SD 0.15) and the mean MIRD calculated absorbed dose is 0.11 Gy (SD 0.03), giving an RBE=4+/-0.4 for this study.
Publisher: Ivyspring International Publisher
Date: 2020
DOI: 10.7150/THNO.39486
Publisher: Springer Science and Business Media LLC
Date: 23-04-2013
DOI: 10.1007/S10555-013-9423-Y
Abstract: The most common ovarian cancer is epithelial ovarian cancer (EOC) characterised by few early symptoms, widespread peritoneal dissemination and ascites at advanced stages that result in poor prognosis. Despite the recent progress in its management, including surgery and chemotherapy, EOC remains the most lethal gynaecological malignancy in women. Due to the limitations of current therapeutic approaches, many patients die of secondary disease (metastasis). MUC1 is associated with cellular transformation and tumorigenicity and is considered as an attractive therapeutic target for cancer therapy owning to its over-expression in most adenocarcinomas including EOC. Tumour-associated MUC1 plays an important role in EOC metastasis and progression. In neoplastic tissues, MUC1 is underglycosylated and reveals epitopes that are masked in the normal cells. This feature makes it possible to target tumour-associated MUC1 with antibodies, toxins or radionuclides or use a vaccine targeting tumour-associated MUC1 antigen. The shed tumour-associated MUC1 in blood can be used as a diagnostic biomarker for EOC detection and monitoring. Our recent results have shown that over-expression of MUC1 plays a very important role in EOC progression and MUC1 is an ideal target for targeted therapy to control metastatic and recurrent EOC. This review will summarize some important new findings supporting the role of MUC1 in EOC metastasis and progression and focus on the MUC1-based targeted therapy for control of metastatic and recurrent EOC.
Publisher: JMIR Publications Inc.
Date: 21-12-2022
Abstract: hile it is well known that adolescents frequently turn to their friends for support around mental health and substance use problems, there are currently no evidence-based digital programs to support them to do this. o evaluate the efficacy of the Mind your Mate program, a digital peer support program, in improving mental health symptoms, reducing the uptake of substance use, and increasing help-seeking. The Mind your Mate program consists of an online 40-minute classroom lesson and a companion smartphone mobile application (app). The active control group received school-based health education as usual. cluster randomized controlled trial (RCT) was conducted with 12 secondary schools and 166 students (mean age=15.3 years, SD=0.41, 46% female, 80% born in Australia). Participants completed self-reported questionnaires assessing symptoms of mental health (depression, anxiety, and psychological distress), substance use (alcohol and other drug use) and help-seeking measures at baseline, 6- and 12-month follow-up. tudents who received the Mind your Mate program had greater reductions in depressive symptoms over a 12-month period, compared to controls (b=-1.86, 95% CI=-3.73 – 0.02, d=-0.31). Anxiety symptoms decreased among students in the intervention group however, these reductions did not meet statistical significance thresholds. No differences were observed in relation to psychological distress or help-seeking. mall to moderate reductions in depression symptoms were observed among students allocated to receive the Mind your Mate intervention. While the current results are encouraging there is a need to continue to refine, develop and evaluate innovative applied approaches to the prevention of mental disorders in real-world settings. he study was approved by the University of Sydney Human Research Ethics Committee, Australia (project number: 2020/054), and prospectively registered on the Australian New Zealand Clinical Trials Registry (#ACTRN12620000753954). Access to schools was granted by the New South Wales (NSW) Department of Education and Communities State Education Research Applications Process (2020130). R2-10.2196/26796
No related grants have been discovered for Yong Li.