ORCID Profile
0000-0002-2071-5308
Current Organisation
University of Adelaide
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Publisher: Anticancer Research USA Inc.
Date: 05-2019
DOI: 10.21873/ANTICANRES.13367
Abstract: Ovarian cancer (OC) is the 5th most common cancer among European women. Approximately 70-80% of OC is diagnosed at advanced stage resulting in an elevated mortality rate. The aim of this study was to examine whether Annexin A2 and S100A10 expression can be used as prognostic markers for epithelial ovarian cancer (EOC). Expression of Annexin A2 and S100A10 was evaluated in EOC tissue s les (n=303) by immunohistochemistry. The staining of the membrane, cytoplasmic and stroma was assessed according to intensity. The expression of both markers correlated to histological subtype, histological grading, International Federation of Gynecology and Obstetrics (FIGO) stage, and macro-radical surgery. Univariate Cox regression analysis showed that Annexin A2 and S100A10 in stromal tissue correlated with shorter overall survival (OS). Multivariate Cox regression analysis demonstrated no independent prognostic significance of stromal Annexin A2 expression. High expression of Annexin A2 and S100A10 in stromal tissue from EOC patients was associated with reduced OS however, no independent prognostic value was found for any of the markers.
Publisher: Springer Science and Business Media LLC
Date: 03-04-2017
DOI: 10.1038/ONC.2017.66
Abstract: Missense mutations in the TP53 tumor-suppressor gene inactivate its antitumorigenic properties and endow the incipient cells with newly acquired oncogenic properties that drive invasion and metastasis. Although the oncogenic effect of mutant p53 transcriptome has been widely acknowledged, the global influence of mutant p53 on cancer cell proteome remains to be fully elucidated. Here, we show that mutant p53 drives the release of invasive extracellular factors (the 'secretome') that facilitates the invasion of lung cancer cell lines. Proteomic characterization of the secretome from mutant p53-inducible H1299 human non-small cell lung cancer cell line discovered that the mutant p53 drives its oncogenic pathways through modulating the gene expression of numerous targets that are subsequently secreted from the cells. Of these genes, alpha-1 antitrypsin (A1AT) was identified as a critical effector of mutant p53 that drives invasion in vitro and in vivo, together with induction of epithelial-mesenchymal transition markers expression. Mutant p53 upregulated A1AT transcriptionally through the involvement with its family member p63. Conditioned medium containing secreted A1AT enhanced cell invasion, while an A1AT-blocking antibody attenuated the mutant p53-driven migration and invasion. Importantly, high A1AT expression correlated with increased tumor stage, elevated p53 staining and shorter overall survival in lung adenocarcinoma patients. Collectively, these findings suggest that A1AT is an indispensable target of mutant p53 with prognostic and therapeutic potential in mutant p53-expressing tumors.
Publisher: Wiley
Date: 10-05-2016
Abstract: Metastasis is a crucial step of malignant progression and is the primary cause of death from endometrial cancer. However, clinicians presently face the challenge that conventional surgical-pathological variables, such as tumour size, depth of myometrial invasion, histological grade, lymphovascular space invasion or radiological imaging are unable to predict with accuracy if the primary tumour has metastasized. In the current retrospective study, we have used primary tumour s les of endometrial cancer patients diagnosed with (n = 16) and without (n = 27) lymph node metastasis to identify potential discriminators. Using peptide matrix assisted laser desorption/ionisation mass spectrometry imaging (MALDI-MSI), we have identified m/z values which can classify 88% of all tumours correctly. The top discriminative m/z values were identified using a combination of in situ sequencing and LC-MS/MS from digested tumour s les. Two of the proteins identified, plectin and α-Actin-2, were used for validation studies using LC-MS/MS data independent analysis (DIA) and immunohistochemistry. In summary, MALDI-MSI has the potential to identify discriminators of metastasis using primary tumour s les.
Publisher: MDPI AG
Date: 06-04-2023
Abstract: Eighty percent of ovarian cancer patients initially respond to chemotherapy, but the majority eventually experience a relapse and die from the disease with acquired chemoresistance. In addition, 20% of patients do not respond to treatment at all, as their disease is intrinsically chemotherapy resistant. Data-independent acquisition nano-flow liquid chromatography–mass spectrometry (DIA LC-MS) identified the three protein markers: gelsolin (GSN), calmodulin (CALM1), and thioredoxin (TXN), to be elevated in high-grade serous ovarian cancer (HGSOC) tissues from patients that responded to chemotherapy compared to those who did not the differential expression of the three protein markers was confirmed by immunohistochemistry. Analysis of the online GENT2 database showed that mRNA levels of GSN, CALM1, and TXN were decreased in HGSOC compared to fallopian tube epithelium. Elevated levels of GSN and TXN mRNA expression correlated with increased overall and progression-free survival, respectively, in a Kaplan–Meier analysis of a large online repository of HGSOC patient data. Importantly, differential expression of the three protein markers was further confirmed when comparing parental OVCAR-5 cells to carboplatin-resistant OVCAR-5 cells using DIA LC-MS analysis. Our findings suggest that GSN, CALM1, and TXN may be useful biomarkers for predicting chemotherapy response and understanding the mechanisms of chemotherapy resistance. Proteomic data are available via ProteomeXchange with identifier PXD033785.
Publisher: Springer Science and Business Media LLC
Date: 21-04-2015
DOI: 10.1007/S10585-015-9718-1
Abstract: Ovarian cancer, the most lethal gynaecological cancer, is characterised by the shedding of epithelial cells from the ovarian surface, followed by metastasis and implantation onto the peritoneal surfaces of abdominal organs. Our proteomic studies investigating the interactions between peritoneal (LP-9) and ovarian cancer (OVCAR-5) cells found transketolase (TKT) to be regulated in the co-culture system. This study characterized TKT expression in advanced stage (III/IV) serous ovarian cancers (n = 125 primary and n = 54 peritoneal metastases), normal ovaries (n = 6) and benign serous cystadenomas (n = 10) by immunohistochemistry. In addition, we also evaluated the function of TKT in ovarian cancer cells in vitro. Nuclear TKT was present in all primary serous ovarian cancer tissues examined (median 82.0 %, range 16.5-100 %) and was significantly increased in peritoneal metastases compared with matching primary cancers (P = 0.01, Wilcoxon Rank test). Kaplan-Meier survival and Cox regression analyses showed that high nuclear TKT positivity in peritoneal metastases (>94 %) was significantly associated with reduced overall survival (P = 0.006) and a 2.8 fold increased risk of ovarian cancer death (95 % CI 1.29-5.90, P = 0.009). Knockdown of TKT by siRNAs significantly reduced SKOV-3 cell proliferation but had no effect on their motility or invasion. Oxythiamine, an inhibitor of TKT activity, significantly inhibited the proliferation of four ovarian cancer cell lines (OV-90, SKOV-3, OVCAR-3 and OVCAR-5) and primary serous ovarian cancer cells isolated from patient ascites. In conclusion, these findings indicate that TKT plays an important role in the proliferation of metastatic ovarian cancer cells and could be used as novel therapeutic target for advanced disease.
Publisher: Impact Journals, LLC
Date: 27-01-2017
Publisher: Springer Science and Business Media LLC
Date: 14-10-2013
Publisher: MDPI AG
Date: 02-06-2022
Abstract: Chemoresistance remains the major barrier to effective ovarian cancer treatment. The molecular features and associated biological functions of this phenotype remain poorly understood. We developed carboplatin-resistant cell line models using OVCAR5 and CaOV3 cell lines with the aim of identifying chemoresistance-specific molecular features. Chemotaxis and CAM invasion assays revealed enhanced migratory and invasive potential in OVCAR5-resistant, compared to parental cell lines. Mass spectrometry analysis was used to analyse the metabolome and proteome of these cell lines, and was able to separate these populations based on their molecular features. It revealed signalling and metabolic perturbations in the chemoresistant cell lines. A comparison with the proteome of patient-derived primary ovarian cancer cells grown in culture showed a shared dysregulation of cytokine and type 1 interferon signalling, potentially revealing a common molecular feature of chemoresistance. A comprehensive analysis of a larger patient cohort, including advanced in vitro and in vivo models, promises to assist with better understanding the molecular mechanisms of chemoresistance and the associated enhancement of migration and invasion.
Publisher: Bioscientifica
Date: 11-2016
DOI: 10.1530/ERC-16-0320
Abstract: Ovarian cancer has a distinct tendency for metastasising via shedding of cancerous cells into the peritoneal cavity and implanting onto the peritoneum that lines the pelvic organs. Once ovarian cancer cells adhere to the peritoneal cells, they migrate through the peritoneal layer and invade the local organs. Alterations in the extracellular environment are critical for tumour initiation, progression and intra-peritoneal dissemination. To increase our understanding of the molecular mechanisms involved in ovarian cancer metastasis and to identify novel therapeutic targets, we recently studied the interaction of ovarian cancer and peritoneal cells using a proteomic approach. We identified several extracellular matrix (ECM) proteins including, fibronectin, TGFBI, periostin, annexin A2 and PAI-1 that were processed as a result of the ovarian cancer–peritoneal cell interaction. This review focuses on the functional role of these proteins in ovarian cancer metastasis. Our findings together with published literature support the notion that ECM processing via the plasminogen–plasmin pathway promotes the colonisation and attachment of ovarian cancer cells to the peritoneum and actively contributes to the early steps of ovarian cancer metastasis.
Publisher: Wiley
Date: 15-10-2019
Abstract: Malignant ascites is a fluid, which builds up in the abdomen and contains cancer cells in the form of single cells or multicellular clusters called spheroids. Malignant ascites has been observed in patients suffering from ovarian, cervical, gastric, colorectal, pancreatic, endometrial, or primary liver cancer. The spheroids are believed to play a major role in chemo resistance and metastasis of the cancer. To ease the discomfort of patients, malignant ascites (MA) is often drained from the abdomen using a procedure called paracentesis. MA retrieved via this minimal invasive procedure is a great source for cancer spheroids, which can be used for testing chemotherapeutic drugs and drug combinations. Herein, the existing workflow is adapted to make concurrent monitoring of drug accumulation, drug response, and drug metabolites feasible using primary spheroids or spheroids grown without a scaffolding matrix. To achieve this, those spheroids are embedded in matrigel, before fixing them with formalin. This makes it possible to process, store, and ship s les at room temperature. This new approach might be used to choose the best targeted therapy for each patient and thereby facilitate personalized medicine.
Publisher: MDPI AG
Date: 11-09-2023
Publisher: Wiley
Date: 09-02-2018
Abstract: Multicellular tumor spheroids (MCTS) are a powerful biological in vitro model, which closely mimics the 3D structure of primary avascularized tumors. Mass spectrometry (MS) has established itself as a powerful analytical tool, not only to better understand and describe the complex structure of MCTS, but also to monitor their response to cancer therapeutics. The first part of this review focuses on traditional mass spectrometry approaches with an emphasis on elucidating the molecular characteristics of these structures. Then the mass spectrometry imaging (MSI) approaches used to obtain spatially defined information from MCTS is described. Finally the analysis of primary spheroids, such as those present in ovarian cancer, and the great potential that mass spectrometry analysis of these structures has for improved understanding of cancer progression and for personalized in vitro therapeutic testing is discussed.
Publisher: MDPI AG
Date: 10-08-2012
DOI: 10.3390/IJMS13089959
Publisher: Impact Journals, LLC
Date: 14-07-2013
Publisher: Elsevier BV
Date: 05-2018
DOI: 10.1016/J.CANLET.2018.02.006
Abstract: The majority of ovarian cancer patients present with advanced disease and despite aggressive treatment, prognosis remains poor. Response to first-line carboplatin-containing chemotherapy is usually good, however, recurrence rates and subsequent chemoresistance are very high and ultimately responsible for the fatal outcome of the disease. To improve treatment outcomes pre-clinical models that can predict in idual patient response to 1st line chemotherapy and novel therapeutics are urgently required. In this study, we employed an ex vivo ovarian cancer tissue explant assay to assess response to carboplatin and an inhibitor of the extracellular matrix molecule, hyaluronan (4-methylubelliferone, 4-MU), shown to inhibit cancer metastasis. Cryopreserved ovarian cancer tissues were cultured on gelatine sponges for 48-120 h with increasing concentrations of carboplatin (0-400 μM) or 4-MU (1 mM) alone or the combination of both drugs. Effects on apoptosis and proliferation were assessed by immunohistochemistry using antibodies to cleaved caspase 3 or Ki67, respectively. The ex vivo tissue explant assay maintained viable tumor cells in an intact tumor microenvironment similar to the in vivo situation over the 120 h culture period. Carboplatin treatment promoted apoptosis in chemosensitive (P = 0.0047) but not chemoresistant cancer tissues. The combination of 4-MU (1 mM) and carboplatin (100 μM) significantly increased apoptosis (P = 0.0111) and reduced proliferation (P = 0.0064) in chemoresistant tissues. Overall, our results show that the ex vivo explant assay is a robust and cost effective model to assess chemosensitivity and the effect of novel therapeutics in ovarian cancer.
Publisher: Springer Science and Business Media LLC
Date: 08-01-2019
Publisher: MDPI AG
Date: 15-08-2019
Abstract: We have recently shown that the extracellular matrix molecule hyaluronan (HA) plays a role in the development of ovarian cancer chemoresistance. This present study determined if HA production is increased in chemotherapy-resistant ovarian cancers and if the HA inhibitor 4-methylubelliferone (4-MU) can overcome chemoresistance to the chemotherapeutic drug carboplatin (CBP) and inhibit spheroid formation and the expression of cancer stem cell (CSC) markers. We additionally assessed whether 4-MU could inhibit in vivo invasion of chemoresistant primary ovarian cancer cells in the chicken embryo chorioallantoic membrane (CAM) assay. The expression of the HA synthases HAS2 and HAS3 was significantly increased in chemoresistant compared to chemosensitive primary ovarian cancer cells isolated from patient ascites. 4-MU significantly inhibited HA production, cell survival, and spheroid formation of chemoresistant serous ovarian cancer cells. In combination with CBP, 4-MU treatment significantly decreased ovarian cancer cell survival and increased apoptosis of chemoresistant primary cells compared to CBP alone. 4-MU significantly reduced spheroid formation, expression of CSC markers ALDH1A1 and ABCG2 in primary cell spheroid cultures, and ALDH1 immunostaining in patient-derived tissue explant assays following treatment with CBP. Furthermore, 4-MU was very effective at inhibiting in vivo invasion of chemoresistant primary cells in CAM assays. Inhibition of HA is therefore a promising new strategy to overcome chemoresistance and to improve ovarian cancer survival.
Publisher: MDPI AG
Date: 19-12-2018
DOI: 10.3390/IJMS19124122
Abstract: S100A10, which is also known as p11, is located in the plasma membrane and forms a heterotetramer with annexin A2. The heterotetramer, comprising of two subunits of annexin A2 and S100A10, activates the plasminogen activation pathway, which is involved in cellular repair of normal tissues. Increased expression of annexin A2 and S100A10 in cancer cells leads to increased levels of plasmin—which promotes the degradation of the extracellular matrix—increased angiogenesis, and the invasion of the surrounding organs. Although many studies have investigated the functional role of annexin A2 in cancer cells, including ovarian cancer, S100A10 has been less studied. We recently demonstrated that high stromal annexin A2 and high cytoplasmic S100A10 expression is associated with a 3.4-fold increased risk of progression and 7.9-fold risk of death in ovarian cancer patients. Other studies have linked S100A10 with multidrug resistance in ovarian cancer however, no functional studies to date have been performed in ovarian cancer cells. This article reviews the current understanding of S100A10 function in cancer with a particular focus on ovarian cancer.
Publisher: American Chemical Society (ACS)
Date: 19-09-2016
DOI: 10.1021/ACS.JPROTEOME.6B00053
Abstract: Although acetylation is regarded as a common protein modification, a detailed proteome-wide profile of this post-translational modification may reveal important biological insight regarding differential acetylation of in idual proteins. Here we optimized a novel peptide IEF fractionation method for use prior to LC-MS/MS analysis to obtain a more in depth coverage of N-terminally acetylated proteins from complex s les. Application of the method to the analysis of the serous ovarian cancer cell line OVCAR-5 identified 344 N-terminally acetylated proteins, 12 of which are previously unreported. The protein peptidyl-prolyl cis-trans isomerase A (PPIA) was detected in both the N-terminally acetylated and unmodified forms and was further analyzed by data-independent acquisition in carboplatin-responsive parental OVCAR-5 cells and carboplatin-resistant OVCAR-5 cells. This revealed a higher ratio of unacetylated to acetylated N-terminal PPIA in the parental compared with the carboplatin-resistant OVCAR-5 cells and a 4.1-fold increase in PPIA abundance overall in the parental cells relative to carboplatin-resistant OVCAR-5 cells (P = 0.015). In summary, the novel IEF peptide fractionation method presented here is robust, reproducible, and can be applied to the profiling of N-terminally acetylated proteins. All mass spectrometry data is available as a ProteomeXchange repository (PXD003547).
Publisher: Elsevier BV
Date: 05-2016
DOI: 10.1016/J.TRSL.2016.02.002
Abstract: Annexin A2, a calcium phospholipid binding protein, has been shown to play an important role in ovarian cancer metastasis. This study examined whether annexin A2 and S100A10 can be used as prognostic markers in serous ovarian cancer. ANXA2 and S100A10 gene expressions were assessed in publicly available ovarian cancer data sets and annexin A2 and S100A10 protein expressions were assessed by immunohistochemistry in a uniform cohort of stage III serous ovarian cancers (n = 109). Kaplan-Meier and Cox regression analyses were performed to assess the relationship between annexin A2 or S100A10 messenger RNA (mRNA) and protein expressions with clinical outcome. High ANXA2 mRNA levels in stage III serous ovarian cancers were associated with reduced progression-free survival (PFS P = 0.023) and overall survival (OS P = 0.0038), whereas high S100A10 mRNA levels predicted reduced OS (P = 0.0019). Using The Cancer Genome Atlas data sets, ANXA2 but not S100A10 expression was associated with higher clinical stage (P = 0.005), whereas both ANXA2 and S100A10 expressions were associated with the mesenchymal molecular subtype (P < 0.0001). Kaplan-Meier and Cox regression analyses showed that high stromal annexin A2 immunostaining was significantly associated with reduced PFS (P = 0.013) and OS (P = 0.044). Moreover, high cytoplasmic S100A10 staining was significantly associated with reduced OS (P = 0.027). Multivariate Cox regression analysis showed stromal annexin A2 (P = 0.009) and cytoplasmic S100A10 (P = 0.016) levels to be independent predictors of OS. Patients with high stromal annexin A2 and high cytoplasmic S100A10 expressions had a 3.4-fold increased risk of progression (P = 0.02) and 7.9-fold risk of ovarian cancer death (P = 0.04). Our findings indicate that together annexin A2 and S100A10 expressions are powerful predictors of serous ovarian cancer outcome.
Publisher: Wiley
Date: 21-08-2019
Publisher: American Association for Cancer Research (AACR)
Date: 14-09-2017
DOI: 10.1158/0008-5472.CAN-17-0025
Abstract: Sphingosine kinase 1 (SK1) is a key regulator of the cellular balance between proapoptotic and prosurvival sphingolipids. Oncogenic signaling by SK1 relies on its localization to the plasma membrane, which is mediated by the calcium and integrin binding protein CIB1 via its Ca2+-myristoyl switch function. Here we show that another member of the CIB family, CIB2, plays a surprisingly opposite role to CIB1 in the regulation of SK1 signaling. CIB2 bound SK1 on the same site as CIB1, yet it lacks the Ca2+-myristoyl switch function. As a result, CIB2 blocked translocation of SK1 to the plasma membrane and inhibited its subsequent signaling, which included sensitization to TNFα-induced apoptosis and inhibition of Ras-induced neoplastic transformation. CIB2 was significantly downregulated in ovarian cancer and low CIB2 expression was associated with poor prognosis in ovarian cancer patients. Notably, reintroduction of CIB2 in ovarian cancer cells blocked plasma membrane localization of endogenous SK1, reduced in vitro neoplastic growth and tumor growth in mice, and suppressed cell motility and invasiveness both in vitro and in vivo. Consistent with the in vitro synergistic effects between the SK1-specific inhibitor SK1-I and standard chemotherapeutics, expression of CIB2 also sensitized ovarian cancer cells to carboplatin. Together, these findings identify CIB2 as a novel endogenous suppressor of SK1 signaling and potential prognostic marker and demonstrate the therapeutic potential of SK1 in this gynecologic malignancy. Cancer Res 77(18) 4823–34. ©2017 AACR.
Publisher: MDPI AG
Date: 08-07-2016
DOI: 10.3390/IJMS17071088
Publisher: MDPI AG
Date: 31-12-2022
DOI: 10.3390/IJMS24010696
Abstract: Disabled-2 (DAB2), a key adaptor protein in clathrin mediated endocytosis, is implicated in the regulation of key signalling pathways involved in homeostasis, cell positioning and epithelial to mesenchymal transition (EMT). It was initially identified as a tumour suppressor implicated in the initiation of ovarian cancer, but was subsequently linked to many other cancer types. DAB2 contains key functional domains which allow it to negatively regulate key signalling pathways including the mitogen activated protein kinase (MAPK), wingless/integrated (Wnt) and transforming growth factor beta (TGFβ) pathways. Loss of DAB2 is primarily associated with activation of these pathways and tumour progression, however this review also explores studies which demonstrate the complex nature of DAB2 function with pro-tumorigenic effects. A recent strong interest in microRNAs (miRNA) in cancer has identified DAB2 as a common target. This has reignited an interest in DAB2 research in cancer. Transcriptomics of tumour associated macrophages (TAMs) has also identified a pro-metastatic role of DAB2 in the tumour microenvironment. This review will cover the broad depth literature on the tumour suppressor role of DAB2, highlighting its complex relationships with different pathways. Furthermore, it will explore recent findings which suggest DAB2 has a more complex role in cancer than initially thought.
Publisher: Springer Science and Business Media LLC
Date: 05-03-2011
Publisher: Wiley
Date: 28-01-2011
DOI: 10.1002/IJC.25494
Abstract: Ovarian cancer metastasis is characterized by the shedding of malignant cells from the surface of the ovary and their implantation onto the peritoneal surface, which lines the abdominal cavity. As the factors promoting this process are poorly understood, we investigated the ovarian cancer-peritoneal interaction by means of in vitro coculture experiments with ovarian cancer (OVCAR-5 and SKOV-3) and peritoneal (LP-9) cells. One of the proteins differentially expressed in the coculture secretome was identified by MALDI-TOF/TOF mass spectrometry as the extracellular matrix protein transforming growth factor-beta-induced protein (TGFBIp, also known as βig-H3). Immunohistochemistry showed high TGFBIp levels in normal surface ovarian epithelial and peritoneal cells, whereas TGFBIp levels in primary serous ovarian carcinomas and matching metastatic implants was very low. In functional in vitro experiments, treatment with recombinant TGFBIp significantly increased the motility and invasiveness of OVCAR-5 and SKOV-3 cells and significantly increased ovarian cancer cell (OVCAR-5, OVCAR-3 and SKOV-3) adhesion to LP-9 cells. TGFBIp was found to be processed at both the N- and C-terminus in the secretome of the ovarian cancer-peritoneal cell coculture. Plasmin inhibitors blocked TGFBIp processing and significantly reduced OVCAR-5 cell adhesion to peritoneal cells. We conclude that TGFBIp expressed by peritoneal cells increases the metastatic potential of ovarian cancer cells. TGFBIp is therefore a potential novel therapeutic target against ovarian cancer.
Publisher: MDPI AG
Date: 03-12-2018
Abstract: Hyaluronan (HA), a glycosaminoglycan located in the extracellular matrix, is important in embryo development, inflammation, wound healing and cancer. There is an extensive body of research demonstrating the role of HA in all stages of cancer, from initiation to relapse and therapy resistance. HA interacts with multiple cell surface receptors, including CD44, receptor for hyaluronan mediated motility (RHAMM) and intracellular signaling pathways, including receptor tyrosine kinase pathways, to promote the survival and proliferation of cancer cells. Additionally, HA promotes the formation of cancer stem cell (CSC) populations, which are hypothesized to be responsible for the initiation of tumors and therapy resistance. Recent studies have identified that the molecular weight of HA plays differing roles on both normal and cancer cell behavior. This review explores the role of HA in cancer progression and therapy resistance and how its molecular weight is important in regulating CSC populations, epithelial to mesenchymal transition (EMT), ATP binding cassette (ABC) transporter expression and receptor tyrosine kinase pathways.
No related grants have been discovered for Noor Lokman.