ORCID Profile
0000-0001-7427-2277
Current Organisation
The University of Newcastle
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Publisher: MDPI AG
Date: 12-04-2022
DOI: 10.3390/IJMS23084260
Abstract: There is increasing evidence that nerve growth factor (NGF) and its receptors, the neurotrophic receptor tyrosine kinase 1 (NTRK1/TrkA), the common neurotrophin receptor (NGFR 75NTR) and the membrane receptor sortilin, participate in cancer growth. In melanoma, there have been some reports suggesting that NGF, TrkA and p75NTR are dysregulated, but the expression of the NGF precursor (proNGF) and its membrane receptor sortilin is unknown. In this study, we investigated the expression of NGF, proNGF, TrkA, p75NTR and sortilin by immunohistochemistry in a series of human tissue s les (n = 100), including non-cancerous nevi (n = 20), primary melanomas (n = 40), lymph node metastases (n = 20) and distant metastases (n = 20). Immunostaining was digitally quantified and revealed NGF and proNGF were expressed in all nevi and primary melanomas, and that the level of expression decreased from primary tumors to melanoma metastases (p = 0.0179 and p 0.0001, respectively). Interestingly, TrkA protein expression was high in nevi and thin primary tumors but was strongly downregulated in thick primary tumors (p 0.0001) and metastases (p 0.0001). While p75NTR and sortilin were both expressed in most nevi and melanomas, there was no significant difference in expression between them. Together, these results pointed to a downregulation of NGF/ProNGF and TrkA in melanoma, and thus did not provide evidence to support the use of anti-proNGF/NGF or anti-TrkA therapies in advanced and metastatic forms of melanoma.
Publisher: Springer Science and Business Media LLC
Date: 16-11-2022
DOI: 10.1038/S41388-021-02108-6
Abstract: Nerve infiltration in the tumor microenvironment is emerging as a promoter of cancer progression that could be targeted in therapies, but the mechanisms initiating tumor innervation remain to be elucidated. Here we report that endoplasmic reticulum (ER) stress in cancer cells is transmitted to neuronal cells, resulting in neurite outgrowth and tumor innervation. In vitro, the induction of ER stress in various human cancer cells resulted in the synthesis and release of the precursor for brain-derived neurotrophic factor (proBDNF) through a mechanism dependent on the transcription factor X-box binding protein 1 (XBP1). Cancer cell-released proBDNF was found to mediate the transmission of ER stress to neurons, resulting in the stimulation of neurite outgrowth. Next-generation sequencing indicated the increased expression of the Egl-9 family hypoxia inducible factor 3 (EGLN3) that was mediated by c-MYC and necessary to neurite outgrowth induced by proBDNF. In orthotopic tumor xenograft, ER stress stimulated XBP1 and proBDNF expression as well as tumor innervation. Anti-proBDNF antibody inhibited both tumor innervation and cancer progression induced by ER stress. Interestingly, the chemotherapeutic drug 5-Fluorouracil (5-FU) was found to induce ER stress and tumor innervation, and this effect was inhibited by anti-proBDNF antibody. Finally, in human tumors, cancer tissues with nerve infiltration expressed high XBP1 and proBDNF while EGLN3 was upregulated in infiltrated nerves. This study reveals that ER stress participates in tumor innervation through the release of proBDNF and that targeting this pathway could be used in future therapies.
Publisher: MDPI AG
Date: 13-01-2023
DOI: 10.3390/IJMS24021616
Abstract: Glioblastoma multiforme (GBM) is the most lethal adult brain cancer. Temozolomide (TMZ), the standard chemotherapeutic drug used in GBM, has limited benefit and alternate therapies are needed to improve GBM treatment. Nerve growth factor (NGF) and its precursor proNGF are increasingly recognized as stimulators of human tumor progression. The expression and stimulatory effect of NGF on GBM cell growth has previously been reported, but the status of proNGF in GBM is unreported. In this study, we have investigated proNGF expression and biological activity in GBM. A clinical cohort of GBM (n = 72) and low-grade glioma (n = 20) was analyzed by immunohistochemistry for proNGF and digital quantification. ProNGF expression was significantly increased in GBM compared to low grade gliomas and proNGF was also detected in patient plasma s les. ProNGF was also detected in most GBM cell lines by Western blotting. Although anti-proNGF blocking antibodies inhibited cell growth in GBM cells with methylated MGMT gene promoter, targeting proNGF could not potentiate the efficacy of TMZ. In subcutaneous xenograft of human GBM cells, anti-proNGF antibodies slightly reduced tumor volume but had no impact on TMZ efficacy. In conclusion, this data reveals that proNGF is overexpressed in GBM and can stimulate cancer cell growth. The potential of proNGF as a clinical biomarker and therapeutic target warrants further investigations.
Publisher: Springer Science and Business Media LLC
Date: 04-2021
DOI: 10.1038/S41598-021-86831-W
Abstract: Pancreatic cancer is a highly aggressive malignancy characterized by poor survival, recurrence after surgery and resistance to therapy. Nerves infiltrate the microenvironment of pancreatic cancers and contribute to tumor progression, however the clinicopathological significance of tumor innervation is unclear. In this study, the presence of nerves and their cross-sectional size were quantified by immunohistochemistry for the neuronal markers S-100, PGP9.5 and GAP-43 in a series of 99 pancreatic cancer cases versus 71 normal adjacent pancreatic tissues. A trend was observed between the presence of nerves in the tumor microenvironment of pancreatic cancer and worse overall patient survival (HR = 1.8, 95% CI 0.77–4.28, p = 0.08). The size of nerves, as measured by cross-sectional area, were significantly higher in pancreatic cancer than in the normal adjacent tissue ( p = 0.002) and larger nerves were directly associated with worse patient survival (HR = 0.41, 95% CI 0.19–0.87, p = 0.04). In conclusion, this study suggests that the presence and size of nerves within the pancreatic cancer microenvironment are associated with tumor aggressiveness.
No related grants have been discovered for Mark Marsland.