Nerve Growth Factor in Cancer Cell Death and Survival

Abstract

One of the major challenges for cancer therapeutics is the resistance of many tumor cells to induction of cell death due to pro-survival signaling in the cancer cells. Here we review the growing literature which shows that neurotrophins contribute to pro-survival signaling in many different types of cancer. In particular, nerve growth factor, the archetypal neurotrophin, has been shown to play a role in tumorigenesis over the past decade. Nerve growth factor mediates its effects through its two cognate receptors, TrkA, a receptor tyrosine kinase and p75NTR, a member of the death receptor superfamily. Depending on the tumor origin, pro-survival signaling can be mediated by TrkA receptors or by p75NTR. For example, in breast cancer the aberrant expression of nerve growth factor stimulates proliferative signaling through TrkA and pro-survival signaling through p75NTR. This latter signaling through p75NTR promotes increased resistance to the induction of cell death by chemotherapeutic treatments. In contrast, in prostate cells the p75NTR mediates cell death and prevents metastasis. In prostate cancer, expression of this receptor is lost, which contributes to tumor progression by allowing cells to survive, proliferate and metastasize. This review focuses on our current knowledge of neurotrophin signaling in cancer, with a particular emphasis on nerve growth factor regulation of cell death and survival in cancer.

Evaluation of the association between perineural invasion and clinical and histopathological features of cervical cancer

“…Specifically, nerve cells secret a number of cytokines that promote the growth and invasion of tumor cells (19,20). Moreover, tumor cells improve the growth of nerve cells by secreting a number of cytokines, such as neurotrophic factors, chemokines, and nerve adhesion factors (1,17,21,22). It has been reported previously that some tumor-derived cytokines are involved in the development and invasion of pancreatic and head and neck cancers (4,5,23,24), however, the role of tumor-derived cytokines in the invasion of cervical cancer is not well understood.…”

Molecular mechanisms of perineural spread of cutaneous carcinoma: a potential role for receptor tyrosine kinases and other biomarkers

“…There is increasing literature to suggest that neurotrophins are involved in pro-survival signalling in many different forms of cancer. (55) (56,57) NGF was seen to be prevalent in both normal and tumorigenic prostate tissue in a study by Geldof et al (1998). (56) One study demonstrated higher intensity staining for NGF/TrkA in oral tongue SCC with PNI (n=21) compared to those without PNI (n=21).…”

Role of Growth Factor Signaling in Cancer

“…P75 interacts with caveolin following TNF-α and NFKβ activation 158 . NFG was discovered from sarcoma while human colon cancer biopsy revealed TrkA and P75 was isolated from human melanoma cell lines 159 . In breast cancer there is increase in NGF expression leading to phosphorylation mitogenesis, invasion, metastasis and angiogenesis via activation of all the three pathways i.e MAPK, PI3K/AKT and PLCγ 160 .…”