Image provided by William Grady
NTRK3 is a member of the neurotrophin receptor family and is critical for nervous system development. Previously published studies suggested that NTRK3 is a dependence receptor, which signals in both the ligand-bound ("on") state and ligand-free ("off") state (see figure). When the ligand neurotrophin-3 (NT-3) is present, NTRK3 triggers signals inside the cell via a tyrosine kinase domain to promote cell proliferation and survival. In the absence of NT-3, NTRK3 signals for cell death by activating apoptosis. Therefore, NTRK3 has the potential to be either an oncogene or a tumor suppressor gene depending on the presence of NT-3. In breast and liver cancer, NTRK3 has been identified as an oncogene that promotes tumorigenesis. Conversely, DNA methylation of the NTRK3 promoter suggests that NTRK3 could function as a tumor suppressor in colon cancer.
The Grady lab found that DNA methylation of the NTRK3 promoter occurred in tumors isolated from all molecular classes of colon cancer, in 67% colorectal adenocarcinomas and 60% of adenomas, and was not associated with other common DNA mutations. DNA methylation of the promoter silenced both NTRK3 mRNA and protein expression in colon cancer cell lines and primary tumor samples. In addition, the expression of the ligand NT-3 was significantly lower in both colon cancer cell lines and primary colon cancer tissue compared to normal tissue, and was directly correlated with NTRK3 expression levels. The NT-3 promoter was also methylated in select colon cancer cell lines and expression could be turned on with drugs that reverse DNA methylation, indicating this was the mechanism for reduced expression in colon cancer.
In the absence of NT-3 expression, reintroducing NTRK3 expression induced cell death through apoptosis in colon cancer cell lines, suggesting that NTRK3 was functioning as a tumor suppressor. Treatment of cells with NT-3 reversed NTRK3-induced cell death, confirming that NTRK3 is a dependence receptor. Re-expression of NTRK3 also suppressed anchorage-independent cell growth of colon cancer cell lines, a hallmark of cancer in vitro, and tumor growth in vivo in a mouse model of colon cancer. Further supporting the notion that NTRK3 is a tumor suppressor gene, DNA mutations are present in the NTRK3 gene in colon, breast, lung, and liver cancer. Luo et al. also found a number of mutations in NTRK3 in primary human colorectal cancers. They expressed a subset of these NTRK3 mutants (G608S, I695V and L760I) in colon cancer cell lines and found that the NTRK3 L760I mutant inactivated the ability of NTRK3 to induce apoptosis. The other mutant NTRK3 genes did not affect NTRK3 function. These results demonstrate that both genetic and epigenetic mechanisms inactivate NTRK3 in colorectal cancer, and also show that some of the NTRK3 mutations are likely passenger mutations.
According to Dr. Grady, "Our studies show that NT-3 is absent in the colon, which we argue creates selective pressure to inactivate NTRK3 by both genetic and epigenetic mechanisms." These results are similar to another study describing the role of NTRK3 in colon cancer (Genevoi et al., 2013). "Our findings suggest that soluble receptors for NT-3 may be an effective anti-cancer treatment. In addition, the high frequency of NTRK3 methylation in adenoma samples suggests that methylated NTRK3 might be a useful biomarker for the early detection of colorectal cancer."
Luo Y, Kaz AM, Kanngurn S, Welsch P, Morris SM, Wang J, Lutterbaugh JD, Markowitz SD, Grady WM. 2013. NTRK3 Is a Potential Tumor Suppressor Gene Commonly Inactivated by Epigenetic Mechanisms in Colorectal Cancer. PLoS Genetics 9:e1003552.
Also see: Genevois AL, Ichim G, Coissieux MM, Lambert MP, Lavial F, Goldschneider D, Jarrosson-Wuilleme L, Lepinasse F, Gouysse G, Herceg Z, Scoazec JY, Tauszig-Delamasure S, Mehlen P. 2013. Dependence receptor TrkC is a putative colon cancer tumor suppressor. Proc Natl Acad Sci U S A. 110:3017-22.