TrkA is amplified in malignant melanoma patients and induces an anti-proliferative response in cell lines

Abstract

BackgroundThe nerve growth factor (NGF) receptor tyrosine-kinase TrkA is a well-known determinant of the melanocytic lineage, through modulation of the MAPK and AKT cascades. While TrkA gene is frequently rearranged in cancers, its involvement in malignant melanoma (MM) development is still unclear.MethodsWe analyzed a dataset of primary cutaneous MM (n = 31) by array comparative genomic hybridization (aCGH), to identify genomic amplifications associated with tumor progression. The analysis was validated by genomic quantitative PCR (qPCR) on an extended set of cases (n = 64) and the results were correlated with the clinical outcome. To investigate TrkA molecular pathways and cellular function, we generated inducible activation of the NGF-TrkA signaling in human MM cell lines.ResultsWe identified amplification of 1q23.1, where the TrkA locus resides, as a candidate hotspot implicated in the progression of MM. Across 40 amplicons detected, segmental amplification of 1q23.1 showed the strongest association with tumor thickness. By validation of the analysis, TrkA gene amplification emerged as a frequent event in primary melanomas (50 % of patients), and correlated with worse clinical outcome. However, experiments in cell lines revealed that induction of the NGF-TrkA signaling produced a phenotype of dramatic suppression of cell proliferation through inhibition of cell division and pronounced intracellular vacuolization, in a way straightly dependent on NGF activation of TrkA. These events were triggered via MAPK activity but not via AKT, and involved p21cip1 protein increase, compatibly with a mechanism of oncogene-induced growth arrest.ConclusionsTaken together, our findings point to TrkA as a candidate oncogene in MM and support a model in which the NGF-TrkA-MAPK pathway may mediate a trade-off between neoplastic transformation and adaptive anti-proliferative response.Electronic supplementary materialThe online version of this article (doi:10.1186/s12885-015-1791-y) contains supplementary material, which is available to authorized users.

Tropomyosin-Related Kinase Receptor and Neurotrophin Expression in Cutaneous Melanoma Is Associated with a Poor Prognosis and Decreased Survival

“…The analysis was validated by genomic quantitative polymerase chain reaction, which confirmed TrkA expression in half of 64 melanomas with an association between TrkA expression and a worse prognosis [17]. Furthermore, they used induced activation of NGF-TrkA receptor signaling to induce a cell proliferation suppression phenotype in human melanoma cells in vitrocharacterized by inhibited cell division and pronounced intracellular vacuolization [17].…”

“…This positivity in nevi might reflect an adaptive antiproliferative response involving MAPK activation [17], which may trigger an oncogene-driven senescence process involving NTs/TRKs, similar to that described for B-Raf expression in nevi [24]. This senescence may take some time to occur, allowing an initial proliferation phase that results in a benign tumor [25, 26].…”

“…Furthermore, they used induced activation of NGF-TrkA receptor signaling to induce a cell proliferation suppression phenotype in human melanoma cells in vitrocharacterized by inhibited cell division and pronounced intracellular vacuolization [17]. These events were triggered by MAPK activity, suggesting that the NGF-TrkA-MAPK pathway may mediate a trade-off between neoplastic transformation and an adaptive antiproliferative response [17]. …”

“…Pasini et al [17] analyzed 31 cutaneous melanoma samples by array comparative hybridization and identified amplification of the 1q23.1 genomic locus, a melanoma progression hot spot candidate locus that includes the TrkA-encoding gene. The analysis was validated by genomic quantitative polymerase chain reaction, which confirmed TrkA expression in half of 64 melanomas with an association between TrkA expression and a worse prognosis [17].…”

“…Additionally, it has been suggested that TrkA may mediate a trade-off between neoplastic transformation and an adaptive antiproliferative response [17], in addition to being associated with shorter survival [18]. Trk receptors can activate important intracellular signaling pathways involving receptor autophosphorylation and downstream induction of mitogen-activated protein kinase (MAPK) and protein kinase B (PKB/Akt) [17]. …”