Brain derived neutrophic factor (BDNF) coordinates lymphovascular metastasis through a fibroblast-governed paracrine axis in the tumor microenvironment

Abstract

It has long been known that the tumor microenvironment contributes to the proliferation and survival of neoplasms through the constant interaction with the stromal and immune compartments. In this investigation, we explored the role of cancer-associated fibroblasts (CAFs) in the regulation of the tumor microenvironment in head and neck squamous cell carcinoma (HNSCC) though a complex intercellular BDNF-TrkB signaling system. Our studies show that conditioned media derived from patient-derived CAFs promoted HNSCC cell proliferation, in vitro cell migration, cell invasion and chemotherapy resistance, compared to normal fibroblasts. Furthermore, examination of the in vivo impact of CAF pathophysiology in the tumor microenvironment in animal xenograft models revealed that HNSCC cell lines in combination with CAFs promoted tumor growth and increased incidence of lymphovascular metastasis as compared to injection of tumor cells or CAF cells alone. Using pharmacological and genetic alterations, we mechanistically demonstrate the critical importance of BDNF-TrkB signaling in the tumor microenvironment. These investigations further support the rationale for BDNF/TRKB targeted therapy against in the treatment of HNSCC.

Brain-Derived Neurotrophin and TrkB in Head and Neck Squamous Cell Carcinoma

“…The TrkB staining pattern or its presence or absence did not show relation with patient survival, but TrkB staining was visibly more frequent in cases with higher levels of lymph node metastasis, was significantly more frequent in cases with secondary tumor or recurrence, and with altered p53. These data are consistent with the published evidence that the BDNF (which is sufficiently available in HNSCC)–TrkB (the receptor is available in 40% of the cases, frequently focally localized at the border of the tumor cell nests) system might be related with cell invasivity, and improved tumor cell survival in therapeutic conditions [13,16,18,19,22]. The above-mentioned clinical material-based results justified the investigation of the BDNF–TrkB axis in relation to cell migration, cell survival, and therapy resistance in available SCC-25, Detroit 562, and UPCI-SCC090 cells.…”

“…The newest data from the Kupferman group [22] further confirms our previous studies and claims that conditioned media derived from patient-derived carcinoma associated fibroblasts (CAFs) promotes HNSCC cell proliferation, in vitro cell migration, cell invasion, and chemotherapy resistance. Furthermore, they claim CAF and tumor cell interaction to be responsible for lymphovascular metastasis and mechanistically demonstrate the critical importance of BDNF-TrkB signaling in this process [22].…”

“…As displayed on Figure 4, BDNF induced a morphological change in UPCI-SCC090 cells and we were wondering if BDNF induces epithelial–mesenchymal transition (EMT). This function of BDNF could have been expected based on available references [16,18,22].…”

“…A further issue to be introduced here is a BDNF-independent oncogenic function of TrkB kinase based on gene fusion PAN3–NTRK2 , which is as rare as one case in 411 in HNSCC [23]. Both the role of the BDNF/TrkB axis in chemotherapy resistance and lymphovascular metastasis of HNSCC [13,16,22] and a potential of oncogenic gene fusion of neurotrophin receptors [23] warrant investigation into the rationale for BDNF/NTRK2 -targeted therapy in the treatment of HNSCC.…”

Role of the nervous system in cancer metastasis

“…The expression of TrkB associates with nodal metastasis and peritoneal metastasis; whereas, TrkC expression associates with liver metastasis in colorectal cancer patients [ 81 ]. BDNF-TrkB signaling pathway mediates metastatic effect through modulation of cancer-associated fibroblasts (CAFs) as demonstrated in mouse model co-injected with OSC19-Luc transfected cell line and CAFs [ 84 ]. In melanoma, neurotrophin (NT)-3, NT-4, and NGF induce cell migration, with a stronger effect on metastatic cell lines via binding to p75NTR coreceptor sortilin [ 85 ].…”