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.
Highlights
The involvement of regional lymph nodes is the primary mode of metastasis for most solid tumors, a clinical phenotype that has a profound impact on therapeutic strategies and survival in cancer patients
We first characterized cancer-associated fibroblasts (CAFs) extracted from surgically-resected head and neck squamous cell carcinomas and compared their phenotypic properties to normal human fibroblasts (NF)
We identify novel mechanisms for fibroblast-induced metastasis in human cancers, primarily via a paracrine neurotrophin axis in the tumor microenvironment
Summary
The involvement of regional lymph nodes is the primary mode of metastasis for most solid tumors, a clinical phenotype that has a profound impact on therapeutic strategies and survival in cancer patients. Metastasis to the regional nodes represents a coordinated cellular and molecular ballet of distinct cell populations in the tumor microenvironment, the fundamental contributions of these protagonists to lymphatic metastasis are still poorly understood. Termed cancer-associated fibroblasts (CAFs), these mesenchymal cells have been shown to mediate diverse pro-oncogenic processes, including malignant transformation, inflammation, angiogenesis and invasion. The extent of fibroblastic response is has been linked to survival outcomes among patients with various cancers, including HNSCC. Recent evidence implicates CAF-controlled signaling pathways in modulating the tumor microenvironment, the molecular mechanisms underlying these CAF-mediated processes are incompletely understood [6,7,8,9,10]. While the elucidation of some of these micro-environmental cues has shed light on how bi-directional communication between CAF and tumor cells impacts malignant progression, whether CAFs are instrumental in vascular and lymphatic metastasis has not been fully explored to date
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