Abstract

BackgroundThe robust desmoplasia associated with head and neck squamous cell carcinoma (HNSCC) suggests that the tumor microenvironment may be an important component in the pathophysiology of this cancer. Moreover, the high recurrence rate and poor clinical response to chemotherapy and radiation treatment further underscores that the non-cancerous cells of the microenvironment, such as mesenchymal stromal cells (MSCs), cancer associated fibroblasts (CAFs), and pericytes, may be important in the pathophysiology of HNSCC.MethodsConfocal microscopy and immunohistomchemistry approaches were used to identify MSCs tumor microenvironment from patients with oral cavity and oral pharyngeal squamous cell carcinoma (SCC). In vitro Boyden chamber assays and multiplex magnetic bead assays were used to measure MSC chemotaxis and to identify the chemokines secreted by JHU-011, -012, -019, three cells lines derived from patients with oral pharyngeal SCC.ResultsWe show here that MSCs reside in the tumor microenvironment of patients with oral cavity and oral pharyngeal SCC and are recruited via paracrine mediated tumor cell secretion of (platelet derived growth factor) PDGF-AA. The MSC markers CD90+, CD105+, and gremlin-1+ were found to co-localize on cells within the tumor microenvironment in oral cavity SCC specimens distinct from α-smooth muscle actin staining CAFs. The conditioned media from JHU-011, -012, and -019 caused a significant increase in MSC migration (>60%) and invasion (>50%; p < 0.0001) compared to oral keratinocyte (OKT) controls. Tumor cell induced MSC chemotaxis appears to be mediated through paracrine secretion of PDGF-AA as inhibition of the PDGF-AA receptor, PDGFR-α but not PDGFR-β, resulted in near arrest of MSC chemotaxis (p < 0.0001).ConclusionsTumor microenvironment expression of PDGFR-α has been shown to correlate with a worse prognosis in patients with prostate, breast, ovarian, non-small cell lung cancer and osteosarcoma. This is the first evidence that a similar signaling paradigm may be present in HNSCC. PDGFR-α inhibitors have not been studied as adjunctive treatment options in the management of HNSCC and may prove to be an important driver of the malignant phenotype in this setting.Electronic supplementary materialThe online version of this article (doi:10.1186/s12967-016-1091-6) contains supplementary material, which is available to authorized users.

Highlights

  • The robust desmoplasia associated with head and neck squamous cell carcinoma (HNSCC) suggests that the tumor microenvironment may be an important component in the pathophysiology of this cancer

  • We report here that mesenchymal stromal cells (MSCs) reside within the tumor microenvironment from patients with oral cavity (OC) and oropharyngeal squamous cell carcinoma (OPSCC) along with α-SMA+ cancer associated fibroblasts (CAFs)

  • Mesenchymal stromal cells are identified within the OC and OPSCC tumor microenvironment Using an immunohistochemical approach, human OPSCC specimens were screened using the MSC marker gremlin-1

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Summary

Introduction

The robust desmoplasia associated with head and neck squamous cell carcinoma (HNSCC) suggests that the tumor microenvironment may be an important component in the pathophysiology of this cancer. The high recurrence rate and poor clinical response to chemotherapy and radiation treatment further underscores that the non-cancerous cells of the microenvironment, such as mesenchymal stromal cells (MSCs), cancer associated fibroblasts (CAFs), and pericytes, may be important in the pathophysiology of HNSCC. Mesenchymal stromal cells (MSCs), myofibroblasts/ cancer associated fibroblasts (CAFs), pericytes, and other non-cancerous cells form a dense desmoplastic microenvironment around tumor cells and are known to be critical contributors to the growth of several solid tumors [1]. This rich desmoplastic reaction is a pathognomonic feature of HNSCC further driving the hypothesis that the tumor microenvironment is likely a key component in pathophysiology of this cancer. The conditioned media alone from MSC was not enough to induce increased ALDH expression on the breast cancer cells, suggesting that the paracrine signaling feedback loop between the breast cancer cells and MSCs is necessary to drive the increase in ALDH expression [2]

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