PDGF-AA mediates mesenchymal stromal cell chemotaxis to the head and neck squamous cell carcinoma tumor microenvironment

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.

Overexpression of Platelet-Derived Growth Factor and Its Receptor Are Correlated with Oral Tumorigenesis and Poor Prognosis in Oral Squamous Cell Carcinoma

“…The PDGFRA/JNK-1 pathway is critical in the control of apoptosis because this signaling pathway not only influences apoptosis but also fosters p21 expression and inhibits the transition from the G1 to the S phase of the cell cycle [42]. The different types of PDGFR are inducing different downstream responses; PDGFRA and PDGFRB facilitate cell growth [43], angiogenesis [44], and chemotaxis [45]. PDGFRB inhibits apoptosis and PDGFRA/B can promote cell division [46,47].…”

Matrix elasticity regulates mesenchymal stem cell chemotaxis

“…While studies have individually demonstrated the role of chemical (Yoon et al, 2016;Ball et al, 2007;Watts et al, 2016) and physical cues (Hadden et al, 2017;Hou et al, 2011;Vincent et al, 2013) in directing hMSC migration, there have been no studies that have comprehensively probed the collective influence of these two cues. Here, we address this question by studying epidermal growth factor (EGF)-induced chemotaxis of hMSCs through PDMS microchannels with varying substrate stiffness.…”

Toward a Molecular Classification of the Head and Neck Squamous Cell Carcinoma

“…Concerning PDGF and their receptor it was found a prognostic role of PDGF serum level in patients with OSCC and a worse prognostic of HNSCC patients induced by the presence of PDGFR-alfa expression in the tumor microenvironment [56,57].…”