title: PDGF-AA mediates mesenchymal stromal cell chemotaxis to the head and neck squamous cell carcinoma tumor microenvironment.
abstract: 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. 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.
  
  
  
  Confocal 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.
  
  
  
  We 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).
  
  
  
  Tumor 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.
authors.affiliation: Department of Otolaryngology, University of Texas Medical Branch, 301 University Blvd, Galveston, TX, 77555-0521, USA. tlwatts@utmb.edu.
authors.forename: Tammara L
authors.identifier: 0000-0001-7814-4491
authors.initials: TL
authors.lastname: Watts
authors.affiliation: Department of Otolaryngology, University of Texas Medical Branch, 301 University Blvd, Galveston, TX, 77555-0521, USA.
authors.forename: Ruwen
authors.initials: R
authors.lastname: Cui
authors.affiliation: Department of Otolaryngology, University of Texas Medical Branch, 301 University Blvd, Galveston, TX, 77555-0521, USA.
authors.forename: Peter
authors.initials: P
authors.lastname: Szaniszlo
authors.affiliation: Department of Otolaryngology, University of Texas Medical Branch, 301 University Blvd, Galveston, TX, 77555-0521, USA.
authors.forename: Vicente A
authors.initials: VA
authors.lastname: Resto
authors.affiliation: Internal Medicine, Division of Gastroenterology, University of Texas Medical Branch, Galveston, TX, 77555, USA.
authors.forename: Don W
authors.initials: DW
authors.lastname: Powell
authors.affiliation: Internal Medicine, Division of Gastroenterology, University of Texas Medical Branch, Galveston, TX, 77555, USA.|Microbiology and Immunology Department, University of Texas Medical Branch, Galveston, TX, 77555, USA.
authors.forename: Irina V
authors.initials: IV
authors.lastname: Pinchuk
mesh_terms: D014408:Biomarkers, Tumor / Q000378:metabolism; D002294:Carcinoma, Squamous Cell / Q000378:metabolism / Q000473:pathology*; D045744:Cell Line, Tumor; D018925:Chemokines / Q000378:metabolism; D002633:Chemotaxis / Q000187:drug effects*; D017077:Culture Media, Conditioned / Q000494:pharmacology; D006258:Head and Neck Neoplasms / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D059630:Mesenchymal Stem Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D009055:Mouth / Q000187:drug effects / Q000473:pathology; D009960:Oropharynx / Q000187:drug effects / Q000473:pathology; D010982:Platelet-Derived Growth Factor / Q000494:pharmacology*; D000077195:Squamous Cell Carcinoma of Head and Neck; D017154:Stromal Cells / Q000378:metabolism; D059016:Tumor Microenvironment / Q000187:drug effects*
chemical_list: D014408:Biomarkers, Tumor; D018925:Chemokines; D017077:Culture Media, Conditioned; D010982:Platelet-Derived Growth Factor; C075278:platelet-derived growth factor A
keywords: Head and neck cancer; Invasion; Mesenchymal stromal cells; Migration; Tumor microenvironment