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

Publication ,  Journal Article
Watts, TL; Cui, R; Szaniszlo, P; Resto, VA; Powell, DW; Pinchuk, IV
Published in: J Transl Med
December 8, 2016

BACKGROUND: 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. METHODS: 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. RESULTS: 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). CONCLUSIONS: 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.

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Published In

J Transl Med

DOI

EISSN

1479-5876

Publication Date

December 8, 2016

Volume

14

Issue

1

Start / End Page

337

Location

England

Related Subject Headings

  • Tumor Microenvironment
  • Stromal Cells
  • Squamous Cell Carcinoma of Head and Neck
  • Platelet-Derived Growth Factor
  • Oropharynx
  • Mouth
  • Mesenchymal Stem Cells
  • Immunology
  • Humans
  • Head and Neck Neoplasms
 

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Watts, T. L., Cui, R., Szaniszlo, P., Resto, V. A., Powell, D. W., & Pinchuk, I. V. (2016). PDGF-AA mediates mesenchymal stromal cell chemotaxis to the head and neck squamous cell carcinoma tumor microenvironment. J Transl Med, 14(1), 337. https://doi.org/10.1186/s12967-016-1091-6
Watts, Tammara L., Ruwen Cui, Peter Szaniszlo, Vicente A. Resto, Don W. Powell, and Irina V. Pinchuk. “PDGF-AA mediates mesenchymal stromal cell chemotaxis to the head and neck squamous cell carcinoma tumor microenvironment.J Transl Med 14, no. 1 (December 8, 2016): 337. https://doi.org/10.1186/s12967-016-1091-6.
Watts TL, Cui R, Szaniszlo P, Resto VA, Powell DW, Pinchuk IV. PDGF-AA mediates mesenchymal stromal cell chemotaxis to the head and neck squamous cell carcinoma tumor microenvironment. J Transl Med. 2016 Dec 8;14(1):337.
Watts, Tammara L., et al. “PDGF-AA mediates mesenchymal stromal cell chemotaxis to the head and neck squamous cell carcinoma tumor microenvironment.J Transl Med, vol. 14, no. 1, Dec. 2016, p. 337. Pubmed, doi:10.1186/s12967-016-1091-6.
Watts TL, Cui R, Szaniszlo P, Resto VA, Powell DW, Pinchuk IV. PDGF-AA mediates mesenchymal stromal cell chemotaxis to the head and neck squamous cell carcinoma tumor microenvironment. J Transl Med. 2016 Dec 8;14(1):337.
Journal cover image

Published In

J Transl Med

DOI

EISSN

1479-5876

Publication Date

December 8, 2016

Volume

14

Issue

1

Start / End Page

337

Location

England

Related Subject Headings

  • Tumor Microenvironment
  • Stromal Cells
  • Squamous Cell Carcinoma of Head and Neck
  • Platelet-Derived Growth Factor
  • Oropharynx
  • Mouth
  • Mesenchymal Stem Cells
  • Immunology
  • Humans
  • Head and Neck Neoplasms