Semaphorin 4D in human head and neck cancer tissue and peripheral blood: A dense fibrotic peri-tumoral stromal phenotype
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Roshanak Derakhshandeh1,6, Sonia Sanadhya1, Kyu Lee Han1, Haiyan Chen3, Olga Goloubeva5,7, Tonya J. Webb6,7 and Rania H. Younis1,2,4,7
1Department of Oncology and Diagnostic Sciences, School of Dentistry, University of Maryland Baltimore, Baltimore, Maryland, USA
2Oral Pathology Consultants, School of Dentistry, University of Maryland Baltimore, Baltimore, Maryland, USA
3Department of Dental Public Health, School of Dentistry, University of Maryland Baltimore, Baltimore, Maryland, USA
4Department of oral Pathology, Faculty of Dentistry, Alexandria University, Alexandria, Egypt
5Department of Epidemiology and Public Health, School of Medicine, University of Maryland Baltimore, Baltimore, Maryland, USA
6Department of Microbiology and Immunology, School of Medicine, University of Maryland Baltimore, Baltimore, Maryland, USA
7The Marlene and Stewart Greenebaum Cancer Center, University of Maryland Baltimore, Baltimore, Maryland, USA
Rania H. Younis, email: [email protected]
Keywords: semaphorin 4D; head and neck cancer; fibrotic stroma; non-inflamed; peripheral blood
Received: October 17, 2016 Accepted: January 09, 2018 Published: January 19, 2018
The search for stromal biomarkers in cancer patients is a challenge in the field. Semaphorin 4D (Sema4D), known for its various developmental, physiological and pathological effects, plays a role in pro and anti-inflammatory responses. It is expressed in many epithelial tumors including head and neck squamous cell carcinoma (HNSCC). Recently, we found that HNSCC-associated Sema4D modulates an immune-suppressive, tumor-permissible environment by inducing the expansion of myeloid derived suppressor cells. The purpose of this study was to determine the value of Sema4D as a biomarker for the peri-tumoral stromal phenotype in human HNSCC. Our data showed Sema4D+ve/high tumor cells in 34% of the studied cohort with positive correlation to Stage III (p=0.0001). Sema4D+ve/high tumor cells correlated directly with dense fibrotic peri-tumoral stroma (p=0.0001) and inversely with infiltrate of Sema4D+ve/high tumor-associated inflammatory cells (TAIs) (p=0.01). Most of the Sema4D+ve/high TAIs were co-positive for the macrophage biomarker CD163. Knockdown of Sema4D in WSU-HN6 cells inhibited collagen production by fibroblasts, and decreased activated TGF-β1 levels in culture medium of HNSCC cell lines. In a stratification model of HNSCC using combined Sema4D and the programmed death ligand 1 (PDL-1), Sema4D+ve/high tumor cells represented a phenotype distinct from the PDL-1 positive tumors. Finally,Sema4D was detected in plasma of HNC patients at significantly higher levels (115.44, ± 39.37) compared to healthy donors (38.60± 12.73) (p <0.0001). In conclusion, we present a novel HNSCC tumor stratification model, based on the expression of the biomarker Sema4D. This model opens new avenues to novel targeted therapeutic strategies.
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