title: Hypoxia-induced autophagic response is associated with aggressive phenotype and elevated incidence of metastasis in orthotopic immunocompetent murine models of head and neck squamous cell carcinomas (HNSCC).
abstract: Hypoxia confers resistance to chemoradiation therapy and promotes metastasis in head and neck squamous cell carcinomas (HNSCC). We investigated the effects of hypoxia in tumor phenotype using immunocompetent murine HNSCC models. Balb/c mice were injected intraorally with murine squamous cell carcinoma cells LY-2 and B4B8. Intratumoral hypoxia fraction was evaluated by the immunohistochemical detection of hypoxic probe pimonidazole and carbonic anhydrase IX (CAIX). Tumor cell apoptosis and autophagy in hypoxic areas of these tumors were examined immunohistochemically. Hypoxia-induced apoptotic and autophagic responses in vitro were examined by treating LY2 cells with CoCl(2). B4B8 tumors exhibited a non-aggressive phenotype characterized by its slow growth rate and the lack of metastatic spread. LY2 tumors demonstrated an aggressive phenotype characterized by rapid growth rate with regional and distant metastasis. Intratumoral hypoxia fraction in B4B8 tumors was significantly lower than in LY2 tumors. The hypoxic areas in B4B8 tumors exhibited increased apoptosis rate than that of LY2 tumors. In contrast, the hypoxic areas in LY2 tumors revealed autophagy. The induction of hypoxia in vitro elicited autophagy and not apoptosis in LY2 cells. The induction of autophagy coupled with blockage of apoptosis in hypoxic areas promotes tumor cell survival and confers aggressive phenotype in immunocompetent murine HNSCC models.
authors.affiliation: Department of Diagnostic Sciences, The University of Texas Health Science Center at Houston, Dental Branch, Houston, TX 77030, USA. nadarajah.vigneswaran@uth.tmc.edu
authors.forename: Nadarajah
authors.initials: N
authors.lastname: Vigneswaran
authors.forename: Jean
authors.initials: J
authors.lastname: Wu
authors.forename: Anren
authors.initials: A
authors.lastname: Song
authors.forename: Ananth
authors.initials: A
authors.lastname: Annapragada
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Zacharias
mesh_terms: D000818:Animals; D017209:Apoptosis; D051017:Apoptosis Regulatory Proteins / Q000378:metabolism; D001343:Autophagy; D000071186:Beclin-1; D002294:Carcinoma, Squamous Cell / Q000201:enzymology / Q000276:immunology* / Q000473:pathology*; D053148:Caspase 3 / Q000378:metabolism; D015687:Cell Hypoxia; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D004195:Disease Models, Animal; D006258:Head and Neck Neoplasms / Q000201:enzymology / Q000276:immunology* / Q000473:pathology*; D007121:Immunocompetence; D007150:Immunohistochemistry; D051379:Mice; D009062:Mouth Neoplasms / Q000473:pathology; D009362:Neoplasm Metastasis; D010641:Phenotype; D015854:Up-Regulation
chemical_list: D051017:Apoptosis Regulatory Proteins; D000071186:Beclin-1; C115010:Becn1 protein, mouse; D053148:Caspase 3