Agradecimentos: This work was conducted during a visiting scholar period at the University of Michigan, sponsored by the Capes Foundation within the Brazilian Ministry of Education (Grant BEX/88881.135014/2016-01 PDSE). This work was partially supported by University of Michigan Cancer Center Support Grant P30 CA046592, and by the U.S. National Institutes of Health (NIH), National Institute of General Medical Sciences Research Grant 5R01GM120056. This grant was funded by the University of Michigan School of Dentistry faculty, and by The Robert Wood Johnson Foundation (AMFDP-72425). The monoclonal antibody AMF-17b, developed by A. B. Fulton, was obtained from the Developmental Studies Hybridoma Bank, created by the NIH Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD) and maintained at The University of Iowa (Iowa City, IA, USA). The authors declare no conflict of interest Ver menos

Head and neck squamous cell carcinoma (HNSCC) is the sixth most common malignancy worldwide and is characterized by a fast-paced growth. Like other solid tumors, the HNSCC growth rate results in the development of hypoxic regions identified by the expression of hypoxia-inducible factor 1 alpha (HIF-1 alpha). Interestingly, clinical data have shown that pharmacological induction of intratumoral hypoxia caused an unexpected rise in tumor metastasis and the accumulation of cancer stem cells (CSCs). However, little is known on the molecular circuitries involved in the presence of intratumoral hypoxia and the augmented population of CSCs. Here we explore the impact of hypoxia on the behavior of HNSCC and define that the controlling function of phosphatase and tensin homolog (PTEN) over HIF-1 alpha expression and CSC accumulation are de-regulated during hypoxic events. Our findings indicate that hypoxic niches are poised to accumulate CSCs in a molecular process driven by the loss of PTEN activity. Furthermore, our data suggest that targeted therapies aiming at the PTEN/PI3K signaling may constitute an effective strategy to counteract the development of intratumoral hypoxia and the accumulation of CSCs Ver menos