Hypoxic niches are endowed with a protumorigenic mechanism that supersedes the protective function of PTEN

Abstract

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 1a (HIF-1a). 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-1a 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.-Nascimento-Filho,

CSC Radioresistance: A Therapeutic Challenge to Improve Radiotherapy Effectiveness in Cancer

“…During tumor growth, most solid tumors undergo hypoxia, which is responsible for a more aggressive tumor behavior [ 108 , 114 ] and resistance to radio- and chemotherapy because hypoxia promotes the CSC properties associated with EMT, maintains their plasticity, stimulates early EMT by suppressing E-cadherin and induces unfolded protein response (UPR) [ 61 , 64 , 111 , 114 ]. The effect of hypoxia on cells is controlled by a family of transcriptional regulators, hypoxia-inducible factors (HIF) [ 61 , 108 , 109 ], which can also inhibit cellular apoptosis [ 30 ].…”

“…Little is known about the molecular pathways involved, although CSC accumulation has shown that the tumor suppressor gene PTEN is downregulated. Hypoxia-driven PTEN deregulation also causes HIF-1α activation and mTOR signaling along with EMT induction [ 114 ].…”

“…The development of hypoxic niches is also due to reduced vascularity in the tumor [ 114 ]. However, the hypoxic condition itself stimulates pro-angiogenic factors for the formation of new blood vessels from the pre-existing vasculature [ 109 ].…”

Targeting Hypoxia-Driven Metabolic Reprogramming to Constrain Tumor Progression and Metastasis

“…Despite the low prevalence of CSCs (1–3%), this subpopulation has a high resistance to conventional therapy due to its ability to self-renewal, differentiation, and tumorigenicity. Recent evidence indicates that hypoxic niches modify the CSC and promote the EMT-like phenotype under the deregulation of phosphatase and tensin homolog (PTEN) [ 86 ]. Interestingly the metabolic switch induced for hypoxia also contributes to it regulating certain genes related to CSCs, through increased secretion of exosomes [ 87 ].…”

Effectiveness of Hypoxia-Induced Accumulation of Cancer Stem Cells in Head and Neck Squamous Cell Carcinoma

“…The cell culture was sealed inside a plastic bag with an O 2 absorber and an O 2 sensor. Upon reaching hypoxia, an O 2 concentration below 2%, a clip was used to separate the cells in cultivation from the O 2 absorber hermetically, thus keeping the O 2 concentration within the desired area stable [14] (Figure 1). All samples were submitted to hypoxia for 12 hours.…”