HIF expression and the role of hypoxic microenvironments within primary tumours as protective sites driving cancer stem cell renewal and metastatic progression

Abstract

Hypoxic microenvironments frequently exist in many solid tumours with oxygen levels fluctuating temporally and spatially from normoxia to hypoxia. The response to hypoxia in human cells is mainly regulated by hypoxia-inducible factors (HIFs), a family of transcription factors which orchestrate signalling events leading to angiogenesis and tumorigenesis. Several events conspire together to lead to the stabilization of HIF-α, commonly expressed in many cancer cell types. These events can result from low oxygen tensions occurring within the expanding tumour mass to produce hypoxic microenvironments or from mutations whereby the HIFs cause changes in expression of genes involved in several cellular functions. Hypoxia-mediated HIF-α regulation has gained significant prominence in tumour biology over recent years, and the hypoxic microenvironments have been shown to facilitate and trigger major molecular and immunological processes necessary to drive the progression of tumours to malignancy. More recently, it has been realized that the hypoxic microenvironments also play significant roles in shielding tumour cells from immune attack by promoting immune suppression. In addition, the hypoxic microenvironment promotes many other oncogenic events, such as the metabolic reconfiguration of tumour cells, neovascularization, epithelial to mesenchymal transition (EMT), and cancer stem cell renewal and accumulation. This article reviews the molecular mechanisms underlying tumour hypoxia and their pro-tumour contributions, such as immune suppression, development of nascent and more permeable tumour vasculature, selective cancer stem cell renewal, accumulation, mobilization and promotion of EMT leading to tumour cell metastasis.

Metabolic control of cancer cell stemness: Lessons from iPS cells

“…95,96 Given the unique role of MAGL in providing lipolytic sources of free fatty acids for the synthesis of oncogenic signaling lipids, CSCs might co-opt lipolytic enzymes such as MAGL to translate their lipogenic state of stem cells into an array of protumorigenic signals. The recent discovery that cancer adaptation to antiangiogenic treatments, which generate hypoxic and nutrient-starved tumor microenvironments that suppress cell cycle progression but enrich non-proliferating CSC, [97][98][99][100][101][102][103] involves a significant upregulation of lipid synthesis that fuels tumor regrowth and metastasis after angiogenic therapy withdrawal, 104 strongly supports the notion that key enzymes involved in lipid metabolism such as FASN could play key roles in the reprogramming of CSC cellular states.…”

High expression of HIF-2α and its anti-radiotherapy effect in lung cancer stem cells

“…There have been numerous studies on the role of HIF-2α in stem cells (Kaufman, 2010;Cummins, 2012;Xu et al, 2012;Philip et al, 2013). HIF-2α regulates the expression of the stem cell marker Oct-4 (Covello et al, 2006), and Oct-4 plays an important role in the maintenance of cell stemness.…”

“…HIFs are highly expressed during stress, and in turn induce the expression of anti-stress molecules within cells (Kaelin and Ratcliffe, 2008;Greer et al, 2012). However, several studies have demonstrated that there is an important relationship between HIF-2α and stem cell induction (Kaufman, 2010;Cummins, 2012;Xu et al, 2012;Philip et al, 2013). For example, HIF-2α can induce cells to express the stem cell-specific factor Oct-4, which is important for maintaining stemness (Covello et al, 2006;Koh et al, 2011).…”

Targeting Cellular Signaling Pathways in Breast Cancer Stem Cells and its Implication for Cancer Treatment

“…In part, it is probably justified by the observation that cancer stem cells are located in hypoxic microenvironment areas, which confers a high metastatic potential and increases resistant to conventional treatments in these cells. Hypoxic cancer stem cells are mainly responsible for repopulating in situ and distant tumors after treatment (59,60).…”

“…Given the role of hypoxia in tumor progression and the formation of a tumor stem cell niche in breast cancer (59,60), novel therapeutic approaches that target hypoxia factors, especially HIF-1α and HIF-2α, are of interest (58). Combination of conventional chemotherapies with hypoxia factor inhibitors appears to be promising for therapeutic alternatives, including BCSC, thereby preventing the onset of metastasis and recurrence after treatment (62,65).…”