Hypoxia signalling in cancer and approaches to enforce tumour regression

Abstract

Tumour cells emerge as a result of genetic alteration of signal circuitries promoting cell growth and survival, whereas their expansion relies on nutrient supply. Oxygen limitation is central in controlling neovascularization, glucose metabolism, survival and tumour spread. This pleiotropic action is orchestrated by hypoxia-inducible factor (HIF), which is a master transcriptional factor in nutrient stress signalling. Understanding the role of HIF in intracellular pH (pH(i)) regulation, metabolism, cell invasion, autophagy and cell death is crucial for developing novel anticancer therapies. There are new approaches to enforce necrotic cell death and tumour regression by targeting tumour metabolism and pH(i)-control systems.

Hypoxia and cancer

“…This gradient of cell viability parallels that of a decreasing gradient of oxygen, which is accompanied by an increase in HIF-1α levels, a decrease in the extracellular pH and an increase in the resistance to radio-and chemo-therapy Although many studies have pointed at the pro-apoptotic features of these two gene products, these findings are largely controversial. We propose instead that the BH3 domains of BNIP3 and BNIP3L belong to another class, like the BH3 domain of Beclin1, that do not induce cell death but survival by triggering autophagy [12,23,24]. Macroautophagy is a process that allows cells to recycle intracellular organelles such as ribosomes and mitochondria for nutritional and protective purposes [25].…”

“…Activation resides in the inhibition of posttranslational hydroxylation of the alpha subunit that permits stabilization, heterodimerisation and binding to hypoxiaresponse elements (HRE) in target genes. The details of the mechanisms of regulation of the stability and activity of HIF-α have been extensively reviewed by us [10][11][12] and others [13][14][15][16]. Suffice it to say that posttranslational hydroxylation by oxygen-dependent oxygenases, prolyl hydroxylase domain proteins and factor inhibiting HIF (FIH) destabilize and inactivate, respectively, HIF-α.…”

“…A broad range of genes that are implicated in events such as angiogenesis, cell survival/death, metabolism, pH regulation, adhesion, extracellular matrix remodeling, migration and metastasis are targeted [12,15,17,18]. The functional consequences of enhanced expression of a small selection of some of these gene products are discussed below (Fig.…”

“…On the one hand, growth factors and nutrients potentiate the mTOR pathway in conveying signals of growth and survival through increased protein synthesis, and on the other hand, energy depletion and hypoxia suppress mTOR, saving on energy-consuming protein heterodimer HIF bound to hypoxia-response elements (HRE) in target genes mediates the expression of a vast array of proteins implicated in functions such as angiogenesis, cell survival/death, metabolism, pH homeostasis and metastasis. A small selection of proteins (boxed, in blue) is shown and include: AMF autocrine motility factor; ANG-2 angiopoïetin-2; BNIP3 Bcl-2/adenovirus EIB 19 kDa-interacting protein 3; BNIP3L Bcl-2/adenovirus EIB 19 kDa-interacting protein synthesis, allowing for cellular adaptation and subsequent survival [12].…”

The p53 isoform, Δ133p53α, stimulates angiogenesis and tumour progression

“…Hypoxia is one of the principal angiogenic stimuli leading to synthesis of angiogenic growth factors and inducing formation of new blood vessels. 7,8 Such vessels, in addition to their ability to feed tumour cells, provide a way for cells to disseminate and form metastases. p53 inhibits angiogenesis by at least three mechanisms: (1) by regulating expression and activity of the central regulator of hypoxia, the hypoxia-induced transcription factor-1a; (2) by inhibiting production of proangiogenic factors, such as vascular endothelial growth factor (VEGF) and fibroblast growth factor 2 (FGF2); and (3) by increasing production of anti-angiogenic factors.…”