Wednesday, June 20, 2012

Hypoxia


(Image from: Hypoxia)



Hypoxia is a pathological condition in which either the whole body (generalized hypoxia) or a region of the body (tissue hypoxia ) is deprived of oxygen. Tissue hypoxia commonly occurs in cancerous tumors when rapid growth causes the tumor to outgrow its blood supply resulting in regions with significantly lower oxygen concentrations. It is a negative prognostic and predictive factor, as it contributes to chemoresistance, radioresistance, angiogenesis, vasculogenesis, invasiveness, metastasis, altered metabolism and genomic instability.


The effects of tissue hypoxia are mediated through the HIF (hypoxia inducible factor) signaling cascade. Under normoxic conditions, the alpha subunits of HIF are hydroxylated by HIF prolyl-hydroxylases, which leads to ubiquitination by the VHL E3 ubiquitin ligase and subsequent degradation of HIF by proteasomes. Under hypoxic conditions, a buildup of succinate combined with a lack of oxygen results in the inhibition of HIF prolyl-hydroxylase. HIF subsequently accumulates and translocates to the nucleus where it dimerizes with the beta isoform of HIF. This dimer interacts with cofactors such as ARNT, CBP/p300 and the Pol II complex to activate the HRE (hypoxic response element), which initiates the transcription of various genes including VEGFA, Glut1 and CA9.


Hypoxia in tumors is closely associated with tumor aggressiveness and resistance to radio- and chemotherapeutic treatment. Therefore, reliable markers for hypoxia represent both valuable diagnostic markers and potential targets for investigation. CAIX (carbonic anhydrase IX) has recently been identified as a hypoxia and tumor biomarker. CAIX is a transmembrane protein that belongs to the 15 member carbonic anhydrase enzyme family and is involved in regulating cellular pH. CAIX expression is restricted to very few normal tissues, in particular the membranes of gastric mucosal epithelial cells. Under hypoxic conditions, the transcription factor HIF-1 transactivates the CA9 gene, resulting in expression of the CAIX protein in the hypoxic cells. Due to its stability, cell surface transmembrane localization and rapid increase in protein level in response to HIF-1 alpha accumulation, CAIX is an excellent biomarker of hypoxic regions in many solid tumors. CAIX has been considered one of the best cellular biomarkers of hypoxia, and recent studies have suggested that CAIX expression may be a valuable prognostic indicator for overall survival.


Tumor hypoxia has recently been proposed as a target for cancer therapy. The strategies for this type of therapy include developing drugs that are activated under hypoxic conditions and taking advantage of the selective induction of HIF under hypoxic conditions to develop gene therapies. Treatments that can exploit the unique features of hypoxic tumors may one day change this negative prognostic indicator into one that is advantageous for targeted treatments.


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