Molecular aspects of tumour hypoxia

Abstract

Hypoxia is an important feature of the microenvironment of a wide range of solid tumours. Its critical role in radio- and chemoresistance and its significance as an adverse prognostic factor have been well established over the last decades. On a cellular level, hypoxia evokes a complex molecular response with a central role for the HIF-1 pathway. The cellular processes under control of HIF-1 contain important prognostic information and comprise potential candidates for directing hypoxia-modifying therapies. This review will provide an overview of the current knowledge on the molecular aspects of tumour hypoxia and the link to clinical practice.

Figure 1

Cellular adaptation to hypoxia. The bars show the approximate hypoxic values below which cellular responses gradually change. Figure adapted from Koumenis and Wouters (2006) and Hockel and Vaupel (2001).

Figure 2

Photomicrographs of two human squamous‐cell carcinoma xenograft cell lines (SCCNij51 and SCCNij58) after immunofluorescent staining. The images show the differences in colocalisation of the exogenous marker pimonidazole (A and B) and three endogenous hypoxi a‐related markers: CAIX (C and D), GLUT‐1 (E and F) and GLUT‐3 (G and H) (all in green), relative to the vasculature (in red).

Figure 3

Schematic representation of the HIF‐1 pathway. Under normoxic conditions HIF‐1α is hydroxylated and rapidly degraded (A). Under hypoxic conditions the HIF‐1 complex is stabilised and initiates the transcription of its target genes. EGFR can activate HIF‐1α in an oxygen‐independent way (B).

Figure 4

The uPA/uPAR system; its activation, the effects and the inhibitory action of PAI‐1.

Figure 5

The three main mediators in the unfolded protein response (UPR). PERK, IRE1 and ATF6 effectuate a decrease in protein synthesis and an upregulation of UPR and ER stress genes.