Fig. 7.

From the extracellular matrix to HIF and from HIF to the extracellular matrix. a The extracellular matrix (ECM) is an essential component of the physicochemical environment of the cell, and includes fibrous proteins, glycoconjugates, growth factors and hormones. The chemical composition of the ECM can impact on HIF through growth factor stimulation. It has been shown that growth factors, by activating phosphatidylinositol-3-kinase (PI3K), can target mTOR and consequently HIF. As discussed above, the action of mTOR on HIF is a subject of debate. Essentially two options have been proposed: inhibition of HIF translation and/or inhibition of proteasomal degradation. Both converge to activate HIF. Growth factors could also activate HIF through the extracellular-regulated kinase (ERK) pathway. It has been proposed that phosphorylation of HIF by ERK could indirectly increase HIF activity by inhibiting the export of this transcription factor from the nucleus. As a consequence the activation of HIF target genes would be more efficient when HIF is phosphorylated. Moreover the vasoactive hormone angiotensin II has been shown to promote HIF-1α transcription through a protein kinase B (PKB) dependent mechanism. Finally, the physical density of the ECM could also indirectly influence the HIF pathway by modulating the oxygen diffusion length (not shown here). b A variety of HIF-induced genes have been shown to directly play a role on cell motility, invasion and extracellular matrix modulation (blue). A hypothetical mechanism for the loss of cell junctions under hypoxia could implicate the HIF-dependent activation of lysyl oxidase-like 2 (LOXL2) leading to stimulation of Snail. This transcriptional inhibitor could then downregulate E-cadherin (E-cad) and promote invasion. However, the subject of the ECM is also linked to other HIF-dependent actions, for instance, extracellular acidification could participate in mechanisms of invasion. Finally, the growth of neo-vessels, under the control of HIF, is also a crucial element in the penetration of cancer cells into the circulation. Autocrine motility factor (AMF); chemokine receptor CXCR4; receptor tyrosine kinase c-Met; lysyl oxidase (LOX); matrix metalloproteases (MMP)