In contrast, the chemokine CXCL12, expressed at the surface of normal intestinal epi thelium, is decreased in tumor selleck chem inhibitor tissues, such as colon or breast carcinomas. As previously shown in glio blastoma cells, hypoxia and HIF 1 can regulate the ex pression of CXCR4 in colon Inhibitors,Modulators,Libraries cancer cell lines. Others have shown that hypoxia increases CXCR4 expression through HIF 1 activation and that HIF 1 enhances the expression and function of CXCR4 in normal cells mono cytes, macrophages and endothelial cells and in tumor cells. In our hands, siRNAs targeting HIF 1 prevented both HIF 1 and CXCR4 upregulation under hypoxic conditions. In human Inhibitors,Modulators,Libraries colon carcinomas, we observed that CXCR4 expression significantly increased during tumor progres sion as it increased from stages 0 II to III IV, whereas for CXCR7, a significant increase was observed between early stages and liver metastases.

Knowing that metastases develop from circulating tumor cells escaping the primary site of cancer during their passage in the blood stream, these cells switch from a hypoxic to a normoxic en vironment and escape regulation by HIF 1. Fitting with this hypothesis, we demonstrated for the first Inhibitors,Modulators,Libraries time that after a transient Inhibitors,Modulators,Libraries passage through hypoxia, which leads to the upregulation of CXCR4 expression, the receptor protein level remains high at the cell membrane even when the cells returned back to normoxia. The mainten ance of high CXCR4 level could help circulating cells to home in organs Inhibitors,Modulators,Libraries expressing high levels of the CXCL12 ligand, and with the resident CXCR7 may aid endothelial extravasation favoring metastasis development.

Dur ing embryogenesis, it has been shown that CXCR7 is only expressed in the trailing cells of the primordium and is re quired to provide migration directionality. The CXCR4 CXCL12 interaction provokes calcium mobilization and activation of multiple signaling path ways, including selleck bio PI3K Akt, PLC Protein kinase C and Erk Ras. We show that hypoxia alone rapidly ac tivated the PI3K Akt and Erk Ras pathways and that this effect was amplified under short term CXCL12 stimula tion. Interestingly, part of the PI3K Akt activation was induced by the interaction of CXCL12 with CXCR4, as it was blocked by siRNA targeting CXCR4, but not by its interaction with CXCR7. As PI3K Akt activation could not be totally abolished with siRNA targeting CXCR4, other receptors may participate in the activation of this oncogenic pathway, although at present no other recep tors have been shown to interact with CXCL12. Neverthe less, the short term activation of the oncogenic pathway may be sufficient to initiate the migration process ob served when cells are switched to hypoxia, and this activa tion could be blocked with a siRNA against CXCR4.