Hypoxia increases the metastatic ability of breast cancer cells via upregulation of CXCR4

Abstract

BackgroundChemokine SDF1α and its unique receptor CXCR4 have been implicated in organ-specific metastases of many cancers including breast cancer. Hypoxia is a common feature of solid tumors and is associated with their malignant phenotype. We hypothesized that hypoxia would upregulate CXCR4 expression and lead to increased chemotactic responsiveness to its specific ligand SDF1α.MethodsThree breast cancer cell lines MDA-MB-231, MCF7 and 4T1 were subjected to 48 hrs of hypoxia or normoxia. Cell surface receptor expression was evaluated using flow cytometry. An extracellular matrix invasion assay and microporous migration assay was used to assess chemotactic response and metastatic ability.ResultsCXCR4 surface expression was significantly increased in the two human breast cancer cell lines, MDA-MB-231 and MCF7, following exposure to hypoxia. This upregulation of CXCR4 cell surface expression corresponded to a significant increase in migration and invasion in response to SDF1-α in vitro. The increase in metastatic potential of both the normoxic and the hypoxic treated breast cancer cell lines was attenuated by neutralization of CXCR4 with a CXCR4 neutralizing mAb, MAB172 or a CXCR4 antagonist, AMD3100, showing the relationship between CXCR4 overexpression and increased chemotactic responsiveness.ConclusionsCXCR4 expression can be modulated by the tissue microenvironment such as hypoxia. Upregulation of CXCR4 is associated with increased migratory and invasive potential and this effect can be abrogated by CXCR4 inhibition. Chemokine receptor CXCR4 is a potential therapeutic target in the adjuvant treatment of breast cancer.

Hypoxia induces CXCR4 expression and biological activity in gastric cancer cells through activation of hypoxia-inducible factor-1α

“…The increase in migratory ability due to hypoxia was abrogated by knockdown of HIF-1α and inhibition of CXCR4. These results are in accordance with previous reports in different types of cancer (16,46) and suggest that upregulation of CXCR4 by HIF-1α in response to hypoxia plays a biological role in gastric cancer cell migration. We previously reported that functional CXCR4 plays an important role in cancer cell migration during normoxia in gastric and gallbladder cancers (18,21), suggesting that the CXCR4/ CXCL12 axis may be significantly involved in cancer progression and may be a potential target for therapeutics that block the interaction between CXCL12 and CXCR4, or that inhibit downstream signaling, in the treatment of cancer.…”

“…Several recent studies provide evidence that hypoxia, primarily acting through HIF-1α, is involved in the upregulation of CXCR4 in carcinomas and hematologic malignancies such as lung, breast cancer and myeloma, with HIF-1α binding directly to the CXCR4 promoter (15,(40)(41)(42)(43)(44)(45). In this study, hypoxia increased CXCR4 protein levels and cell surface expression by activating HIF-1α, thereby supporting previous findings from other cancer cell lines and suggesting that tumor hypoxia plays a crucial role in the regulation of CXCR4 (15,16,41).…”

“…Moreover, the CXCR4 promoter contains four potential hypoxia-response elements upstream of the transcriptional start site, as well as one intra-intronic site (12)(13)(14). CXCR4 is upregulated on monocytes and endothelial cells, as well as tumor-associated macrophages and cancer cell lines, including melanoma and breast cancer cell lines, under hypoxic conditions (7,(15)(16)(17). However, the role of hypoxia in regulating CXCR4 in gastric cancer remains poorly understood.…”

Cryptotanshinone targets tumor-initiating cells through down-regulation of stemness genes expression

“…Recently, CXCR4 was detected on TICs and mRNA levels were found to be significantly higher in this population in comparison to the non-TICs (44)(45)(46)(47)(48). The upregulation of CXCR4 cell surface expression corresponded to a significant increase in EMT in response to SDF1-α in vitro (64,65). In the present study, CT was shown to down-regulate CXCR4 expression in total LNCaP cells and the TIC population; hence, it is possible CT can further regulate TICs by regulating the CXCR4-SDF1 axis and disrupting its ability to interact with the microenvironment.…”

Evidence that β7 Integrin Regulates Hematopoietic Stem Cell Homing and Engraftment Through Interaction with MAdCAM-1

“…It is thus possible that b7 integrin expression on HSCs may directly regulate CXCR4 cell surface expression and/or reduce its internalization. Alternatively, several reports have shown that exposure to hypoxia led to upregulation of CXCR4 expression in a diverse range of cancer cells [36][37][38][39][40][41][42]. Thus, the surface expression of b7 integrin on HSCs may influence HSC locomotion within a specific BM niche, where low oxygen tension may favor the expression of CXCR4.…”