Abstract
2798
The chemokine CXCL12 is abundantly expressed in the bone marrow microenvironment, and plays an important role in hematopoietic stem cell homing. Cancer cells expressing the CXCR4 receptor may also use this mechanism to metastasize to bone and other organs. CXCR4 expression was compared in a panel of twelve human breast cancer cell lines, and found to be highly variable. High HER2 expression has been associated with CXCR4 expression. For example, MDA-MB-361 cells have high HER2 and high CXCR4 expression. However, DU4475 cells, which also express high levels of CXCR4 have minimal HER2 expression, suggesting heterogeneity in regulation of CXCR4 among different breast cancers. CXCL12 was detected in the supernatants of two breast cancer cell lines, T47D and Hs578T, at relatively low concentrations (40 and 150 pg/ml/105 cells, respectively, measured by ELISA). In contrast, immortalized mouse bone derived endothelial cells released >6,0000 pg/ml/105 cells. This was 13-fold more than CXCL12 concentrations measured in culture supernatants from mouse lung and brain endothelial cells. Mouse bone marrow stroma-derived cells also released high levels of CXCL12 in culture supernatants (~3,000 pg/ml/105 cells). CXCL12 stimulated migration of CXCR4-expressing SUM149 breast cancer cells, but had minimal effect on cell growth and survival in low-serum conditions. CXCL12 stimulated ERK1/2 phosphorylation in serum-starved SUM149 cells, and treatment with the MEK inhibitor U0126 abrogated CXCL12- stimulated migration. Migration of breast cancer cells towards bone stromal cell- or endothelial cell-conditioned media, or through monolayers of bone endothelial cells was significantly reduced by the CXCR4 antagonist AMD3100. Identifying key mediators of interactions between malignant and stromal cells may provide additional therapeutic targets for breast cancer bone metastasis. (Supported by an award from the Susan G. Komen Breast Cancer Foundation).
98th AACR Annual Meeting-- Apr 14-18, 2007; Los Angeles, CA
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