The diagnostic and therapeutic role of the stromal cell-derived factor (SDF)-1/CXCR4 axis in breast cancer metastasis.

摘要

Breast cancer kills through the process of metastasis. In order to improve the prognosis of patients with breast cancer, a better understanding of the underlying factors driving the metastatic process in patients is required. One theory that helps explain the metastatic process suggests that chemokines, such as stromal cell-derived factor (SDF)-1, are overexpressed in specific distant metastatic organs, such as lung, liver, and bone, and serve to home in cancer cells that express their receptors, like CXCR4. The hypothesis of this thesis is that the SDF-1/CXCR4 axis plays an important role in the process of metastasis in breast cancer, and that this ligand/receptor axis can be exploited in the diagnostics and therapy of breast cancer. The first objective of this thesis was to determine if circulating levels of SDF-1 could predict breast cancer metastasis. We found low levels of plasma SDF-1 to be a strong independent prognostic marker, suggesting that the concentration gradient of low plasma SDF-1 and high SDF-1 expressed in the metastatic organ may be critical in driving cancer cells from the circulation to the target organ. We further determined that the levels of plasma SDF-1 were tumor-independent, identifying the first host-derived blood marker predictive of distant metastasis. The second objective was to determine if tumor expression of CXCR4 could modulate the prognostic effect of plasma SDF-1 levels. We found that patients with tumors that highly expressed the activated form of the receptor, phosphorylated-CXCR4, and low plasma SDF-1 levels had a much poorer prognosis than those patients with either risk factor alone. These results highlighted the importance of the dysfunctional relationship between the tumor and the host in the metastatic process. The third objective assessed the therapeutic potential of targeting CXCR4 with a peptide antagonist in a transgenic mouse model. In combination with an anti-angiogenic agent, targeting CXCR4 resulted in a 40% decrease in primary tumor volume and 75% reduction in distant metastasis. Together, these results suggest the potential role for both plasma SDF-1 as a prognostic tool that may assist in the selection of adjuvant therapy, and tumor CXCR4, as a promising druggable target.