Tumor progression and metastasis has been linked to immune suppression, angiogenesis and matrix metalloproteinases (MMPs). Chemokines such as CCL2/MCP-1 and CXCL2/MIIP-2 known for their angiogenic activity are expressed by the T lymphocytes of mammary tumor-bearing mice. MMP-9 is highly expressed in aggressive metastatic breast cancers. We have previously shown that CCL2 induces the expression of MMP-9 by the T lymphocytes of mammary tumor-bearing mice. We have evidence that CCL2 induces the expression of CCL2 and CXCL2 but inhibits the production of interferon-gamma (IFN-?) which is a crucial cytokine involved in all aspect of immune response, by the T lymphocytes. Thus, we hypothesize that silencing of either the CCL2 or its receptor CCR2 will decrease the production of angiogenic molecules and MMP-9 while increasing IFN-? production, resulting in decreased tumor growth and metastasis with enhanced immune responses. Using a well characterized metastatic mouse breast cancer model, the DA-3 mammary adenocarcinoma, we have reported decreased IFN-? but increased level of CCL2/MCP-1 and MMP-9. In this tumor system, we have also recently observed the induction of CXCL2. Furthermore, our preliminary studies indicate that T lymphocytes express CCR2. Since it is known that CCL2 interacts through its receptor CCR2, we hypothesize that silencing of CCL2 and/or CCR2 will result in decreased tumor growth and metastasis by inhibition of angiogenesis and MMP secretion and higher IFN-? levels. We believe that selective silencing of chemokines or their receptors will have a favorable outcome towards treatment of breast cancer. Therefore CCL2 and CCR2 might be the next set of novel targets for inhibiting breast tumors. ?
The inflammatory chemokine CCL2 has been found to promote tumor growth and the aggressive behavior of tumors has been linked to CCL2 as CCL2 can inhibit interferon-gamma production but induce production of angiogenic and matrix degrading molecules. Using an in vivo model of breast cancer, we have found that the tumor induces CCL2 production by the T lymphocyte population. As T lymphocytes are found in the mammary tumor and can secrete CCL2, we hypothesized that silencing the CCL2 gene will have a favorable effect on the host. The rates of breast cancer still remain high in the United States. The limited options for targeted treatment provide a strong rationale for identifying new, selective molecular targets that can be modulated offer a potential for chemoprevention. Selective silencing of angiogenic chemokines or their receptors might be the next novel targets for inhibiting breast tumors. ? ? ?
