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.
