Interfering with CCL2 and CCR2 to limit tumor growth

描述(申请人提供)：肿瘤的进展和转移与免疫抑制、血管生成和基质金属蛋白酶(MMPs)有关。趋化因子，如CCL2/MCP-1和CXCL2/MIIP-2，以其血管生成活性而闻名，在乳腺癌荷瘤小鼠的T淋巴细胞中表达。基质金属蛋白酶-9在侵袭性转移性乳腺癌中高表达。我们先前已经证明，CCL2可以通过荷瘤小鼠的T淋巴细胞诱导基质金属蛋白酶-9的表达。我们有证据表明，CCL2诱导CCL2和CXCL2的表达，但抑制干扰素-γ的产生。这是一种关键的细胞因子，通过T淋巴细胞参与免疫反应的各个方面。因此，我们假设，沉默CCL2或其受体CCR2会减少血管生成分子和基质金属蛋白酶-9的产生，而增加干扰素-？产生，从而减少肿瘤的生长和转移，增强免疫反应。利用一种具有良好特征的转移性小鼠乳腺癌模型--DA-3乳腺癌，我们报告了干扰素-？而CCL2/MCP-1和基质金属蛋白酶-9水平升高。在这个肿瘤系统中，我们最近也观察到了CXCL2的诱导。此外，我们的初步研究表明，T淋巴细胞表达CCR2。由于已知CCL2通过其受体CCR2相互作用，我们推测沉默CCL2和/或CCR2将通过抑制血管生成和基质金属蛋白酶的分泌以及增加干扰素？级别。我们相信，选择性沉默趋化因子或其受体将对乳腺癌的治疗产生有利的结果。因此，CCL2和CCR2可能是下一组抑制乳腺肿瘤的新靶点。 公共卫生相关性：已发现炎性趋化因子CCL2促进肿瘤生长，肿瘤的侵袭行为与CCL2有关，因为CCL2可以抑制干扰素-γ的产生，但诱导血管生成和基质降解分子的产生。利用乳腺癌的体内模型，我们发现肿瘤通过T淋巴细胞群诱导CCL2的产生。由于在乳腺肿瘤中发现T淋巴细胞能够分泌CCL2，我们假设沉默CCL2基因对宿主有有利的作用。在美国，乳腺癌的发病率仍然很高。靶向治疗的有限选择为确定新的、选择性的分子靶点提供了强有力的理由，这些靶点可以被调节，从而为化学预防提供了潜力。选择性沉默血管生成趋化因子或其受体可能是抑制乳腺肿瘤的下一个新靶点。

DESCRIPTION (provided by applicant): 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. PUBLIC HEALTH RELEVANCE: 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.