Interfering with CCL2 and CCR2 to limit tumor growth

描述（由申请人提供）：肿瘤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。已知具有血管生成活性的趋化因子如CCL 2/MCP-1和CXCL 2/MIIP-2由乳腺肿瘤荷瘤小鼠的T淋巴细胞表达。MMP-9在侵袭性转移性乳腺癌中高度表达。我们以前已经表明，CCL 2诱导表达MMP-9的T淋巴细胞的乳腺癌荷瘤小鼠。我们有证据表明，CCL 2诱导CCL 2和CXCL 2的表达，但抑制干扰素-γ（IFN-γ）的产生。其是T淋巴细胞参与免疫应答的所有方面的关键细胞因子。因此，我们假设，无论是CCL 2或其受体CCR 2沉默将减少血管生成分子和MMP-9的生产，而增加IFN-？产生，导致肿瘤生长和转移减少，免疫应答增强。使用一个很好的特点转移性小鼠乳腺癌模型，DA-3乳腺癌，我们已经报告减少IFN-？而CCL 2/MCP-1和MMP-9水平升高。在这个肿瘤系统中，我们最近也观察到了CXCL 2的诱导。此外，我们的初步研究表明，T淋巴细胞表达CCR 2。由于它是已知的，CCL 2通过其受体CCR 2相互作用，我们假设，CCL 2和/或CCR 2的沉默将导致通过抑制血管生成和MMP分泌和更高的IFN-？程度.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，CCL 2和CCR 2可能是抑制乳腺肿瘤的下一组新靶点。 公共卫生相关性：已经发现炎性趋化因子CCL 2促进肿瘤生长，并且肿瘤的侵袭行为与CCL 2相关，因为CCL 2可以抑制干扰素-γ产生，但诱导血管生成和基质降解分子的产生。使用乳腺癌的体内模型，我们发现肿瘤诱导T淋巴细胞群体产生CCL 2。由于T淋巴细胞存在于乳腺肿瘤中并能分泌CCL 2，我们假设CCL 2基因沉默将对宿主产生有利的影响。乳腺癌的发病率在美国仍然很高。靶向治疗的有限选择为确定新的、可调节的选择性分子靶点提供了强有力的理由，这些分子靶点提供了化学预防的潜力。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.