Interfering with CCL2 and CCR2 to limit tumor growth

干扰 CCL2 和 CCR2 以限制肿瘤生长

• 批准号: 7914760
• 负责人: VIJAYA L IRAGAVARAPU-CHARYULU
• 金额: $ 16.03万
• 依托单位: FLORIDA ATLANTIC UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-08-01 至 2011-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7914760
• 关键词: Affinity; Aggressive behavior; Angiogenesis Inhibition; Biological Assay; Bone Marrow Neoplasms; Breast Adenocarcinoma; Breast Cancer Model; Breast Cancer Treatment; CCL2 gene; CXCL2 gene; Cells; Chemoprevention; Chemotaxis; Complex; Data; Detection; Dose; Effectiveness; Endothelial Cells; Enzyme-Linked Immunosorbent Assay; Flow Cytometry; Gelatin Zymography; Gelatinase B; Gene Silencing; Genes; Genetic Transcription; Immature Monocyte; Immune; Immune response; Immunohistochemistry; Immunosuppressive Agents; In Vitro; Inflammation; Inflammatory; Injection of therapeutic agent; Interferon Type II; Interferons; Kinetics; Leukocytes; Ligands; Link; Liver; Lung; Lymphocyte Function; Mammary Neoplasms; Matrix Metalloproteinases; Measurement; Mediating; Messenger RNA; Methods; Microscopic; Molecular Target; Monocyte Chemoattractant Protein-1; Mus; Neoplasm Metastasis; Outcome; Peritoneal; Population; Production; Proteins; RNA; Recruitment Activity; Reporting; Reverse Transcriptase Polymerase Chain Reaction; Serum; Site; Small Interfering RNA; Staging; Surface; System; T-Lymphocyte; Tail; Techniques; Technology; Testing; Translations; Tube; United States; Veins; Western Blotting; angiogenesis; atelocollagen; base; beta-Chemokines; chemokine; chemokine receptor; cytokine; immune function; in vivo; in vivo Model; mRNA Expression; macrophage; malignant breast neoplasm; migration; monocyte chemoattractant protein 1 receptor; novel; prevent; protein expression; public health relevance; receptor; response; success; tumor; tumor growth; tumor progression

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.

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。具有血管生成活性的趋化因子如CCL2/MCP-1和CXCL2/MIIP-2在乳腺荷瘤小鼠的T淋巴细胞中表达。MMP-9在侵袭性转移性乳腺癌中高表达。我们之前已经证明CCL2诱导乳腺肿瘤小鼠T淋巴细胞表达MMP-9。我们有证据表明，CCL2诱导CCL2和CXCL2的表达，但抑制T淋巴细胞产生干扰素- γ (IFN- γ)，干扰素- γ是一种重要的细胞因子，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将减少血管生成分子和MMP-9的产生，同时增加IFN-？产生，导致肿瘤生长和转移减少，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，即DA-3乳腺腺癌，我们报道了IFN-？CCL2/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CXCL2的诱导作用。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，我们假设CCL2和/或CCR2的沉默将通过抑制血管生成和MMP分泌以及更高的IFN-？的水平。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可能是抑制乳腺肿瘤的下一组新靶点。