G-CSF inhibition as a colorectal cancer therapy

G-CSF 抑制作为结直肠癌治疗

• 批准号: 9152355
• 负责人: Ellen J. Beswick
• 金额: $ 34.66万
• 依托单位: UNIVERSITY OF NEW MEXICO HEALTH SCIS CTR
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-07-06 至 2021-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9152355
• 关键词: Antibodies; Bone Marrow; CD8B1 gene; CSF3 gene; Cancer Etiology; Cancer Model; Cell Proliferation; Cells; Cessation of life; Chemotherapy-Oncologic Procedure; Colitis; Colony-Stimulating Factor Overexpression; Colony-Stimulating Factor Receptors; Colorectal Cancer; Colorectal Neoplasms; Data; Development; Diagnosis; Disease; Disease Outcome; Granulocyte Colony-Stimulating Factor; Human; Immune; Immune response; Immune system; Individual; Inflammatory; Interleukin-10; Knowledge; Laboratories; Lead; Lytic; Malignant Neoplasms; Malignant neoplasm of gastrointestinal tract; Metastatic Neoplasm to Lymph Nodes; Metastatic Neoplasm to the Liver; Mus; Myeloid Cells; Natural Killer Cells; Neoplasm Metastasis; Pathology; Pathway interactions; Patients; Population; Process; Production; Regulatory T-Lymphocyte; Risk; Role; Sampling; T cell response; T-Lymphocyte; Testing; Therapeutic; Tissue Sample; Tissues; Tumor Immunity; Tumor Tissue; United States; cancer stem cell; cancer therapy; clinical care; colitis associated cancer; cytokine; cytotoxic; fighting; human tissue; improved; knock-down; macrophage; metastatic colorectal; migration; mortality; mouse model; neoplasm regression; neoplastic cell; neutrophil; new therapeutic target; novel; novel therapeutics; overexpression; prevent; response; stem; success; translational approach; tumor; tumor growth; tumor immunology; tumor microenvironment; tumor progression

Project Summary: Colorectal cancer conveys a high mortality risk as the second most common cause of cancer in the US. While newer chemotherapy regimens have improved survival, 37% of all patients diagnosed with CRC in the United States will die of this disease. Clearly, new tumor targets are needed to develop improved treatment approaches. Harnessing natural anti-tumor immunity is a promising approach to develop new therapies. develop new therapies. We have found that one potential way to do this is by blocking a critical cytokine that induces tumor cell proliferation and invasion along with inhibitory immune responses in CRC. Granulocyte colony-stimulating factor (G-CSF) is a key cytokine present in 88% of human colorectal tumors. Blockade of this cytokine in a mouse model of colorectal cancer led to activation of protective immune responses and neoplasm regression. G-CSF may induce regulatory T cell accumulation and potent inhibition of cytotoxic cell responses. Since these responses may have critical tumor promoting functions, we hypothesize that G-CSF blockade is protective in CRC by inhibiting tumor progression and inducing anti-tumor immunity. To test this hypothesis, the following Specific Aims will be completed: Specific Aim 1: Delineate the role of G-CSF/G-CSFR in colorectal cancer progression and the potential of blockade as a therapeutic approach. We hypothesize that G-CSF/G-CSFR inhibition will prevent or regress colorectal cancer metastasis. This will be examined by knocking down G-CSF/G-CSFR in tumor cells, overexpressing G-CSF/G-CSFR in tumor cells, and employing therapeutic approaches in mouse models of CRC metastasis. Human CRC tissues will be examined for an association with G-CSF/G-CSFR expression and metastasis. Specific Aim 2: Delineate the role of G-CSF/G-CSFR inhibition on enhancing anti-tumor immunity to protect against CRC progression. We hypothesize that G-CSF induces a tumor immune evasive microenvironment by inducing immune cell IL-10 production and by inhibiting cytotoxic immune cell responses. The direct effects of G-CSF on myeloid cell and T cell IL-10 production will be examined. The direct effects of G-CSF on NK and CD8+ T cells will be examined along with indirect effects through modulation of IL-10 in the tumor microenvironment will be examined. The ability of G-CSF to inhibit NK cell and CD8+ T cell tumor lytic function will be assessed. Human CRC and liver metastasis tissues with high vs low G-CSF/G-CSFR expression will be examined for NK and CD8+ T cell activity. Thus, for this project, we will examine multiple mechanisms of G-CSF blockade on tumor proliferation and invasion, activation of protective myeloid and T cell responses, and test blockade of this pathway in an invasive colorectal cancer model and in human tumor tissues in translational approaches that could lead to a new treatment for colorectal cancer.

项目总结: