Papillary thyroid cancer and tumor-associated macrophages

甲状腺乳头状癌和肿瘤相关巨噬细胞

• 批准号: 7893374
• 负责人: Mabel Ryder
• 金额: $ 16.99万
• 依托单位: SLOAN-KETTERING INST CAN RESEARCH
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-01 至 2015-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7893374
• 关键词: Adoptive Transfer; Bone Marrow; Breast; Cancer Biology; Cancer Model; Cells; Chemotactic Factors; Coculture Techniques; Data; Disease; Event; Fibroblasts; Genetic; Grant; Growth Factor; Home environment; Human; Immune; Immune response; In Vitro; Infiltration; Investigation; Kinetics; Knowledge; Lymphangiogenesis; Lymphatic vessel; Macrophage Colony-Stimulating Factor; Malignant Neoplasms; Malignant neoplasm of cervix uteri; Malignant neoplasm of thyroid; Mediating; Memorial Sloan-Kettering Cancer Center; Mentors; Mesenchymal Stem Cells; Modeling; Mus; Mutation; Myofibroblast; Neoplasm Metastasis; Oncogenic; Papillary; Papillary thyroid carcinoma; Pathogenesis; Patients; Peptide Hydrolases; Pericytes; Phenotype; Population; Prostate; Proteins; Radioactive Iodine; Recruitment Activity; Refractory; Research; Research Personnel; Role; Scientist; Staging; Stromal Neoplasm; Structure; Testing; Thyroid Gland; Training; Transgenic Mice; Tumor Angiogenesis; Tumor Promoters; Tumor-Derived; Undifferentiated; angiogenesis; cancer cell; cancer initiation; cancer therapy; chemokine; density; macrophage; monocyte; mouse model; outcome forecast; progenitor; public health relevance; research study; skills; thyroid neoplasm; tumor; tumor growth; tumor progression; tumorigenesis

DESCRIPTION (provided by applicant): The objective of this proposal is to use this 5-year training grant to acquire the knowledge and skills necessary to become an independent researcher. The PI will be mentored by Dr. James Fagin who is a leading scientist in thyroid cancer biology at Memorial-Sloan Kettering Cancer Center. The purpose of this research is to explore the role of tumor-associated macrophages (TAMs) in thyroid cancer progression. Multiple lines of evidence demonstrate that tumors paradoxically alter the host anti-tumor immune response to promote tumor progression through immune-mediated tumor growth, angiogenesis, lymphangiogenesis, invasion and metastases. We have shown that in human thyroid cancers, TAMs correlate with tumor grade. In advanced stages of thyroid cancer, TAMs correlate with invasion and decreased survival. This suggests that TAMs facilitate thyroid cancer progression. Our lab has several mouse models of Braf- induced thyroid cancers, which is the most common oncogenic event in human thyroid cancers. Thyroid cancers in this model, similar to humans, are infiltrated with TAMs, and tumors progress to invasion, poorly- differentiated cancers and metastases. Our hypothesis is that TAMs facilitate thyroid cancer progression. We will test this hypothesis using several genetic approach to deplete TAMs in thyroid cancer mouse models. In preliminary data, we show that the depletion of TAMs in thyroid cancers impairs thyroid cancer initiation and progression. This may be in part through TAM-dependent tumor stromal expansion with cancer-associated fibroblasts (CAFs) and pericytes, as we will show in preliminary data. Our specific aims are to characterize the kinetics and differentiation status of TAMs in thyroid cancers and determine which chemokines are required for TAM recruitment and/or differentiation. We will examine the effects of TAMs on the recruitment, differentiation and/or proliferation of CAF progenitors from the bone-marrow and thyroid. Finally examine the effects of TAMs directly on thyroid cancer derived CAFs and pericytes. The results of these investigations will help identify potential mechanisms of thyroid cancer pathogenesis through recruitment and interactions of host immune cells. This knowledge and understanding can then be used to develop new targets for cancer therapy for patients whose disease has not responded to traditional treatments. PUBLIC HEALTH RELEVANCE: The results of these investigations will help identify potential mechanisms of thyroid cancer pathogenesis through recruitment and interactions of host immune cells. This knowledge and understanding can then be used to develop new targets for cancer therapy for patients whose disease has not responded to traditional treatments.

描述（由申请人提供）：本提案的目的是利用这5年的培训补助金，以获得必要的知识和技能，成为一名独立的研究人员。PI将由James Fagin博士指导，他是Memorial-Sloan Kettering癌症中心甲状腺癌生物学的领先科学家。 本研究的目的是探讨肿瘤相关巨噬细胞（TAMs）在甲状腺癌进展中的作用。多种证据表明，肿瘤矛盾地改变宿主抗肿瘤免疫应答，以通过免疫介导的肿瘤生长、血管生成、淋巴管生成、侵袭和转移来促进肿瘤进展。我们已经证明，在人类甲状腺癌中，TAM与肿瘤分级相关。在甲状腺癌的晚期阶段，TAM与侵袭和生存率降低相关。这表明TAM促进甲状腺癌进展。我们的实验室有几个Braf诱导的甲状腺癌的小鼠模型，这是人类甲状腺癌中最常见的致癌事件。该模型中的甲状腺癌与人类相似，被TAM浸润，并且肿瘤进展为侵袭、低分化癌症和转移。我们的假设是TAM促进甲状腺癌进展。我们将使用几种遗传方法来测试这一假设，以消除甲状腺癌小鼠模型中的TAM。在初步数据中，我们表明甲状腺癌中TAM的消耗会损害甲状腺癌的发生和进展。这可能部分是通过TAM依赖性肿瘤间质扩张与癌症相关的成纤维细胞（CAF）和周细胞，我们将在初步数据中显示。我们的具体目标是表征甲状腺癌中TAM的动力学和分化状态，并确定TAM招募和/或分化所需的趋化因子。我们将研究TAM对来自骨髓和甲状腺的CAF祖细胞的募集、分化和/或增殖的影响。最后检查TAM直接对甲状腺癌源性CAFs和周细胞的影响。这些研究的结果将有助于通过宿主免疫细胞的募集和相互作用来确定甲状腺癌发病的潜在机制。这些知识和理解可以用于开发癌症治疗的新靶点，以治疗那些对传统治疗没有反应的患者。 公共卫生相关性：这些研究的结果将有助于通过宿主免疫细胞的募集和相互作用来确定甲状腺癌发病的潜在机制。这些知识和理解可以用于开发癌症治疗的新靶点，以治疗那些对传统治疗没有反应的患者。