Papillary thyroid cancer and tumor-associated macrophages

描述(由申请人提供)：这项建议的目的是利用这笔为期5年的培训补助金来获得成为独立研究人员所需的知识和技能。PI将由詹姆斯·费金博士指导，他是纪念-斯隆·凯特琳癌症中心甲状腺癌生物学方面的领先科学家。 本研究旨在探讨肿瘤相关巨噬细胞(TAMs)在甲状腺癌进展中的作用。多条证据表明，肿瘤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，矛盾地改变宿主抗肿瘤免疫反应，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。在晚期甲状腺癌中，TAMs与侵袭性和存活率降低有关。这表明TAMs促进了甲状腺癌的进展。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。在这个模型中，甲状腺癌类似于人类，被TAMs浸透，肿瘤进展为侵袭、低分化癌症和转移。我们的假设是TAMs促进了甲状腺癌的进展。我们将使用几种基因方法在甲状腺癌小鼠模型中去除TAMs来验证这一假说。在初步数据中，我们显示甲状腺癌中TAMs的缺失损害了甲状腺癌的发生和发展。这可能部分是通过依赖的肿瘤间质与肿瘤相关成纤维细胞(CAF)和周细胞的扩张而实现的，我们将在初步数据中展示这一点。我们的具体目标是研究甲状腺癌组织中TAMS的动力学和分化状态，并确定募集和/或分化所需的趋化因子。我们将研究TAMS对骨髓和甲状腺CAF前体细胞的募集、分化和/或增殖的影响。最后，研究TAMS对甲状腺癌来源的CAF和周细胞的直接作用。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。然后，这种知识和理解可以用来为那些对传统治疗无效的患者开发新的癌症治疗目标。 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招募和相互作用来确定甲状腺癌发病的潜在机制。然后，这种知识和理解可以用来为那些对传统治疗无效的患者开发新的癌症治疗目标。

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.