Tumor Microenvironment in Cancer Progression

癌症进展中的肿瘤微环境

基本信息

批准号：
8553110
负责人：
Rosandra Kaplan
金额：
$ 48.81万
依托单位：
DIVISION OF BASIC SCIENCES - NCI
依托单位国家：
美国
项目类别：
财政年份：
资助国家：
美国
起止时间：
至
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/8553110
关键词：
Acute Lymphocytic Leukemia Adhesions Adult Area Binding Bioinformatics Blood Circulation Bone Marrow Breast Adenocarcinoma Breast Carcinoma Cell Line Cell Survival Cell physiology Cells Cessation of life Characteristics Childhood Lymphoma Childhood Rhabdomyosarcoma Clinical Colon Carcinoma Conditioned Culture Media Core Facility Disease Distant Endothelial Cells Environment Event Ewings sarcoma Excision Extracellular Matrix Fibroblasts Fibronectins Gene Proteins Goals Growth Hematopoietic Hematopoietic Stem Cell Mobilization Hematopoietic stem cells Homing ITGAM gene Immune Individual Investigation Malignant Neoplasms Malignant neoplasm of lung Medicine Membrane Metalloproteases Modeling Molecular Mus Myelogenous Myeloid Cells Nature Neoplasm Metastasis Neuroblastoma Operative Surgical Procedures Patients Pediatric Neoplasm Phenotype Physiological Population Primary Neoplasm Publications Publishing Recruitment Activity Recurrence Rhabdomyosarcoma Role Sampling Seeds Signal Transduction Site Soil Stem cells Stromal Neoplasm Time Tissues Tumor-Derived Vascular Endothelial Growth Factor Receptor-1 Work Wound Healing angiogenesis breast lumpectomy cancer therapy cancer type chemokine design human tissue lung Carcinoma malignant breast neoplasm medulloblastoma melanoma metastatic process mouse model neglect neoplastic cell novel novel strategies particle prevent progenitor response stem cell niche therapy design translational study tumor tumor growth tumor progression

项目摘要

Summary: We have established that developing primary tumors can establish a pre-metastatic niche, which is a distant microenvironment that contributes to effective metastatic progression. We have delineated key components essential to creating this conducive microenvironment including activation of fibroblasts, increased expression of fibronectin and resultant homing of bone marrow-derived cells. The pre-metastatic tissue has an influx of bone marrow-derived cells including VEGFR1 expressing cells, CD11b myeloid cells and myeloid progenitors which provide factors such as matrix metalloproteases to remodel extracellular matrix and pro-growth and survival signals to the colonizing metastatic tumor cells. These sites are created as a systemic response to tumor progression. We have shown that injecting mice with tumor-conditioned media containing tumor-derived exosomes, which are small membrane-bound particles, can induce pre-metastatic niche formation. These microvesicles as well as tumor -secreted chemokines can induce bone marrow-derived cell recruitment to pre-metastatic sites and serve to induce specific pro-vasculogenic phenotype in the bone marrow-derived cells and provide a pro-survival environment for tumor cells. This work was recently published (Nature Medicine 2012). Over the past year, using syngeneic cells lines that have a high spontaneous metastatic rate, we have identified a unique population of bone marrow-derived VEGFR1-expressing cells that are recruited to the pre-metastatic niche in multiple tumor models including E0771 breast carcinoma, 76-9 pediatric rhabdomyosarcoma and B16 melanoma. Previously we have shown that Cd11b myeloid cells expressed VEGFR1 in the pre-metastatic tissue. We have now discovered a subset of these cells are not only myeloid but a unique population that alter the local immune environment favoring immune evasion similar to sanctuary sites in stem cell niches. We are currently investigating the role of VEGFR1 signaling in these cells and the pro-metastatic features of this population.The pre-metastatic niche appears to have similar features to physiological stem cell niches in order to promote distant tumor cell survival. We have found that the localized tumor prior to evidence of metastatic spread is activating the hematopoietic stem cell niche within the bone marrow and inducing proliferation of hematopoietic stem cells and mobilization of these cells into the circulation. We also have evidence that the bone marrow-derived cell mobilization is enhanced in response to surgical resection of the primary tumor. It is likely surgical resection of the primary tumor enhances wound healing responses that include bone marrow-derived cell activation and mobilization and enhanced pre-metastatic niche formation. We have demonstrated this mobilization in mouse models and in patients undergoing tumor lumpectomy for breast adenocarcinoma. Treatments targeting the tumor microenvironment changes at the time of primary tumor resection may provide a novel approach to prevent metastatic recurrence. We plan to submit this work for publication shortly. In addition to investigations into the recruited cell populations, the transcriptional changes in the pre-metastatic niche are also an active area of investigation. We are working with the bioinformatics core facility to perform transcriptional profiling studies in different metastatic sites.

摘要：我们已经确定，发展中的原发性肿瘤可以建立转移前生态位，这是一种有助于有效转移进展的遥远微环境。我们已经描述了创建这种有利微环境所必需的关键组成部分，包括成纤维细胞的激活、纤连蛋白表达的增加以及由此产生的骨髓来源细胞的归巢。转移前组织大量涌入骨髓源性细胞，包括 VEGFR1 表达细胞、CD11b 骨髓细胞和骨髓祖细胞，它们提供基质金属蛋白酶等因子来重塑细胞外基质，并向定植的转移肿瘤细胞提供促生长和生存信号。这些位点是作为对肿瘤进展的全身反应而产生的。我们已经证明，给小鼠注射含有肿瘤源性外泌体（膜结合的小颗粒）的肿瘤条件培养基，可以诱导转移前生态位的形成。这些微泡以及肿瘤分泌的趋化因子可以诱导骨髓来源的细胞募集至转移前位点并用于在骨髓来源的细胞中诱导特定的促血管生成表型并为肿瘤细胞提供促生存环境。这项工作最近发表（Nature Medicine 2012）。在过去的一年里，我们利用具有高自发转移率的同基因细胞系，鉴定了一个独特的骨髓源性 VEGFR1 表达细胞群，这些细胞被招募到多种肿瘤模型的转移前生态位，包括 E0771 乳腺癌、 76-9 小儿横纹肌肉瘤和 B16 黑色素瘤。之前我们已经证明 Cd11b 骨髓细胞在转移前组织中表达 VEGFR1。我们现在发现这些细胞的一个子集不仅是骨髓细胞，而且是一个独特的群体，可以改变局部免疫环境，有利于免疫逃避，类似于干细胞生态位中的避难所。我们目前正在研究 VEGFR1 信号传导在这些细胞中的作用以及该群体的促转移特征。转移前生态位似乎与生理干细胞生态位具有相似的特征，以促进远处肿瘤细胞的存活。我们发现，在出现转移扩散的证据之前，局部肿瘤正在激活骨髓内的造血干细胞生态位，并诱导造血干细胞增殖并将这些细胞动员到循环中。我们还有证据表明，原发肿瘤手术切除后，骨髓来源的细胞动员得到增强。原发肿瘤的手术切除可能会增强伤口愈合反应，包括骨髓源性细胞的激活和动员以及增强转移前生态位的形成。我们已经在小鼠模型和接受乳腺癌肿瘤切除术的患者中证明了这种动员。针对原发肿瘤切除时肿瘤微环境变化的治疗可能提供一种预防转移复发的新方法。我们计划很快提交这项工作以供出版。除了对招募的细胞群的研究之外，转移前生态位中的转录变化也是一个活跃的研究领域。我们正在与生物信息学核心设施合作，在不同的转移部位进行转录谱研究。