Tumor Microenvironment in Cancer Progression

癌症进展中的肿瘤微环境

基本信息

批准号：
10262289
负责人：
Rosandra Kaplan
金额：
$ 67.68万
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/10262289
关键词：
Acute Lymphocytic Leukemia Adhesions Adjuvant Adult Area Biology Blood Circulation Blood Vessels Bone Marrow Breast Carcinoma CSF1R gene Cancer Cell Growth Cell Communication Cell Compartmentation Cell Line Cell Survival Cells Cessation of life Characteristics Childhood Lymphoma Childhood Rhabdomyosarcoma Clinical Colon Carcinoma Data Disease Distant Endothelial Cells Environment Event Ewings sarcoma Extracellular Matrix FLT3 gene Fibroblasts Gene Proteins Genes Goals Growth Hematopoietic Hematopoietic Stem Cell Mobilization Hematopoietic stem cells ITGAM gene Immune Immune Evasion Immunosuppression Individual Inflammation Investigation Lead Malignant Neoplasms Malignant neoplasm of gastrointestinal tract Malignant neoplasm of lung Mediating Metalloproteases Modeling Molecular Myelogenous Myeloid Cells Myeloid-derived suppressor cells Neoplasm Metastasis Neuroblastoma Pathway interactions Patients Pediatric Neoplasm Pericytes Pharmaceutical Preparations Physiological Play Population Primary Neoplasm Proteins Rhabdomyosarcoma Role Sampling Seeds Signal Transduction Site Soil Stromal Cells Stromal Neoplasm T-Lymphocyte Tissues Tumor-Derived Vascular Endothelial Growth Factor Receptor-1 Vascular Endothelial Growth Factors Work angiogenesis anticancer research arginase cancer therapy cancer type design exosome genetic manipulation hematopoietic stem cell niche human tissue lung Carcinoma malignant breast neoplasm medulloblastoma melanoma metastatic process mouse model neglect neoplastic cell neurofibroma novel novel strategies osteosarcoma prevent recruit response scaffold small molecular inhibitor stem cell biology stem cell niche stem cells therapy design transcription factor translational study tumor tumor growth tumor microenvironment tumor progression

项目摘要

We have established that during primary tumor growth there is a formation of a niche environment in distant tissue sites that promote metastatic progression. This pre-metastatic tissue has an influx of bone marrow-derived cells including populations of myeloid hematopoietic cells, which provide factors such as matrix metalloproteases to remodel extracellular matrix and pro-growth and survival signals such as VEGF and arginase to support the colonizing disseminated tumor cells. These sites are created as a systemic response to tumor progression. Using syngeneic cells lines that have a high spontaneous metastatic rate, we have identified unique changes within the bone marrow microenvironment that lead to mobilization of bone marrow-derived hematopoietic stem and progenitor cells that are recruited to the pre-metastatic niche in multiple tumor models including E0771 breast carcinoma, 76-9 and M3-9M pediatric rhabdomyosarcomas and B16 melanoma. Previously we have shown that CD11b myeloid cells expressed VEGFR1 in the pre-metastatic tissue. We have now discovered these cells are hematopoietic progenitor cells that become a unique myeloid population that alter the local immune environment favoring immune evasion similar to sanctuary sites in stem cell niches (Giles et al Cancer Research 2016). We are currently investigating the role of immune suppression in creation of pre-metastatic and early metastatic niche and the means of reprogramming this immune suppression to limit metastasis. These cells that are immune suppressive myeloid cells derived from mobilized hematopoietic stem and progenitor cells from the bone marrow play a role in regulating tumor specific T cells. We have also been able to manipulate metastatic progression by altering these unique bone marrow-derived cell enriched areas. We have new data demonstrating that the pre-metastatic niche has similar features to physiological stem cell niches in order to promote distant tumor cell survival. We have found that the localized tumor prior to established metastasis 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 have found that there are changes that occur in the bone marrow microenvironment in response to tumor secreted factors that induce the myeloid skewing and expansion of hematopoietic progenitor cells that we have seen during tumor progression (Giles et al Cancer Research 2016). Targeting the skewing to prevent the expansion in hematopoietic progenitor cells and myeloid cells may be a way to reset this maladaptive response to a growing tumor and prevent metastatic progression. We have on-going investigations examining the small molecular inhibitor PLX3397 that targets CSF1R found on myeloid cells, cKit and FLT3-ITD which we have determined that when the drug is given in the adjuvant setting can limit metastatic progression in tumor bearing hosts. In addition to investigations into the recruited hematopoietic progenitor bone marrow derived cell populations that become immune suppressive cells in pre-metastatic sites, we continue to investigate the essential changes in stromal cells including pericytes, vascular cells and fibroblasts as well as the extracellular matrix in the pre-metastatic and metastatic niche. We have established several lineage tracing models to better track and characterize these stromal cell populations as well as genetically manipulate key genes within specific cell populations. Using these models, we can interrogate the function of specific proteins to these cells and their role in the metastatic process. A specific transcription factor KLF4 we have discovered is critical to mediating this stromal cell plasticity. These stromal cells that become activated create a distinct extracellular matrix that support disseminated tumor cell survival. We are currently investigating the role of tumor conditioned media and tumor derived exosomes in making local changes in the stromal cell compartment and matrix that provides the scaffolding for bone marrow-derived cells and are essential component of the pre-metastatic niche. We have identified two critical cellular pathways in pre-metastatic niche formation related to inflammation and stem cell biology including hematopoietic cells and stromal cell populations. Understanding the activation of these stem cell- and inflammation- related pathways in the metastatic process are an active area of investigation. Using stem cell niche biology to better understand how cancer spreads has begun to allow us to uncover new targets for preventing the necessary cell-cell communication that provides a conducive environment for disseminated cancer cell growth.

我们已经确定，在原发性肿瘤生长过程中，远处组织部位会形成促进转移进展的利基环境。这种转移前组织大量涌入骨髓源性细胞，包括骨髓造血细胞群，这些细胞提供基质金属蛋白酶等因子来重塑细胞外基质，并提供促生长和存活信号（例如 VEGF 和精氨酸酶）来支持定植播散性肿瘤细胞。这些位点是作为对肿瘤进展的全身反应而产生的。使用具有高自发转移率的同基因细胞系，我们发现了骨髓微环境内的独特变化，这些变化导致骨髓源性造血干细胞和祖细胞的动员，这些细胞被招募到多种肿瘤模型中的转移前生态位，包括E0771 乳腺癌、76-9 和 M3-9M 儿童横纹肌肉瘤和 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是造血祖细胞，它们成为独特的骨髓细胞群，改变局部免疫环境，有利于类似于干细胞生态位中的避难所位点的免疫逃避（Giles et al Cancer Research 2016）。我们目前正在研究免疫抑制在转移前和早期转移生态位创建中的作用，以及重新编程这种免疫抑制以限制转移的方法。这些细胞是源自骨髓的动员造血干细胞和祖细胞的免疫抑制性骨髓细胞，在调节肿瘤特异性 T 细胞中发挥作用。我们还能够通过改变这些独特的骨髓来源细胞富集区域来控制转移进展。我们有新的数据表明，转移前的微环境与生理干细胞微环境具有相似的特征，以促进远处肿瘤细胞的存活。我们发现，在发生转移之前的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。我们发现，在肿瘤进展过程中，我们已经看到，肿瘤分泌因子会导致骨髓微环境发生变化，这些变化会诱导造血祖细胞的骨髓偏斜和扩张（Giles 等癌症研究 2016）。针对这种倾斜以防止造血祖细胞和骨髓细胞的扩张可能是重置这种对生长肿瘤的适应不良反应并防止转移进展的一种方法。我们正在进行研究，检查针对骨髓细胞、cKit 和 FLT3-ITD 上发现的 CSF1R 的小分子抑制剂 PLX3397，我们已经确定，当在辅助环境中给予该药物时，可以限制荷瘤宿主的转移进展。除了研究招募的造血祖细胞骨髓来源的细胞群在转移前成为免疫抑制细胞外，我们还继续研究基质细胞（包括周细胞、血管细胞和成纤维细胞）以及细胞外基质的基本变化。转移前和转移生态位。我们建立了几种谱系追踪模型，以更好地追踪和表征这些基质细胞群，并对特定细胞群内的关键基因进行遗传操作。使用这些模型，我们可以探究特定蛋白质对这些细胞的功能及其在转移过程中的作用。我们发现的一种特定转录因子 KLF4 对于介导这种基质细胞可塑性至关重要。这些被激活的基质细胞产生独特的细胞外基质，支持播散性肿瘤细胞的存活。我们目前正在研究肿瘤条件培养基和肿瘤源性外泌体在基质细胞区室和基质发生局部变化中的作用，基质细胞区室和基质为骨髓源性细胞提供支架，并且是转移前生态位的重要组成部分。我们已经确定了与炎症和干细胞生物学（包括造血细胞和基质细胞群）相关的转移前生态位形成中的两条关键细胞途径。了解转移过程中这些干细胞和炎症相关途径的激活是一个活跃的研究领域。利用干细胞生态位生物学更好地了解癌症如何扩散，使我们能够发现新的目标，以防止必要的细胞间通讯，从而为扩散的癌细胞生长提供有利的环境。