Bone Marrow MSCs/Pericytes: Gatekeepers Controlling Skeletal Metastasis.

骨髓间充质干细胞/周细胞：控制骨骼转移的把关人。

• 批准号: 8690795
• 负责人: Arnold Irwin Caplan
• 金额: $ 31.6万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-08-22 至 2017-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8690795
• 关键词: Address; Adult; Apoptosis; Architecture; Binding; Biochemical; Biological Process; Bioluminescence; Blood Vessels; Bone Marrow; Bone Marrow Stem Cell; Breast Cancer Cell; Cancer cell line; Cells; Clinical; Cytology; Disseminated Malignant Neoplasm; Dissociation; Distant; Endothelial Cells; Engraftment; Excision; Extravasation; Foundations; Future; Gatekeeping; Genetic; Genetic Models; Growth; Histology; Homing; Immune response; In Vitro; Indium; Invaded; Kidney; Kinetics; Liver; Location; Lung; Malignant Neoplasms; Malignant neoplasm of lung; Melanoma Cell; Mesenchymal Stem Cells; Metastatic Neoplasm to the Bone; Metastatic Neoplasm to the Liver; Modeling; Molecular; Molecular Biology; Molecular Mechanisms of Action; Mus; Neoplasm Metastasis; Organ; Osteolysis; Outcome; Pathway interactions; Patients; Pericytes; Physiological; Platelet-Derived Growth Factor; Primary Neoplasm; Prognostic Marker; Property; Prostate; Quality of life; Recruitment Activity; Regulation; Research; Research Design; Research Proposals; Role; Scheme; Serum Markers; Signal Transduction; Skeleton; Specificity; Stromal Cells; Survival Rate; Testing; Therapeutic; Time; Tissues; Tyrosine Kinase Inhibitor; Work; X-Ray Computed Tomography; adult stem cell; angiogenesis; base; bone; bone invasion; cancer cell; cancer therapy; circulating cancer cell; clinically relevant; improved; in vitro Assay; in vivo; in vivo Model; malignant breast neoplasm; melanoma; mortality; new therapeutic target; novel; novel therapeutics; prevent; skeletal; success; therapy design; tool; tumor; tumor growth; tumor microenvironment

DESCRIPTION (provided by applicant): Metastasis is a leading prognostic indicator for cancer survival and a major contributor to cancer mortality. The skeleton is one of the preferred organs for cancer dissemination in various malignancies. Current targeted cancer therapies are designed to alter not only specific biological functions in cancer cells, but also components of the tumor stroma/microenvironment such as blood vessels. Contrary to the established role of pericytes limiting cancer cell dissemination from the primary tumor, the role(s) of these stromal components at the target organ during cancer metastasis are not understood. The main objective of this research proposal is to understand the function of the Bone Marrow (BM) microenvironment, and specifically of its vascular components, in the establishment of skeletal metastasis, based on a novel hypothesis that suggests that BM Mesenchymal Stem Cells (BM-MSCs), as perivascular cells (pericytes), function as gatekeepers controlling cancer cell invasion to the bone. This new hypothesis provides clinically relevant information for therapeutic strategies that innovately aim at reducing the engraftment of circulating cancer cells by closing the gate through which the metastatic cell transit into the normal bone. To experimentally do so, a genetic model of perturbed pericyte coverage of the vasculature (PDGF-Bret/ret mice), in which the physical association between endothelial cells and pericytes is disrupted due to altered PDGF-B signaling, will be used to test the BM engraftment of circulating osteotropic melanoma and breast cancer cells. This model will help: first, to establish how the integrity/stability of te BM sinusoidal network, and the presence of BM-MSCs in their perivascular niche, participate in the extravasation of cancer cells (SA1); and second, to identify the cellular interactions and molecular pathways required for this cancer cell/tissue stroma relationship during BM invasion. These interactions will be further tested using in vitro and in vivo models (SA2). In SA1, Bioluminescence will be used to track the BM engraftment of circulating cells, their progression in time as metastatic tumors and the anatomical/functional correlation of resulting osteolysis (analyzed by ?CT imaging), which will be also assessed by histology, histomorphometry and serum markers. Immunohistochemical analysis using specific cellular markers will reveal the details of the interaction between engrafted melanoma cells and the altered vascular components of the BM stroma. In SA2 a mechanistic assessment will be performed using in vivo and in vitro assays with genetically modified MSCs, melanoma and breast cancer cells. In addition to the significant direct clinical impact, this proposed work is expected also to provide the foundation for future projects addressing other known roles of BM-MSCs that may influence skeletal metastasis, such as regulation of locally of other osteotropic malignancies including prostate, renal and lung, thus broadening the significance of the findings and conclusions.

描述（由申请人提供）：转移是癌症存活的主要预后指标，也是导致癌症死亡率的主要贡献者。骨骼是各种恶性肿瘤中癌症传播的首选器官之一。当前的靶向癌症疗法旨在不仅改变癌细胞中的特定生物学功能，还可以改变肿瘤基质/微环境（如血管）的成分。与限制癌细胞从原发性肿瘤传播的周细胞的确定作用相反，在癌症转移过程中，这些基质成分在靶器官中的作用尚不清楚。该研究建议的主要目的是了解骨髓（BM）微环境，尤其是其血管成分的功能，在建立骨骼转移中，基于一个新的假设，该假说表明BM间充质干细胞（BM-MSCS）（BM-MSC）（BM-MSC），是对骨骼癌症的癌症，是癌症的癌症。这一新假设为治疗策略提供了与临床相关的信息，这些信息旨在通过关闭转移性细胞转移到正常骨的栅极，以创新旨在减少循环癌细胞的植入。为了实验，脉管系统（PDGF-BRET/RET小鼠）的遗传模型将由于PDGF-B信号的改变而破坏了内皮细胞和周围细胞之间的物理关联，可用于测试循环蛋白质蛋白质瘤和乳腺癌细胞的BM植入。该模型将有助于：首先，确定TE BM正弦网络的完整性/稳定性以及在其血管周期壁che中的存在如何参与癌细胞的渗出（SA1）；其次，在BM侵袭过程中，该癌细胞/组织基质关系所需的细胞相互作用和分子途径。这些相互作用将使用体外和体内模型（SA2）进一步测试。在SA1中，将使用生物发光来跟踪循环细胞的BM植入，其作为转移性肿瘤的时间的发展以及所得骨溶解的解剖学/功能相关性（通过？CT成像分析）也将由组织学，组织学和血清标记进行评估。使用特定细胞标记的免疫组织化学分析将揭示植入的黑色素瘤细胞与BM基质的血管成分改变的相互作用的细节。在SA2中，将使用体内和体外测定法进行机械评估，并具有转基因MSC，黑色素瘤和乳腺癌细胞。除了重大的直接临床影响外，这项提出的工作还预计还为未来的项目奠定了基础，以解决可能影响骨骼转移的其他已知作用，例如对其他骨质性恶性肿瘤的局部调节，包括前列腺，肾脏，肾脏，肾脏和肺，从而扩大了发现结果和结论的重要性。