The involement of PECAM-1 in cancer metastasis

PECAM-1参与癌症转移

• 批准号: 8698257
• 负责人: HORACE M DELISSER
• 金额: --
• 依托单位: PHILADELPHIA VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-07-01 至 2016-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8698257
• 关键词: Advanced Malignant Neoplasm; Antibodies; Binding; Biological Assay; Blood Vessels; CD31 Antigens; Cause of Death; Cell Proliferation; Cell Survival; Cell physiology; Cells; Clinical; Coculture Techniques; Conditioned Culture Media; Cultured Tumor Cells; Data; Diagnostic Neoplasm Staging; Disease; Elements; Endothelial Cells; Endothelium; Event; Extracellular Matrix; Gene Expression; Gene Expression Profile; Genes; Growth; In Vitro; Interleukin-11; Intravenous; Knockout Mice; Ligand Binding; Lung; Malignant Neoplasms; Manuscripts; Mediating; Mediator of activation protein; Metastatic Neoplasm to the Lung; Methodology; Modeling; Molecular; Mus; Mutate; Neoplasm Metastasis; PDGFRB gene; Patients; Play; Primary Neoplasm; Process; Proteins; Regulation; Role; SMARCB1 gene; STAT3 gene; Signal Transduction; Staging; Stromal Cells; TNFRSF5 gene; Testing; Tissue Inhibitor of Metalloproteinase-1; Tumor-Derived; Wild Type Mouse; angiogenesis; base; in vivo; interest; neoplastic cell; novel; release factor; tumor; tumor growth; tumor microenvironment; tumor progression

Objectives: Stromal cells, including endothelial cells (ECs), are critical elements of the tumor microenvironment (TME), releasing factors that facilitate tumor growth. Although the role of the TME in the growth and spread of primary tumors has been investigated, less is known about the role the TME might play in regulating the progression of metastatic tumor foci. Based on extensive preliminary data we hypothesize that during the late stages of metastatic tumor progression, vascular endothelial PECAM-1 modulates the TME to induce a proliferative tumor cell gene expression profile that promotes metastatic tumor growth. To test this, studies are proposed that will (i) determine the molecular basis for the involvement of endothelial PECAM-1 in tumor metastasis to the lung (Specific Aim 1); (ii) identify PECAM-1-dependent, endothelial-derived mediators that regulate metastatic tumor growth and progression in the lung (Specific Aim 2); and (iii) characterize the influence of endothelial PECAM-1 on the gene profile of metastatic tumors in the lung (Specific Aim 3). Methodology: Specific Aim 1. Determine the molecular basis for the involvement of endothelial PECAM-1 in tumor metastasis to the lung. PECAM-1-null endothelial cells from murine lung will be transduced with wild type PECAM-1 or PECAM-1 mutated in its ability to mediate ligand binding or intracellular signaling. The resulting cells will then be used in tumor-endothelial co-culture studies to assess the effects of perturbing PECAM-1 function on tumor cell proliferation. Specific Aim 2. Identify PECAM-1-dependent, endothelial-derived mediators that regulate metastatic tumor growth and progression in the lung. In vitro cell proliferation will be studied in tumor cells cultured in conditioned media derived from tumor-endothelial co-cultures, for which the levels of expression of suspected, PECAM-1-regulated, endothelial-derived factors have been altered. The in vivo significance of any factor implicated as a PECAM-1-regulated secreted protein by these studies will then be confirmed by assessing lung metastasis in mice injected with tumors over-expressing the factor of interest. Specific Aim 3. Characterize the influence of endothelial PECAM-1 on the gene profile of metastatic tumors in the lung. The gene expression levels in tumor cells of candidate, PECAM-1- regulated, growth-promoting genes, as well as the effects of up- or down-regulating them, will be determined in intravenous and spontaneous models of lung metastasis, using wild type mice treated with anti-PECAM-1 antibody and PECAM-1-null mice. Clinical Relationship: As the vast majority of cancer deaths are caused by metastatic disease, developing a more complete understanding of the events involved in tumor metastasis will be critical to developing novel treatments for patients with advanced cancer. Impact/Significance: The late progression of micro-metastatic tumor foci to macroscopic, clinically apparent tumors and the role that the TME might play in that process has not been vigorously investigated. PECAM-1 expressed on vessels may be a mediator of the late progression of metastatic tumors through a modulation of the TME. This represents an unanticipated, but potentially very important new function for PECAM-1 that may have significant implications for the mechanistic understanding and treatment of late-stage cancer.

目标：包括内皮细胞（EC）在内的基质细胞是肿瘤微环境（TME）的关键要素，释放了促进肿瘤生长的因素。尽管已经研究了TME在原发性肿瘤的生长和扩散中的作用，但对于TME在调节转移性肿瘤灶进展中的作用而言，知之甚少。基于广泛的初步数据，我们假设在转移性肿瘤进展的后期阶段，血管内皮PECAM-1调节TME以诱导增殖性肿瘤细胞基因表达谱，从而促进转移性肿瘤的生长。为了进行测试，提出了（i）确定内皮PECAM-1参与肿瘤转移到肺部的分子基础的研究（特定的目标1）； （ii）确定调节肺部转移性肿瘤生长和进展的PECAM-1依赖性，内皮衍生的介体（特定目标2）； （iii）表征内皮PECAM-1对肺中转移性肿瘤基因谱的影响（特定目标3）。 方法论： 具体目的1。确定内皮PECAM-1参与肿瘤转移到肺部的分子基础。来自鼠肺的PECAM-1无孔内皮细胞将用野生型PECAM-1或PECAM-1转导其介导配体结合或细胞内信号传导的能力。然后，所得细胞将用于肿瘤 - 内皮共培养研究中，以评估PECAM-1功能对肿瘤细胞增殖的影响。 具体目的2。确定调节肺部转移性肿瘤生长和进展的PECAM-1依赖性，内皮衍生的介体。将在源自肿瘤内皮共培养的条件培养基中培养的肿瘤细胞中研究体外细胞增殖，为此，可疑的，PECAM-1调节的，内皮衍生的因素的表达水平已改变。然后，通过评估注射过过表达感兴趣因素的肿瘤的小鼠中，这些研究将证实作为PECAM-1调节的分泌蛋白的任何因素的体内意义。 具体目标3。表征内皮PECAM-1对肺转移性肿瘤基因谱的影响。使用抗肺转移和自发转移模型，使用用抗Pecam-1抗体和PECAM-1抗体和PECAM-1-NULL MICE治疗的野生型小鼠，将确定候选候选者，PECAM-1调控，促进生长基因PECAM-1调控，促进生长基因的基因表达水平以及上调节的基因表达水平。临床关系：由于绝大多数癌症死亡都是由转移性疾病引起的，因此对肿瘤转移涉及的事件的更全面了解对于为晚期癌症患者开发新治疗至关重要。 影响/显着性：微移位肿瘤对宏观，临床明显的肿瘤的晚期进展以及TME在该过程中可能起的作用尚未得到大力研究。在血管上表达的PECAM-1可能是通过TME调节转移性肿瘤晚期进展的介体。这代表了PECAM-1的意外但非常重要的新功能，这可能对晚期癌症的机械理解和治疗具有重要意义。