The involement of PECAM-1 in cancer metastasis

PECAM-1参与癌症转移

• 批准号: 8536076
• 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/8536076
• 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.

目的：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，可释放促进肿瘤生长的因子。尽管已经研究了 TME 在原发性肿瘤生长和扩散中的作用，但人们对 TME 在调节转移性肿瘤病灶进展中可能发挥的作用知之甚少。基于大量的初步数据，我们假设在转移性肿瘤进展的后期，血管内皮 PECAM-1 调节 TME 诱导增殖性肿瘤细胞基因表达谱，从而促进转移性肿瘤生长。为了测试这一点，建议进行研究：(i) 确定内皮 PECAM-1 参与肿瘤肺转移的分子基础（具体目标 1）； (ii) 识别 PECAM-1 依赖性、内皮源性介质，调节肺中转移性肿瘤的生长和进展（具体目标 2）； (iii) 表征内皮 PECAM-1 对肺转移性肿瘤基因谱的影响（具体目标 3）。 方法论： 具体目标 1. 确定内皮 PECAM-1 参与肿瘤肺转移的分子基础。来自鼠肺的 PECAM-1 缺失内皮细胞将被野生型 PECAM-1 或介导配体结合或细胞内信号转导能力突变的 PECAM-1 转导。所得细胞将用于肿瘤内皮共培养研究，以评估干扰 PECAM-1 功能对肿瘤细胞增殖的影响。 具体目标 2. 鉴定调节肺中转移性肿瘤生长和进展的 PECAM-1 依赖性内皮衍生介质。将在来自肿瘤-内皮共培养物的条件培养基中培养的肿瘤细胞中研究体外细胞增殖，其中可疑的、PECAM-1调节的内皮衍生因子的表达水平已被改变。这些研究中涉及 PECAM-1 调节的分泌蛋白的任何因子的体内重要性将通过评估注射有过度表达感兴趣因子的肿瘤的小鼠的肺转移来证实。 具体目标 3. 表征内皮 PECAM-1 对肺转移性肿瘤基因谱的影响。将使用经抗PECAM-1抗体处理的野生型小鼠和PECAM-1缺失小鼠，在静脉内和自发性肺转移模型中测定肿瘤细胞中候选PECAM-1调节的生长促进基因的基因表达水平，以及上调或下调它们的效果。临床关系：由于绝大多数癌症死亡是由转移性疾病引起的，因此更全面地了解肿瘤转移所涉及的事件对于为晚期癌症患者开发新的治疗方法至关重要。 影响/意义：微小转移肿瘤灶晚期发展为肉眼可见的临床明显肿瘤，以及 TME 在这一过程中可能发挥的作用尚未得到充分研究。血管上表达的 PECAM-1 可能通过调节 TME 成为转移性肿瘤晚期进展的介质。这代表了 PECAM-1 的一个意料之外但可能非常重要的新功能，可能对晚期癌症的机制理解和治疗产生重大影响。