RAS Signaling, Senescent Fibroblasts, and Ovarian Cancer Progression

RAS 信号转导、衰老成纤维细胞和卵巢癌进展

• 批准号: 8053814
• 负责人: JINSONG LIU
• 金额: $ 24.8万
• 依托单位: UNIVERSITY OF TX MD ANDERSON CAN CTR
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-07-01 至 2013-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8053814
• 关键词: 1-Phosphatidylinositol 3-Kinase; Aging-Related Process; Am 80; Angiogenesis Inhibitors; Angiogenic Switch; Biological Availability; Cancer cell line; Cells; Communication; DNA damage checkpoint; Development; Diffuse; Endothelial Cells; Epithelial; Epithelial Cells; Epithelial ovarian cancer; Fibroblasts; Gelatinase B; Growth; Health; Human; IL8RB gene; In Vitro; Interleukin-8B Receptor; Malignant Neoplasms; Malignant neoplasm of ovary; Metalloproteases; Molecular; Mutation; Oncogene Activation; Oncogenes; Ovarian; Pathway interactions; Phenotype; Process; Proteins; Regulation; Role; Signal Transduction; Signaling Molecule; Small Interfering RNA; Specimen; Surface; Testing; Therapeutic; Thrombospondin 1; Tumor Angiogenesis; Tumor Promotion; Vascular Endothelial Growth Factors; aged; angiogenesis; bevacizumab; cancer cell; chemokine; improved; in vitro Model; in vivo; neoplastic cell; novel; ovarian neoplasm; overexpression; receptor; response; senescence; telomere; tumor; tumor growth; tumor progression

DESCRIPTION (provided by applicant): Senescence, a permanent form of growth arrest following oncogene activation or telomere attrition, is generally considered a tumor-suppressive mechanism active in vitro and in vivo. However, senescent fibroblasts that are near epithelial cancer cells may promote tumor formation, although in vivo evidence for the existence of such cells and how they act to promote tumor formation remains elusive. Also unknown is how cancer cells communicate with tumor-promoting fibroblasts, if such fibroblasts do exist in vivo. We may have found a novel means for this communication: in the course of profiling RAS-transformed ovarian surface epithelial cells and their isogenic immortalized counterparts, we identified a chemokine, Gro-1, that is up-regulated in RAS- transformed ovarian cancer cell lines and is critical for transformation of ovarian epithelial cells. Unexpectedly, we found that Gro-1 induced senescence in ovarian stromal fibroblasts. Knockdown of the receptor for Gro-1, CXCR2, abrogates the senescence and leads to uncontrolled proliferation of the fibroblasts. We further demonstrated that Gro-1-induced senescent fibroblasts have an increased proangiogenic factor vascular endothelial growth factor (VEGF-A) and decreased antiangiogenic factor thrombospondin-1 (TSP-1). The ratio of VEGF-A:TSP-1 in senescent fibroblasts is 80 fold higher than that in control fibroblasts, suggesting that senescent fibroblasts provide critically needed factors to enhance tumor angiogenesis. We also observed, in the human ovarian cancer specimens, that the stromal fibroblasts near epithelial ovarian cancer cells are senescent. Because Gro-1 is a secreted molecule activated by RAS and can diffuse from epithelial cancer cells to neighboring fibroblasts, Gro-1 may be a signaling molecule by which cancer cells use to accelerate the senescence of neighboring fibroblasts. Our central hypothesis is that RAS activates Gro-1 expression in ovarian tumor cells. Gro-1 signaling through its receptor CXCR2 activates multiple downstream effectors to create a senescent phenotype. Senescent fibroblasts upregulate their VEGF-A:TSP-1 ratio to act on endothelial cells to induce an angiogenic switch, which in turn leads to tumor promotion. We propose the following two specific aims: Specific Aim 1. Define the mechanisms by which Gro-1 induces senescence and creates an angiogenic phenotype of senescent fibroblasts. Specific Aim 2. Determine the mechanisms by which senescent fibroblasts promote the tumor growth. PUBLIC HEALTH RELEVANCE: Development of cancer requires not only genetic alterations in epithelial cells but also changes in the stroma, a heterogeneous group of cells interacting with cancer cells. The predominant component of the stroma is fibroblasts. We have found that the RAS oncogene can send a signaling molecule, Gro-1, a small secreted protein, to fibroblasts to accelerate their aging process (senescence) and that this process promotes tumor formation. This project aims to define the molecular mechanisms by which aged fibroblasts initiate ovarian tumor growth and the signaling involved in the aging process. The improved understanding of the molecular mechanisms will be required for an eventual exploration of the therapeutic relevance of this observation.

描述（由申请人提供）：衰老是癌基因激活或端粒磨损后生长停滞的永久形式，通常被认为是在体外和体内活跃的肿瘤抑制机制。 然而，上皮癌细胞附近的衰老成纤维细胞可能会促进肿瘤形成，尽管此类细胞存在的体内证据以及它们如何促进肿瘤形成仍然难以捉摸。 同样未知的是癌细胞如何与促肿瘤成纤维细胞通讯（如果这种成纤维细胞确实存在于体内）。 我们可能已经找到了这种通讯的新方法：在分析 RAS 转化的卵巢表面上皮细胞及其同基因永生化对应物的过程中，我们鉴定了一种趋化因子 Gro-1，它在 RAS 转化的卵巢癌细胞中上调细胞系，对于卵巢上皮细胞的转化至关重要。 出乎意料的是，我们发现 Gro-1 诱导卵巢基质成纤维细胞衰老。 Gro-1 受体 CXCR2 的敲低会消除衰老并导致成纤维细胞不受控制的增殖。 我们进一步证明，Gro-1诱导的衰老成纤维细胞具有增加的促血管生成因子血管内皮生长因子（VEGF-A）和减少的抗血管生成因子血小板反应蛋白-1（TSP-1）。 衰老成纤维细胞中 VEGF-A:TSP-1 的比率比对照成纤维细胞高 80 倍，表明衰老成纤维细胞提供了增强肿瘤血管生成所急需的因子。 我们还在人类卵巢癌标本中观察到，上皮性卵巢癌细胞附近的基质成纤维细胞正在衰老。 由于Gro-1是一种被RAS激活的分泌分子，可以从上皮癌细胞扩散到邻近的成纤维细胞，因此Gro-1可能是癌细胞用来加速邻近成纤维细胞衰老的信号分子。 我们的中心假设是 RAS 激活卵巢肿瘤细胞中 Gro-1 的表达。 Gro-1 信号通过其受体 CXCR2 激活多个下游效应器以产生衰老表型。 衰老成纤维细胞上调其 VEGF-A:TSP-1 比例，作用于内皮细胞，诱导血管生成开关，进而促进肿瘤生长。 我们提出以下两个具体目标： 具体目标 1. 明确 Gro-1 诱导衰老并产生衰老成纤维细胞血管生成表型的机制。 具体目标2.确定衰老成纤维细胞促进肿瘤生长的机制。 公共卫生相关性：癌症的发展不仅需要上皮细胞的基因改变，还需要基质的变化，基质是与癌细胞相互作用的异质细胞群。 基质的主要成分是成纤维细胞。 我们发现RAS癌基因可以向成纤维细胞发送信号分子Gro-1（一种小分泌蛋白），加速其衰老过程（衰老），并且该过程促进肿瘤形成。 该项目旨在确定衰老成纤维细胞启动卵巢肿瘤生长的分子机制以及衰老过程中涉及的信号传导。 为了最终探索这一观察结果的治疗相关性，需要加深对分子机制的理解。