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: 7810639
• 负责人: JINSONG LIU
• 金额: $ 25.56万
• 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/7810639
• 关键词: 1-Phosphatidylinositol 3-Kinase; Aging-Related Process; Am 80; Angiogenesis Inhibitors; Angiogenic Switch; Biological Availability; Cancer cell line; Cells; Communication; DNA; Development; Diffuse; Endothelial Cells; Epithelial; Epithelial Cells; Epithelial ovarian cancer; Fibroblasts; Figs - dietary; Gelatinase B; Growth; 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; TP53 gene; 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; public health relevance; 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的一种永久性生长停滞形式，通常被认为是一种活跃在体外和体内的肿瘤抑制机制。然而，接近上皮性癌细胞的衰老成纤维细胞可能会促进肿瘤的形成，尽管体内存在这种细胞及其如何促进肿瘤形成的证据仍然难以捉摸。同样未知的是，如果体内确实存在促癌成纤维细胞，癌细胞与促癌成纤维细胞如何沟通也是未知的。我们可能已经发现了一种新的沟通方式：在对RAS转化的卵巢表面上皮细胞及其同基因永生化的对应细胞进行分析的过程中，我们发现了一种趋化因子Gro-1，它在RAS转化的卵巢癌细胞系中上调表达，对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诱导了卵巢间质成纤维细胞的衰老。Gro-1受体CXCR2的敲除可以消除衰老并导致成纤维细胞的不受控制的增殖。我们进一步证明了Gro-1诱导的衰老成纤维细胞具有促血管生成因子血管内皮生长因子(VEGF-A)和降低抗血管生成因子血栓反应蛋白-1(TSP-1)。衰老成纤维细胞中VEGF-A/TSP-1的比例是对照成纤维细胞的80倍，提示衰老成纤维细胞为促进肿瘤血管生成提供了急需的因子。我们还观察到，在人卵巢癌标本中，上皮性卵巢癌细胞附近的间质成纤维细胞衰老。由于Gro-1是一种被RAS激活的分泌型分子，可以从上皮性癌细胞扩散到邻近的成纤维细胞，因此Gro-1可能是一种信号分子，癌细胞通过它来加速邻近成纤维细胞的衰老。我们的中心假设是RAS激活了卵巢肿瘤细胞中Gro-1的表达。GRO-1信号通过其受体CXCR2激活多个下游效应器，从而产生衰老表型。衰老的成纤维细胞上调其VEGF-A：TSP-1的比例，作用于内皮细胞，诱导血管生成开关，进而导致肿瘤的发生。我们提出了以下两个特定的目标：特定的目标1.确定Gro-1诱导衰老并产生衰老成纤维细胞的血管生成表型的机制。具体目的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，也需要间质的改变，间质是一组与癌细胞相互作用的异质细胞。间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，Gro-1是一种分泌的小蛋白，以加速成纤维细胞的衰老过程，这一过程促进了肿瘤的形成。本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参与衰老过程的信号转导机制。为了最终探索这一观察的治疗相关性，需要更好地理解分子机制。