Inter-Cellular Signaling of Invastion Receptors in the Tumor Microenvironment

肿瘤微环境中侵袭受体的细胞间信号转导

基本信息

批准号：
7669247
负责人：
ATHAN KULIOPULOS
金额：
$ 30.59万
依托单位：
TUFTS MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2007
资助国家：
美国
起止时间：
2007-09-19 至 2011-07-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7669247
关键词：
Address Agonist Angiogenic Factor Animal Model Behavior Biological Models Blood Vessels Breast Breast Cancer Cell Breast Cancer Model Breast Carcinoma Cancer Cell Growth Cancerous Cell Communication Cell Surface Receptors Cells Cleaved cell Coculture Techniques Colorectal Communication Data Employee Strikes Endothelial Cells Environment Exhibits Family Fibroblasts G-Protein-Coupled Receptors GTP-Binding Proteins Grant Granulocyte-Macrophage Colony-Stimulating Factor Growth IL8 gene IL8RA gene Infiltration Inflammatory Interleukin-6 Interleukin-8B Receptor Interstitial Collagenase Ligands MAPK phosphatase MAPK14 gene MCF7 cell Malignant Epithelial Cell Malignant Neoplasms Malignant neoplasm of ovary Malignant neoplasm of prostate Mammary Neoplasms Metalloproteases Mitogen Activated Protein Kinase 1 Mitogens Neoplasm Metastasis Oncogenes Oncogenic Ovarian PAR-1 Receptor Paracrine Communication Pathway interactions Peptide Hydrolases Phosphoric Monoester Hydrolases Phosphotransferases Production Regulation Role Signal Transduction Stromal Cells Stromal Neoplasm System Technology Testing Thrombin Tube Tumor Angiogenesis Tumor Biology Tumor Cell Invasion Up-Regulation Vascular Endothelial Growth Factors Xenograft Model Xenograft procedure angiogenesis cancer cell cell motility cell type chemokine chemokine receptor follow-up in vivo inhibitor/antagonist knock-down malignant breast neoplasm member migration mouse model new therapeutic target novel outcome forecast ovarian neoplasm paracrine prevent receptor response rho scaffold tumor tumor growth tumor progression tumorigenesis

项目摘要

DESCRIPTION (provided by applicant): G protein-coupled receptors (GPCRs) are the largest family of cell surface receptors with more than 1000 members yet only a few GPCRs have been found to be oncogenes. Among these, the protease-activated receptor 1 (PAR1) has been identified as a potent oncogene and confers invasive behavior to pre-cancerous breast cells. In this grant we test the hypothesis that PAR1 is critical for cancer-host communication by stimulating production of paracrine and angiogenesis factors in the tumor environment. We recently identified host fibroblast-derived matrix metalloprotease-1 (MMP-1) as a novel agonist that can cleave and activate PAR1 in breast and ovarian tumors. MMP-1 is highly expressed in stromal cells and is a predictive marker for poor prognosis in breast, colorectal and other tumors. Targeting PAR1 with the novel cell-penetrating pepducins described here blocks the pathway downstream of MMP-1 and receptor inhibiting cancer growth and invasion. PAR1 pepducins also resulted in pronounced reduction of stromal infiltration and angiogenesis of breast and ovarian cancers. We will test the hypothesis that stromal-derived PAR1 may have a distinct role from cancer cell-derived PAR1 in tumor biology and stimulation of paracrine factors that promote invasion and angiogenesis. We will utilize two cancer-stromal co-culturing model systems and in vivo cancer- stromal coimplantation xenografts. Activation of PAR1 (and PAR2) have been shown to produce IL-8, Gro-?, VEGF, IL-6 and GM-CSF in a variety of cell types including prostate cancer, but the role of PAR1 in paracrine communication in cancer has not been directly addressed. We hypothesize that activation of PAR1 on cancer cells leads to production of chemokines which stimulate endothelial cells resulting in increased angiogenesis and tumor growth. Pepducin technology will be used to define the role of endothelial chemokine CXCR1 and CXCR2 receptors in blood vessel formation and validate our preliminary data that PAR1 and potentially CXCR1/2 pepducins can block angiogenesis and extend survival in ovarian and breast xenograft animal models. Lastly, we will follow-up our recent discovery of a novel PAR1-effector, BicD1, which acts as a suppressor of PAR1-dependent migration and invasion of breast cancer cells. Knock-down of BicD1 expression greatly prolongs mitogen-activated kinase signaling suggesting that BicD1 may regulate MAPK phosphatase (MKP) activity in breast cancer cells. We will test the hypothesis that upregulation of PAR1 expression or stimulation of PAR1 by MMP-1 or thrombin regulates BicD1 and MKP expression and that these downstream effectors in turn control MAPK-dependent invasion and proliferation of breast cancer. The pepducin approach has the prospect to significantly change our understanding of the role of cross-talk between receptors such PAR1 and CXCR1/2 in cancer growth and blood vessel formation. As envisioned, these studies will develop the first inhibitors of these invasion and chemokine receptors for the potential treatment of advanced breast and ovarian cancers.

描述（由申请人提供）：G蛋白偶联受体（GPCR）是最大的细胞表面受体家族，具有1000多个成员，但发现只有少数GPCR是癌基因。其中，蛋白酶激活的受体1（PAR1）被确定为有效的癌基因，并赋予了对癌前乳腺细胞的侵入性行为。在这笔赠款中，我们检验了以下假设：PAR1通过刺激肌氨酸和血管生成因子在肿瘤环境中的产生而对癌症宿主通信至关重要。我们最近将宿主成纤维细胞衍生的金属蛋白酶-1（MMP-1）确定为一种新型激动剂，可以在乳腺和卵巢肿瘤中裂解和激活PAR1。 MMP-1在基质细胞中高度表达，是乳腺癌，结直肠癌和其他肿瘤预后不良的预测标记。用新颖的细胞渗透腹膜蛋白靶向PAR1，此处描述的pepducins阻断了MMP-1下游的途径和受体抑制癌症的生长和侵袭。 PAR1倍蛋白也导致乳腺癌和卵巢癌的基质浸润和血管生成显着减少。我们将检验以下假设：基质衍生的PAR1在癌细胞衍生的PAR1中可能在肿瘤生物学和促进抗分泌因子刺激促进侵袭和血管生成的刺激中具有明显的作用。我们将利用两个癌症 - 基质共培养模型系统和体内癌 - 基质共植入异种移植物。已显示PAR1（和PAR2）的激活在包括前列腺癌在内的多种细胞类型中产生IL-8，GRO-？，VEGF，IL-6和GM-CSF，但是尚未直接解决PAR1在par1癌中的作用。我们假设PAR1在癌细胞上的激活会导致趋化因子的产生，从而刺激内皮细胞，从而增加血管生成和肿瘤生长。浮力素技术将用于定义内皮趋化因子CXCR1和CXCR2受体在血管形成中的作用，并验证我们的初步数据，即PAR1和潜在的CXCR1/2泛蛋白可以阻止血管生成并扩展卵巢和乳腺癌动物模型中的血管生成并扩展生存率。最后，我们将跟进最近发现的新型PAR1-效应器BICD1的发现，该par1效用是抑制PAR1依赖性迁移和乳腺癌细胞侵袭的抑制剂。 BICD1表达的敲除大大延长了有丝分裂原激活的激酶信号传导，这表明BICD1可能调节乳腺癌细胞中MAPK磷酸酶（MKP）活性。我们将检验以下假设：MMP-1或凝血酶对PAR1表达或PAR1刺激的上调调节BICD1和MKP表达，并且这些下游效应子反过来控制MAPK依赖性依赖MAPK的侵袭和乳腺癌的增殖。全胃蛋白方法的前景可以显着改变我们对PAR1和CXCR1/2等受体在癌症生长和血管形成中的跨语言作用的理解。如前所述，这些研究将开发出这些侵袭和趋化因子受体的第一个抑制剂，以潜在治疗晚期乳腺癌和卵巢癌。