Fibrosis-Protease Cross-Talk Regulating Pancreatic Cancer Invasion

描述(申请人提供)：胰腺导管腺癌(PDAC)目前是美国癌症相关死亡的第四大原因。确诊后的中位生存期不到6个月，而5年无瘤生存率不到5%。较差的预后归因于诊断时疾病的相对晚期，大约80%的患者表现为局部侵袭性或转移性疾病。PDAC与肿瘤周围的一种强烈的纤维化反应有关，这种反应被称为促结缔组织反应。这个反应是由间质细胞外基质(ECM)和增殖的成纤维细胞组成的，主要是I型胶原。然而，胰腺导管细胞、间质ECM和间质成纤维细胞之间的功能相互作用尚不清楚。NCI胰腺癌进展回顾小组表示，需要更好地了解间质形成的基本机制，它与胰腺癌细胞的相互作用，以及它在胰腺癌发病机制中的作用。我们已经证明，胰腺成纤维细胞沉积的细胞外基质促进了PDAC细胞转化生长因子-1的表达，继而增加了MT1-基质金属蛋白酶的表达[Ottaviano AJ等人，癌症研究，2006]。我们的初步数据还表明，在富胶原的微环境中，MT1-MMP1增加了细胞周期蛋白D1的表达，并增强了p38MAPK信号，从而促进了细胞生长。此外，我们的初步数据表明，利用转基因小鼠模型在胰腺中表达MT1-MMP会增加纤维化。综上所述，这些数据支持我们的中心假设，即涉及I型胶原、转化生长因子-1和MT1-MMP之间的串扰的前馈扩增环有助于PDAC的侵袭性表型：促结缔组织反应促进转化生长因子-1的表达和信号增加MT1-MMP的表达，但这反过来又有助于扩大的纤维化，进一步增加转化生长因子-1信号和MT1-MMP的表达，从而增强PDAC的侵袭和转移。目标1中提出的实验旨在了解放大环的前半部分(纤维化？转化生长因子-β1？通过阐明细胞外基质，特别是I型胶原，促进PDAC细胞表达转化生长因子-β1和MT1-基质金属蛋白酶的机制。在目标2中，我们将检查扩增环的后半部分(MT1-MMP？通过使用器官型胰腺癌、原位胰腺癌和转基因胰腺癌模型，阐明MT1-MMP在富含胶原的微环境中促进纤维化和促进胰腺肿瘤生长的机制。我们提出这些研究的理由是，一旦纤维化反应和PDAC细胞之间的串扰机制被完全确定，这些信息最终可能导致新的治疗策略，从而降低胰腺癌的发病率和死亡率。

DESCRIPTION (provided by applicant): Pancreatic ductal adenocarcinoma (PDAC) is currently the fourth leading cause of cancer-related death in the U. S. The median survival time after diagnosis is less than 6 months, while 5-year disease-free survival is less than 5%. Poor outcome is attributed to the relatively advanced stage of disease at time of diagnosis, with approximately 80% of patients presenting with locally aggressive or metastatic disease. PDAC is associated with an intense fibrotic reaction around the tumor known as desmoplastic reaction. This reaction is composed of interstitial extracellular matrix (ECM), predominantly type I collagen, together with proliferating fibroblastic cells. However, the functional interactions among the pancreatic ductal cells, the interstitial ECM and the stromal fibroblasts are poorly understood. According to the NCI Pancreatic Cancer Progress Review Group 'a better understanding is needed of the basic mechanisms involved in the development of the stroma, its interaction with the pancreatic cancer cells and its role in the pathogenesis of pancreatic cancer'. We have demonstrated that extracellular matrix deposited by pancreatic fibroblasts promotes TGF-?1 expression by PDAC cells followed by increased MT1-MMP expression [Ottaviano AJ et al, Cancer Research 2006]. Our preliminary data also indicate that MT1-MMP increases cyclin D1 expression and enhances p38 MAPK signaling to promote growth in collagen-rich microenvironment. Moreover, our preliminary data suggest that expression of MT1- MMP in the pancreas using a transgenic mouse model increases fibrosis. Together these data support our central hypothesis that a feed-forward amplification loop involving cross-talk between type I collagen, TGF-?1 and MT1-MMP contributes to the aggressive phenotype of PDAC: the desmoplastic reaction promotes TGF-?1 expression and signaling to increase MT1-MMP expression, but this in turn contributes to expanded fibrosis and a further increase in TGF-?1 signaling and MT1-MMP expression, thus enhancing PDAC invasion and metastasis. Experiments proposed in Aim 1 have been designed to understand the first half of the amplification loop (fibrosis ? TGF-?1 ? MT1-MMP) by elucidating the mechanism by which the ECM, in particular type I collagen, increases TGF-?1 and MT1-MMP expression by PDAC cells. In Aim 2 we will examine the second half of the amplification loop (MT1- MMP ? fibrosis and growth in 3D collagen) by elucidating the mechanism by which MT1-MMP promotes fibrosis and facilitates pancreatic tumor growth in a collagen-rich microenvironment using organotypic, orthotopic and transgenic models of pancreatic cancer. Our rationale for these proposed studies is that once the mechanism of cross-talk between the fibrotic reaction and PDAC cells is fully determined, this information may ultimately lead to new treatment strategies that reduce the morbidity and mortality of pancreatic cancer.