Stellate cells and their progenitor precursors in pancreas cancer progression

描述（申请人提供）：胰腺癌是一种极具致命性的疾病，是所有癌症中1年和5年生存率最低的疾病。这在一定程度上是由于胰腺癌细胞具有极强的转移性，对治疗也有很高的抵抗力。重要的是，我们现在知道在胰腺导管腺癌（PDA）中存在一种强烈但独特的基质反应。这是高度相关的，因为现在认识到，在许多实体肿瘤中，局部微环境和间质室显著影响疾病进展。在常规胰腺导管腺癌及其最常见的前体PanIN病变中，疾病进展与基质中强烈的纤维化反应或结缔组织增生反应相关，这种反应主要由胰腺星状细胞调节。即使在侵袭前疾病的早期阶段，胰腺星状细胞和细胞外基质沉积的激活也是强劲的。在疾病进展过程中，这种结缔组织增生反应持续并经常加剧，为癌细胞发展为完全转移性疾病提供了关键支持，同时也提供了限制化疗药物使用的无药物庇护所。然而，迄今为止，PSCs在体内调节上皮癌细胞行为的分子和物理机制尚不清楚。同样，肿瘤中活化PSCs的分子机制以及活化PSCs的来源仍有待充分阐明。在培养中，星状细胞被认为

DESCRIPTION (provided by applicant): Pancreatic cancer is an extremely lethal disease with the lowest 1-year and 5-year survival rates of any cancer. This is due, in part, to the extremely metastatic behavior of pancreas carcinoma cells, which are also highly resistant to therapy. Importantly, we now know that a strong, but nevertheless unique, stromal response is present in pancreatic ductal adenocarcinoma (PDA). This is highly relevant as it is now recognized that, in many solid tumors, the local microenvironment and the stromal compartment significantly influences disease progression. In conventional pancreatic ductal adenocarcinoma, and its most common precursor PanIN lesions, disease progression is associated with a robust fibrotic response in the stroma, or desmoplastic reaction, that is largely regulated by pancreatic stellate cells. Even at the early stages of preinvasive disease activation of pancreatic stellate cells and extracellular matrix deposition is robust. Through disease progression this desmoplastic reaction continues and often intensifies, offering critical support to carcinoma cells as they progress to fully metastatic disease while also providing drug-free sanctuaries that limit access of chemotherapeutic agents. However, to date, the molecular and physical mechanisms by which PSCs regulate epithelial carcinoma cell behavior in vivo are not well understood. Likewise, the molecular mechanisms by which PSCs are activated as well as the source of activated PSCs in the tumor remains to be fully elucidated. In culture, stellate cells are known to secrete factors that can promote cell behaviors associated with tumor progression, suggesting a paracrine signaling role for stellate cells in indigenous disease in vivo. Therefore, here, using murine models of pancreas cancer that faithfully mimics the human disease and human cell line grafted tumors, we propose specific experiments to explicitly investigate the source of activated pancreatic stellate cells in pancreas cancer, dissect the role of stromal stellate cells population in preinvasive, invasive and metastatic disease, and specifically target a key stellate cell-derive cytokine that promotes carcinoma cell growth and motility and contributes to the generation and maintenance of the desmoplastic reaction in PDA. We hypothesize that bone marrow-derived progenitor cells are a source of activated pancreatic stellate cells that are co-opted, along with endogenous populations of stellate cells, in early preinvasive lesions to help drive conversion to PDA and ultimately establish successful metastases. Furthermore, we hypothesize that chemical signal draws bone marrow-derived progenitor cells to PDA but that physical features of the stroma also influence their infiltration and subsequent differentiation and that specific strom targeting therapy can disrupt these interactions and the tumor supporting influence of stellate cells in PDA.