Stellate cells and their progenitor precursors in pancreas cancer progression

描述（由申请人提供）：胰腺癌是一种极其致命的疾病，在所有癌症中1年和5年生存率最低。这部分是由于胰腺癌细胞的极端转移行为，其也对治疗具有高度抗性。重要的是，我们现在知道胰腺导管腺癌（PDA）存在强烈但独特的间质反应。这是高度相关的，因为现在认识到，在许多实体瘤中，局部微环境和间质区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，疾病进展与间质中强烈的纤维化反应或促结缔组织增生反应相关，这在很大程度上受到胰腺星状细胞的调节。即使在侵袭前疾病的早期阶段，胰腺星状细胞的活化和细胞外基质沉积也是稳健的。通过疾病进展，这种促结缔组织增生反应持续并经常加剧，为癌细胞提供关键支持，因为它们进展到完全转移性疾病，同时还提供了限制化疗药物进入的无药避难所。然而，迄今为止，PSC调节上皮癌细胞体内行为的分子和物理机制还不清楚。同样，PSC被激活的分子机制以及肿瘤中激活的PSC的来源仍有待充分阐明。在培养中，已知星状细胞 分泌因子，可以促进与肿瘤进展相关的细胞行为，表明星状细胞在体内固有疾病中的旁分泌信号作用。因此，在这里，使用忠实地模拟人类疾病和人类细胞系移植肿瘤的胰腺癌小鼠模型，我们提出了具体的实验来明确研究胰腺癌中活化的胰腺星状细胞的来源，剖析基质星状细胞群体在浸润前、浸润性和转移性疾病中的作用，并且特异性靶向促进癌细胞生长和运动并有助于PDA中促结缔组织增生反应的产生和维持的关键星状细胞衍生的细胞因子。我们假设骨髓来源的祖细胞是活化的胰腺星状细胞的来源，这些细胞与内源性星状细胞群体一起沿着在早期浸润前病变中被选择，以帮助驱动转化为PDA并最终建立成功的转移。此外，我们假设化学信号将骨髓源性祖细胞吸引到PDA，但基质的物理特征也影响其浸润和随后的分化，并且特定的strom靶向治疗可以破坏这些相互作用和PDA中星状细胞的肿瘤支持影响。

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.