Mechanisms of Pancreatic Cancer Inhibition by SPARC

描述（由申请人提供）：胰腺癌是最具侵袭性的人类恶性肿瘤之一。在大多数患者中，它被诊断为晚期，无法进行手术治疗，并且对传统治疗具有高度耐药性。由于中位生存期小于1年，5年生存期小于5%1，对额外治疗策略的需求很高。严重的结缔组织增生是胰腺癌的标志，肿瘤微环境已被证明在该疾病的进展和化疗耐药中发挥重要作用。因此，肿瘤微环境是一个很有前景的胰腺癌治疗靶点。分泌蛋白酸性和富含半胱氨酸（SPARC）是一种基质细胞蛋白，调节细胞与环境之间的相互作用2,3。我们已经证明SPARC通过作为细胞外伴侣修饰细胞外基质的组装和组织。我们的研究表明，SPARC抑制几种类型癌症的生长（6,7和初步研究）。我们已经证实，SPARC的抗肿瘤特性部分是通过抑制血管生成和阻断成纤维细胞激活介导的，而成纤维细胞激活是癌症诱导的结缔组织形成的两个主要特征。通过结构-功能研究，我们发现高度保守的卵泡抑素结构域对应的SPARC肽具有强大的抗血管生成活性8,9，并抑制神经母细胞瘤，胰腺癌，肺癌和乳腺癌的生长（初步研究）。因此，SPARC在广泛的肿瘤中具有肿瘤抑制功能。基于这些数据，我们假设通过与基质蛋白和基质蛋白的相互作用，SPARC通过阻断韧带增生改变来抑制胰腺癌的生长，并创造一个更“正常”的微环境，不允许肿瘤生长。SPARC调节肿瘤微环境和抑制肿瘤生长的机制在很大程度上仍然未知。我们建议使用一种独特的系统方法来阐明这种机制，该方法是由何博士开发的，该研究的共同负责人10-12，以分离胰腺肿瘤组织中SPARC靶向的蛋白质。建立的相互作用将通过与SPARC的共表达和共沉淀来验证。在小鼠异种移植模型中，将通过shRNA下调和抵消SPARC抗肿瘤特性的能力来测试验证靶点的功能意义。

DESCRIPTION (provided by applicant): Pancreatic cancer is one of the most aggressive human malignancies. In most patients it is diagnosed at advanced stages not amenable by surgery, and it is highly resistant to conventional treatments. With median survival less than 1 year and 5-year survival less than 5%1, the need for additional treatment strategies is high. Severe desmoplasia is a hallmark of pancreatic cancer, and the tumor microenvironment has been shown to play an essential role in the progression and chemoresistance of this disease. Thus, the tumor microenvironment is a promising therapeutic target for pancreatic cancer. Secreted Protein Acidic and Rich in Cysteine (SPARC) is a matricellular protein that modulates interactions between cells and their environment2,3. We have shown that SPARC modifies the assembly and organization of the extracellular matrix4 by functioning as an extracellular chaperone5. Our studies have demonstrated that SPARC inhibits the growth of several types of cancers (6,7 and Preliminary Studies). We have established that the anti-tumor properties of SPARC are mediated in part, by its angiogenesis inhibition6 and by blockade of fibroblast activation4, two major features of cancer-induced desmoplasia. Using structure-functional studies, we have shown that SPARC peptides corresponding to the highly conserved follistatin domain have potent anti- angiogenic activity8,9 and inhibit the growth of neuroblastoma9, pancreatic, lung, and breast cancers (Preliminary Studies). Thus SPARC has tumor suppressor functions in a broad range of neoplasms. Based on these data, we hypothesize that by interacting with matrix and stromal proteins, SPARC inhibits the growth of pancreatic cancer by blocking desmoplastic changes, and creating a more "normal" microenvironment that is non-permissive for tumor growth. The mechanisms by which SPARC modulates the tumor microenvironment and inhibits tumor growth remain largely unknown. We propose elucidating the mechanism using a unique systematic approach, developed by Dr. He, the co-PI on this grant10-12, to isolate proteins that are targeted by SPARC in pancreatic tumor tissue. Established interactions will be validated by co-expression and co-precipitation with SPARC. The functional significance of validated targets will be tested by down-regulation with shRNA and the ability to counteract anti-tumor properties of SPARC in a mouse xenograft model.