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，不适合手术，并且对常规治疗具有高度抗性。中位生存期小于1年，5年生存率小于5%1，因此需要额外的治疗策略。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这种疾病的进展和化疗耐药性中起重要作用。因此，肿瘤微环境是胰腺癌的有希望的治疗靶点。 分泌蛋白酸性和富含半胱氨酸（Cys）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。我们已经表明，ESTA修改的组装和组织的细胞外基质4作为一个细胞外伴侣5。我们的研究已经证明，ESTA抑制几种类型的癌症的生长（6，7和初步研究）。我们已经确定，抗肿瘤特性的部分介导，其血管生成抑制6和阻断成纤维细胞活化4，两个主要特征的癌症诱导的结缔组织增生。使用结构-功能研究，我们已经表明，对应于高度保守的卵泡抑素结构域的多肽具有有效的抗血管生成活性8，9，并抑制神经母细胞瘤9、胰腺癌、肺癌和乳腺癌的生长（初步研究）。因此，在广泛的肿瘤中，P450具有肿瘤抑制功能。基于这些数据，我们假设，通过与基质和基质蛋白相互作用，cytokine通过阻断促纤维增生性变化并创造一个不允许肿瘤生长的更“正常”的微环境来抑制胰腺癌的生长。 肿瘤抑制剂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该机制，该方法由该基金的共同PI He博士开发10 -12，以分离胰腺肿瘤组织中被靶向的蛋白质。将通过共表达和与pH 3共沉淀来验证已建立的相互作用。验证的靶标的功能意义将通过用shRNA下调和在小鼠异种移植物模型中抵消cRNA的抗肿瘤特性的能力来测试。

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.