Altered Growth Factor Pathways in Biliary Cancer

胆道癌中生长因子途径的改变

• 批准号: 8829763
• 负责人: ALPHONSE E SIRICA
• 金额: $ 30.73万
• 依托单位: VIRGINIA COMMONWEALTH UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2000
• 资助国家: 美国
• 起止时间: 2000-02-08 至 2016-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8829763
• 关键词: Accounting; Address; Alpha Cell; Behavior; Binding; Biological; CXCR4 gene; Cell Culture Techniques; Cells; Characteristics; Cholangiocarcinoma; Clinical; Clinical Trials; Coculture Techniques; Complement; Data; Desmoplastic; Development; Diagnosis; Disease; Duct (organ) structure; Ductal Epithelial Cell; Epithelial; Etiology; Europe; Exhibits; Fibroblasts; Funding; Genes; Gland; Grant; Growth; Growth Factor; Health; Hepatic; Hepatocyte Growth Factor; Human; Hyperplasia; In Vitro; Incidence; Integrins; Intrahepatic Cholangiocarcinoma; Laboratories; Lead; Ligation; Link; Liver; Malignant - descriptor; Malignant Neoplasms; Malignant neoplasm of gastrointestinal tract; Malignant neoplasm of liver; Mediating; Mediator of activation protein; Modeling; Molecular; Neoplasm Metastasis; Outcome; PTK2 gene; Pathway interactions; Patients; Play; Preclinical Testing; Primary Neoplasm; Primary carcinoma of the liver cells; Progress Reports; Proteins; Rattus; Research; Resistance; Role; Signal Pathway; Signal Transduction; Smooth Muscle Actin Staining Method; Staging; Stromal Cell-Derived Factor 1; Stromal Cells; Testing; Therapeutic; Up-Regulation; advanced disease; base; bile duct; chemokine; cholangiocyte; clinically relevant; hepatobiliary cancer; in vivo; in vivo Model; innovation; meetings; mortality; novel; outcome forecast; periostin; smoothened signaling pathway; treatment strategy; tumor

DESCRIPTION (provided by applicant): Intrahepatic cholangiocarcinoma (ICC) is a highly malignant primary neoplasm that is considered to be clinically important and therapeutically challenging due to its increasing incidence, high mortality rates, and limited treatment options for patients who most often present with advanced fatal disease. A hallmark feature of ICC is a prominent desmoplastic stroma enriched in α-smooth muscle actin-positive cancer-associated fibroblastic cells (α-SMA+CAFs). However, while it is becoming increasingly apparent that α-SMA+CAFs may be playing a crucial role in promoting ICC progression, specific mechanisms through which such myofibroblastic-like cells may act to promote aggressive ICC remain elusive. A major development of the previous grant cycle was our establishment of an orthotopic syngeneic rat model of ICC progression that recapitulates key pathological, molecular, and clinical features of early and advanced stages of human desmoplastic ICC. Recently, we also succeeded in developing and partially characterizing a novel three- dimensional organotypic co-culture model of cholangiocarcinoma that complements our in vivo ICC model. Using co-culturing, we further showed α-SMA+CAFs derived from orthotopic rat ICC to significantly promote cholangiocarcinoma cell ductal growth and invasiveness in vitro, as well as to stimulate up-regulation of specific genes associated with ICC invasive growth and progression (e.g., CXCR4, HGF, Muc1). We further demonstrated periostin, a matricellular protein synthesized and secreted by α-SMA+CAFs in ICC, to be more highly expressed in rapidly growing, invasive ICCs than in slow growing, low invasive ICCs formed in our rat in vivo model. As a logical extension of these findings, we are now proposing two Specific Aims. Specific Aim 1 is focused on clarifying the functional role of periostin as a potentially important mediator of ICC progression. Under this aim, we will also test our hypothesis that α-SMA+CAFs generate convergent proinvasive signals to cholangiocarcinoma cells through periostin/integrin ß4, HGF/Met, and SDF-1/CXCR4-mediated activation of FAK/PI3K-Akt/Rac1. Specific Aim 2 will utilize our unique rat organotypic cholangiocarcinoma cell culture and orthotopic ICC models, together with clinically relevant targeted agents, to preclinically validate an innovative moleculr strategy for ICC therapy based on combinational targeting of interactive α-SMA+CAF/ cholangiocarcinoma cell pathways (e.g., hedgehog signaling pathway, HGF/Met, and SDF-1/CXCR4) associated with ICC progression. We anticipate the results generated by the proposed research to clarify the role of periostin in ICC progression and elucidate its relationship to select growth factor/chemokine-mediated signaling pathways by which α-SMA+CAFs cross-talk with cholangiocarcinoma cells to facilitate aggressive malignant behavior. Moreover, we believe data generated from the proposed research will be of real value in identifying more potentially effective and rational treatment strategies for patients with progressive ICC, which hopefully will lead in a meanigful way to the development of new clinical trials.

描述（由适用提供）：肝内胆管癌（ICC）是一种高度恶性的原发性肿瘤，由于其发病率的增加，高死亡率和治疗方案有限，因此被认为在临床上很重要，并且在治疗方面具有挑战，对于最经常患有晚期致命疾病的患者。 ICC的标志性特征是富含α-光滑肌肉肌动蛋白阳性癌症相关的成纤维细胞（α-SMA+CAF）的突出的脱肿瘤基质。但是，尽管越来越明显的是，α-SMA+CAF可能在促进ICC进展中起着至关重要的作用，但这种肌纤维细胞样细胞可能会促进攻击性ICC仍然难以捉摸。上一个赠款周期的一个重大发展是我们建立了ICC进展的原位合成大鼠模型，该模型概述了人类脱发ICC的早期和晚期阶段的关键病理，分子和临床特征。最近，我们还成功地开发并部分表征了一种新型的胆管癌的三维有机共培养模型，该模型完成了我们的体内ICC模型。使用共培养，我们进一步展示了源自原位大鼠ICC的α-SMA+CAFS，可以显着促进胆管癌细胞导管生长和体外的侵入性，并刺激与ICC侵入性生长和进展相关的特定基因上调的上调（例如我们进一步证明了ICC中由α-SMA+CAFS合成和分泌的基质蛋白的周期，在快速生长，侵入性ICC中比在缓慢生长中更高表达，在我们的大鼠IN VIVO模型中形成的低浸润性ICC。作为这些发现的逻辑扩展，我们现在提出了两个具体目标。具体目标1的重点是阐明SECESTIN作为ICC进展的潜在重要介体的功能作用。在此目标下，我们还将测试我们的假设，即α-SMA+CAFS通过odeStin/inteminβ，HGF/MET和SDF-1/CXCR4介导的FAK/PI3K-AKT/RAC1的活化激活，从而通过odeStin/inteminß4，HGF/MET和SDF-1/CXCR4介导的激活来产生收敛性的促染料信号。 Specific Aim 2 will utilize our unique rat organic cholangiocarcinoma cell culture and orthotopic ICC models, together with clinically relevant targeted agents, to preclinically validate an innovative molecular strategy for ICC therapy based on combined targeting of interactive α-SMA+CAF/ cholangiocarcinoma cell pathways (e.g., hedgehog signaling pathway, HGF/Met, and SDF-1/CXCR4）与ICC进展相关。我们预期拟议的研究产生的结果阐明了时期斯汀在ICC进展中的作用，并阐明了其与选择生长因子/趋化因子介导的信号传导途径的关系 α-SMA+CAF与胆管癌细胞串联，以促进侵袭性恶性行为。此外，我们认为，拟议的研究产生的数据将在确定渐进式ICC患者的更有效和合理的治疗策略方面具有真正的价值，希望该策略能够以有意义的方式领导新的临床试验。