Altered Growth Factor Pathways in Biliary Cancer

胆道癌中生长因子途径的改变

• 批准号: 8499770
• 负责人: ALPHONSE E SIRICA
• 金额: $ 30.7万
• 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 2018-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8499770
• 关键词: Accounting; Address; Adult; 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; Hepatic; Hepatocyte Growth Factor; Human; Hyperplasia; In Vitro; Incidence; Integrins; Intrahepatic Cholangiocarcinoma; Laboratories; Lead; Ligation; Link; Liver; Malignant - descriptor; Malignant Neoplasms; 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; Right lobe of liver; Role; Signal Pathway; Signal Transduction; Smooth Muscle Actin Staining Method; Staging; Stromal Cell-Derived Factor 1; Testing; Therapeutic; Up-Regulation; Western Blotting; advanced disease; base; bile duct; chemokine; cholangiocyte; clinically relevant; gastrointestinal; hepatobiliary cancer; immunoreactivity; in vivo; in vivo Model; innovation; meetings; mortality; novel; outcome forecast; overexpression; periostin; public health relevance; 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 ?-smooth muscle actin-positive cancer-associated fibroblastic cells (?-SMA+CAFs). However, while it is becoming increasingly apparent that ?-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 ?-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 ?-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 ?-SMA+CAFs generate convergent proinvasive signals to cholangiocarcinoma cells through periostin/integrin ?4, 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 ?-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 ?-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（由申请人提供）：肝内胆管癌（ICC）是一种高度恶性的原发性肿瘤，由于其发病率不断上升、死亡率高，并且对于最常出现晚期致命性疾病的患者来说，治疗选择有限，因此被认为具有临床重要性和治疗挑战性。 ICC 的一个标志性特征是富含 β-平滑肌肌动蛋白阳性癌症相关成纤维细胞 (β-SMA+CAF) 的显着促纤维增生基质。然而，虽然越来越明显的是，α-SMA+CAFs可能在促进ICC进展中发挥着至关重要的作用，但这种肌纤维母细胞样细胞促进侵袭性ICC的具体机制仍然难以捉摸。上一个资助周期的一个主要进展是我们建立了 ICC 进展的原位同基因大鼠模型，该模型概括了人类促纤维增生性 ICC 早期和晚期阶段的关键病理、分子和临床特征。最近，我们还成功开发并部分表征了一种新型的胆管癌三维器官型共培养模型，该模型补充了我们的体内 ICC 模型。 通过共培养，我们进一步证明源自原位大鼠 ICC 的 α-SMA+CAF 在体外显着促进胆管癌细胞导管生长和侵袭性，并刺激与 ICC 侵袭性生长和进展相关的特定基因（例如 CXCR4、HGF、Muc1）的上调。我们进一步证明骨膜蛋白（一种由 ICC 中的 α-SMA+CAF 合成和分泌的基质细胞蛋白）在快速生长的侵袭性 ICC 中比在我们的大鼠体内模型中形成的缓慢生长的低侵袭性 ICC 中表达更高。作为这些发现的逻辑延伸，我们现在提出两个具体目标。具体目标 1 侧重于阐明骨膜素作为 ICC 进展的潜在重要介质的功能作用。 在此目标下，我们还将检验我们的假设，即α-SMA+CAF通过骨膜素/整合素α4、HGF/Met和SDF-1/CXCR4介导的FAK/PI3K-Akt/Rac1激活向胆管癌细胞产生会聚的促侵袭信号。具体目标 2 将利用我们独特的大鼠器官型胆管癌细胞培养物和原位 ICC 模型，以及临床相关的靶向药物，以基于交互式 ?-SMA+CAF/胆管癌细胞通路（例如，hedgehog 信号通路、HGF/Met 和 SDF-1/CXCR4) 与 ICC 进展相关。我们预计拟议研究产生的结果将阐明骨膜素在 ICC 进展中的作用，并阐明其与选择生长因子/趋化因子介导的信号通路的关系，通过该通路，α-SMA+CAF 与胆管癌细胞相互作用，促进侵袭性恶性行为。此外，我们相信拟议研究产生的数据对于为进展性 ICC 患者确定更潜在有效和合理的治疗策略将具有真正的价值，这有望以有意义的方式引导新的临床试验的发展。