Cellular Sources of Pathological Stromal Variants

病理性基质变异的细胞来源

• 批准号: 10290395
• 负责人: Peggi M Angel
• 金额: $ 17.23万
• 依托单位: MEDICAL UNIVERSITY OF SOUTH CAROLINA
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-07-01 至 2023-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10290395
• 关键词: Age; Alcohol abuse; Area; COL1A1 gene; COL1A2 gene; Cancer Etiology; Cell Adhesion; Cells; Cessation of life; Chronic; Cicatrix; Cirrhosis; Clinical; Collagen; Complex Mixtures; Complication; Data; Deposition; Development; Diet; Disease; Fibroblasts; Fibrosis; Gender; Goals; Hydroxylation; Incidence; Individual; Injury; Integrin Binding; Link; Liver; Liver parenchyma; Malignant Neoplasms; Measures; Modification; Monitor; Outcome; Pathologic; Pathology; Pathway interactions; Patients; Peptides; Play; Population; Population Projection; Post-Translational Modification Site; Post-Translational Protein Processing; Post-Translational Regulation; Primary Malignant Neoplasm of Liver; Primary carcinoma of the liver cells; Prognostic Marker; Proline; Proteins; Proteomics; Regulation; Research; Resolution; Role; SHH gene; Sampling; Site; Source; Stains; TNM; Testing; Tissue Microarray; Tissue imaging; Tissues; Translational Regulation; Variant; Virus Diseases; Work; base; cell type; cellular pathology; clinical phenotype; clinically relevant; clinically significant; diagnostic biomarker; discoidin receptor; improved; molecular pathology; molecular subtypes; mortality; novel; novel marker; outcome prediction; patient stratification; patient subsets; predictive tools; protein expression; survival outcome; survival prediction; targeted treatment; tool; tumor; tumor microenvironment

Hepatocellular carcinoma (HCC) accounts for >80% of primary liver cancers and is the fourth most common cause of cancer-related death. Based on populations projections in 2005, HCC should have decreased by 8% by the year 2015. However, HCC has tripled since 1980 and continues to grow while mortality has doubled. Stroma changes are a primary feature in the pathological progression of HCC, molecular subtyping of HCC, and are predictive of outcomes, yet the translational and post-translational modifications (PTMs) of stromal proteins related to pathological cell status remains mostly unknown. Our preliminary data shows high complexity in localization of stromal proteins and, particularly, changes in PTM site regulation of collagen hydroxylated prolines (HYPs) localized to pathology. Stromal HYP variants can distinguish molecular subtypes of HCC that differe by outcome, suggesting that HYP variants may have a direct association with survival and progression. From this we hypothesize that A) Regionalized cell populations within the liver tissue have distinctive stromal signatures that contribute to HCC subtypes; B) The PTM HYP sites are a primary regulator differentiating HCC pathology subtypes in primary collagens collagen types α-1(I) chain (COL1A1), α-1(II) chain (COL1A2), and α-1(III) chain (COL3A1); C) Stromal variants, including post-translational HYP modifications, represent a novel, clinically significant contributor to HCC. The Aims work to define stromal variants co-localized to pathological cell status by HCC molecular subtypes and determine the clinical significance of HCC stromal variants by investigating variant regulation relative to progression by grade and stage as well as outcome. Characterization of stromal variants due to pathological cell origin within the tumor microenvironment may help elucidate and/or monitor the functional state of cancer associated fibroblasts contributing to subtype evolvement. We expect that this work will lead to new mechanistic directions in targeting stroma for therapies and the results may be further developed as ancillary clinical tools that help in patient management. A long-term goal is to improve targeting capabilities of stromal therapies and eliminate HCC mortality.

肝细胞癌（HCC）占原发性肝癌的80％，是第四个最常见的 与癌症有关的死亡原因。根据2005年人口项目，HCC应该下降8％ 但是，到2015年。但是，自1980年以来，HCC已经增加了两倍，并且死亡率增加了一倍。 基质变化是HCC，HCC分子亚型的病理进展的主要特征，以及 可以预测结果，但基质蛋白的翻译和翻译后修饰（PTM） 与病理细胞状态相关的大多数未知。我们的初步数据显示 基质蛋白的定位，尤其是PTM位点调节胶原蛋白羟蛋白的变化 （HYP）本地化为病理。基质催眠变体可以区分HCC的分子亚型 结果，表明催眠变体可能与生存和进展直接相关。由此 我们假设a）肝组织内的区域化细胞群具有独特的基质特征 这有助于HCC亚型； b）PTM炒作位点是区分HCC病理学的主要调节剂 原代胶原蛋白胶原类型α-1（I）链（COL1A1），α-1（II）链（COL1A2）和α-1（III）链中的亚型 （col3a1）; c）基质变体，包括翻译后的催眠修饰，代表了一种新颖的临床 HCC的重要贡献者。目的是定义与病理细胞状态共定位的基质变体 通过HCC分子亚型，并通过研究HCC基质变异的临床意义 相对于成绩和阶段以及结果的变化调节。基质的表征 肿瘤微环境内由于病理细胞起源引起的变体可能有助于阐明和/或监测 癌症相关的成纤维细胞的功能状态，导致亚型进化。我们希望这项工作 将导致靶向疗法基质的新机械方向，结果可能会进一步发展 作为有助于患者管理的辅助临床工具。一个长期目标是提高目标能力 基质疗法并消除HCC死亡率。