Cellular Sources of Pathological Stromal Variants

病理性基质变异的细胞来源

• 批准号: 10439877
• 负责人: Peggi M Angel
• 金额: $ 20.39万
• 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 2024-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10439877
• 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% 以上，是第四常见的癌症 癌症相关死亡的原因。根据 2005 年的人口预测，HCC 应该减少 8% 到 2015 年，HCC 数量自 1980 年以来增加了两倍，并且持续增长，而死亡率则翻了一番。 间质变化是 HCC 病理进展、HCC 分子分型的主要特征， 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部分仍然未知。我们的初步数据显示了高度复杂性 基质蛋白的定位，特别是胶原羟基化脯氨酸的 PTM 位点调节的变化 （HYP）局限于病理学。基质 HYP 变异可以区分 HCC 的分子亚型，其不同之处在于 结果表明 HYP 变异可能与生存和进展有直接关系。从这里 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 导致 HCC 亚型的因素； B) PTM HYP 位点是区分 HCC 病理的主要调节因子 初级胶原蛋白的亚型 胶原蛋白类型 α-1(I) 链 (COL1A1)、α-1(II) 链 (COL1A2) 和 α-1(III) 链 （COL3A1）； C) 基质变异，包括翻译后 HYP 修饰，代表了一种新颖的临床 HCC 的重要贡献者。目标致力于定义与病理细胞状态共定位的基质变异 通过研究 HCC 分子亚型并确定 HCC 基质变异的临床意义 与按年级和阶段以及结果进展相关的变异调节。基质的表征 由于肿瘤微环境中病理细胞起源引起的变异可能有助于阐明和/或监测 癌症相关成纤维细胞的功能状态有助于亚型进化。我们期望这项工作 将导致靶向基质治疗的新机制方向，并且结果可能会得到进一步发展 作为帮助患者管理的辅助临床工具。长期目标是提高瞄准能力 基质疗法并消除 HCC 死亡率。