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%以上，是第四常见的肝癌。 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。然而，自1980年以来，HCC增加了两倍，并继续增长，而死亡率增加了一倍。 间质变化是HCC病理进展、HCC分子亚型和HCC预后的主要特征。 是预后的预测因素，但基质蛋白的翻译和翻译后修饰（PTM） 与病理性细胞状态相关的疾病仍然是未知的。我们的初步数据显示， 基质蛋白的定位，特别是胶原羟化脯氨酸的PTM位点调节的变化 （HYPs）局限于病理学。间质HYP变异体可以区分HCC的分子亚型， 结果表明，HYP变异可能与生存和进展直接相关。从这个 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 B）PTM HYP位点是区分HCC病理的主要调节因子 胶原蛋白α-1（I）链（COL 1A 1）、α-1（II）链（COL 1A 2）和α-1（III）链类型中的亚型 （C 0 L3 A1）; C）基质变体，包括翻译后HYP修饰，代表了一种新的，临床上可接受的突变。 是HCC的重要贡献者。目的是确定与病理细胞状态共定位的基质变体 通过研究HCC分子亚型，确定HCC基质变异的临床意义， 不同的调节相对于进展的等级和阶段以及结果。基质表征 由于肿瘤微环境中病理细胞来源的变异可能有助于阐明和/或监测肿瘤微环境中的病理细胞来源。 有助于亚型演变的癌相关成纤维细胞的功能状态。我们希望这项工作 将导致新的机制方向靶向基质的治疗和结果可能会进一步发展 作为辅助临床工具，帮助患者管理。一个长期目标是提高瞄准能力 间质治疗和消除HCC死亡率。