Cellular Sources of Pathological Stromal Variants

肝细胞癌(HCC)占原发性肝癌的80%，是第四大常见肿瘤 癌症相关死亡原因。根据2005年的人口预测，肝细胞癌本应减少8% 到2015年。然而，自1980年以来，肝癌已经增加了两倍，而且还在继续增长，而死亡率则翻了一番。 间质改变是肝细胞癌病理进展、肝细胞癌分子亚型和 可以预测结果，但基质蛋白的翻译和翻译后修饰(PTM) 与病理状态相关的细胞状态大多尚不清楚。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变异体可以区分不同的肝癌分子亚型 结果表明，HYP变异可能与生存和进展有直接关联。由此 我们假设A)肝组织内的区域化细胞群具有独特的间质特征 B)PTM HYP位点是区分肝细胞癌病理的主要调节因子 原发胶原α-1(I)链(COL1A1)、α-1(II)链(COL1A2)和α-1(III)链的亚型 (COL3A1)；C)基质变异，包括翻译后HYP修饰，在临床上代表了一种新的 肝细胞癌的重要贡献者。目标是定义共同定位于病理细胞状态的基质变异体 根据肝细胞癌分子亚型确定肝细胞癌间质变异的临床意义 不同等级、不同阶段和不同结果的发展变化规律。基质的特征 肿瘤微环境中因病理细胞起源而产生的变异可能有助于阐明和/或监测 癌症相关成纤维细胞在亚型演变中的功能状态。我们希望这项工作 将导致针对治疗的间质靶向的新的机制方向，结果可能会进一步发展 作为辅助的临床工具，帮助患者管理。一个长期目标是提高目标能力。 间质疗法和消除肝细胞癌死亡率。

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.