Sirica Alphonse E
Emeritus Professor of Pathology, Virginia Commonwealth University School of Medicine, Richmond, VA, United States.
Adv Cancer Res. 2022;156:249-281. doi: 10.1016/bs.acr.2022.01.010. Epub 2022 Feb 18.
Intrahepatic cholangiocarcinoma (iCCA) is typically characterized by a prominent desmoplastic stroma that is often the most dominant feature of the tumor. This tumor reactive stroma is comprised of a dense fibro-collagenous-enriched extracellular matrix (ECM) surrounding the cancer cells, together with other ECM proteins/peptides, specifically secreted matricellular glycoproteins and proteolytic enzymes, growth factors, and cytokines. Moreover, as enjoined by cholangiocarcinoma cells, this enriched tumor microenvironment is populated by various stromal cell types, most prominently, cancer-associated myofibroblasts (CAFs), along with variable numbers of tumor-associated macrophages (TAMs), inflammatory and vascular cell types. While it is now well appreciated that the interplay between cholangiocarcinoma cells, CAFs, and TAMs in particular play a critical role in promoting cholangiocarcinoma progression, therapeutic resistance, and immune evasion, it is also becoming increasingly evident that over-expression and secretion into the tumor microenvironment of functionally overlapping matricellular glycoproteins, including periostin, osteopontin, tenascin-C, thrombospondin-1, mesothelin and others have an important role to play in regulating or modulating a variety of pro-oncogenic cellular functions, including cholangiocarcinoma cell proliferation, invasion, and metastasis, epithelial-mesenchymal transition, ECM remodeling, and immune evasion. Matricellular proteins have also shown promise as potential prognostic factors for iCCA and may provide unique therapeutic opportunities particularly in relation to targeting iCCA pre-metastatic and metastatic niches, tumor cell dormancy, and immune evasion. This review will highlight timely research and its translational implications for salient matricellular proteins in terms of their structure-function relationships, as modulators of intrahepatic cholangiocarcinoma microenvironment and progression, and potential clinical value for iCCA prognosis and therapy.
肝内胆管癌（iCCA）的典型特征是具有显著的促纤维增生性基质，这通常是肿瘤最主要的特征。这种肿瘤反应性基质由围绕癌细胞的富含纤维胶原的致密细胞外基质（ECM）组成，还包括其他ECM蛋白/肽，特别是分泌的基质细胞糖蛋白和蛋白水解酶、生长因子及细胞因子。此外，在胆管癌细胞的作用下，这种丰富的肿瘤微环境中有多种基质细胞类型，最显著的是癌症相关肌成纤维细胞（CAF），以及数量不等的肿瘤相关巨噬细胞（TAM）、炎症细胞和血管细胞类型。虽然目前人们已经充分认识到胆管癌细胞、CAF和TAM之间的相互作用在促进胆管癌进展、治疗耐药和免疫逃逸中起着关键作用，但越来越明显的是，包括骨膜蛋白、骨桥蛋白、腱生蛋白-C、血小板反应蛋白-1、间皮素等功能重叠的基质细胞糖蛋白在肿瘤微环境中的过度表达和分泌，在调节或调控多种促癌细胞功能方面发挥着重要作用，这些功能包括胆管癌细胞的增殖、侵袭和转移、上皮-间质转化、ECM重塑及免疫逃逸。基质细胞蛋白也显示出有望成为iCCA的潜在预后因素，并且可能提供独特的治疗机会，特别是在靶向iCCA的转移前和转移小生境、肿瘤细胞休眠及免疫逃逸方面。本综述将重点介绍关于重要基质细胞蛋白的及时研究及其转化意义，包括它们的结构-功能关系、作为肝内胆管癌微环境和进展的调节因子以及对iCCA预后和治疗的潜在临床价值。
