Matricellular proteins in intrahepatic cholangiocarcinoma

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.