ADAM and ADAMTS Proteins, New Players in the Regulation of Hepatocellular Carcinoma Microenvironment

Abstract

The tumor microenvironment plays a major role in tumor growth, invasion and resistance to chemotherapy, however understanding how all actors from microenvironment interact together remains a complex issue. The tumor microenvironment is classically represented as three closely connected components including the stromal cells such as immune cells, fibroblasts, adipocytes and endothelial cells, the extracellular matrix (ECM) and the cytokine/growth factors. Within this space, proteins of the adamalysin family (ADAM for a disintegrin and metalloproteinase; ADAMTS for ADAM with thrombospondin motifs; ADAMTSL for ADAMTS-like) play critical roles by modulating cell–cell and cell–ECM communication. During last decade, the implication of adamalysins in the development of hepatocellular carcinoma (HCC) has been supported by numerous studies however the functional characterization of most of them remain unsettled. In the present review we propose both an overview of the literature and a meta-analysis of adamalysins expression in HCC using data generated by The Cancer Genome Atlas (TCGA) Research Network.

ADAM 17 and Epithelial-to-Mesenchymal Transition: The Evolving Story and Its Link to Fibrosis and Cancer

“…This switch in HSCs differentiation was mediated by ADAM proteases, and different molecular mechanisms have been reported related to ADAM-mediated EMT in the liver [ 87 , 88 ]. ADAM17 performs its role in promoting EMT of HCC through the activation of the Notch signalling pathway, which occurs after Notch proteolytic cleavage and active Notch intracellular domain (NICD) release [ 89 ]. Recent discoveries report that the pro-EMT effects of ADAM17 were antagonised by specific micro-RNA whose anti-EMT effects determined a decreased expression of mesenchymal markers ( N -cadherin and Vimentin) and of pro-EMT transcription factors (ZEB1, SNAIL and TWIST), with a concomitant increased expression of epithelial marker E-cadherin [ 90 ].…”

The potential prognostic values of the ADAMTS-like protein family: an integrative pan-cancer analysis

“…The over-expression of these ADAMs predicted poor prognosis in HCC. ADAM18, ADAM21 and ADAM32 were recently associated with HCC invasion (22,26). Conversity, low expression of ADAMTS5 and ADAMTS8 predicted poor prognosis and inhibited the progression of tumor in HCC cells (22,27,28).…”

“…Studies have identified two new members of ADAMTSL proteins such as ADAMTSL-6alpha and -6beta, which were association with fibrillin-1-rich microfibrils in elastic connective tissues (12). Furthermore, recent studies demonstrated that adamalysin family (consisting of ADAM, ADAMTS, ADAMTSL) were associated with TME by regulating the inflammatory response and the epithelial-mesenchymal transition in hepatocellular carcinoma (22). The host ADAM28-deficient was correlated with a decreased lung infiltration by CD8+ T lymphocytes, suggesting ADAM28 involved in T cell mobilization and TME regulation (23).…”

“…The recent study investigated the roles of ADAM-like protein family in hepatocellular carcinoma (HCC) (22). The over-expression of these ADAMs predicted poor prognosis in HCC.…”

“…ADAM18, ADAM21 and ADAM32 were recently associated with HCC invasion (22,26). Conversity, low expression of ADAMTS5 and ADAMTS8 predicted poor prognosis and inhibited the progression of tumor in HCC cells (22,27,28). The balance of pro-tumor and anti-tumor roles of this family were critical processes in cancer progression (22,29).…”