Extracellular Matrix Dynamics in Hepatocarcinogenesis: a Comparative Proteomics Study of PDGFC Transgenic and Pten Null Mouse Models

Abstract

We are reporting qualitative and quantitative changes of the extracellular matrix (ECM) and associated receptor proteomes, occurring during the transition from liver fibrosis and steatohepatitis to hepatocellular carcinoma (HCC). We compared two mouse models relevant to human HCC: PDGFC transgenic (Tg) and Pten null mice, models of disease progression from fibrosis and steatohepatitis to HCC. Using mass spectrometry, we identified in the liver of both models proteins for 26 collagen-encoding genes, providing the first evidence of expression at the protein level for 16 collagens. We also identified post-transcriptional protein variants for six collagens and lysine hydroxylation modifications for 14 collagens. Tumor-associated collagen proteomes were similar in both models with increased expression of collagens type IV, VI, VII, X, XIV, XV, XVI, and XVIII. Splice variants for Col4a2, Col6a2, Col6a3 were co-upregulated while only the short form of Col18a1 increased in the tumors. We also identified tumor specific increases of nidogen 1, decorin, perlecan, and of six laminin subunits. The changes in these non-collagenous ECM proteins were similar in both models with the exception of laminin β3, detected specifically in the Pten null tumors. Pdgfa and Pdgfc mRNA expression was increased in the Pten null liver, a possible mechanism for the similarity in ECM composition observed in the tumors of both models. In contrast and besides the strong up-regulation of integrin α5 protein observed in the liver tumors of both models, the expression of the six other integrins identified was specific to each model, with integrins α2b, α3, α6, and β1 up-regulated in Pten null tumors and integrins α8 and β5 up-regulated in the PDGFC Tg tumors. In conclusion, HCC–associated ECM proteins and ECM–integrin networks, common or specific to HCC subtypes, were identified, providing a unique foundation to using ECM composition for HCC classification, diagnosis, prevention, or treatment.

Adipocyte-derived endotrophin promotes malignant tumor progression

“…COL6 upregulation has been reported in various aspects of tumor progression. Malignant cancer cells can also express COL6; this has been reported for the mammary gland (18), the colon (35,36), pancreatic ductal adenocarcinomas (37), and hepatocarcinomas (38). Thus, the source of ETP in the tumor microenvironment may be heterogeneous, with signals cooperatively influencing cancer cell behavior through paracrine and autocrine pathways.…”

Always cleave up your mess: targeting collagen degradation to treat tissue fibrosis

“…These studies indicate that in addition to an increase in total collagen in IPF (150,151) there is also a shift toward the less elastic type I collagen, which contributes to pathophysiological abnormalities in fibrosis (51,125,145). A relative increase in type I collagen production (as well as an increase in total lung collagen content) has also been demonstrated in the lungs of patients with ARDS (87,140) as well as in human fibrotic livers (85).…”

Extracellular Matrix Remodeling: The Common Denominator in Connective Tissue DiseasesPossibilities for Evaluation and Current Understanding of the Matrix as More Than a Passive Architecture, but a Key Player in Tissue Failure

“…194 A recent mass spectrometry study of the ECM in two rodent models identified 16 different collagens in the liver, and profiled changes in the abundance of collagens and integrins in tumors compared with healthy livers and precancerous fibrotic livers. 195 Neoepitopes of these proteins may serve as valuable markers of liver ECMR. Promising candidates have been reported, including those derived from type IV collagen, 196,197 type I collagen, 198 type V collagen, 199 and type VI collagen.…”