Table 1 Post-translational modifications of ECM and ECM-associated molecules and their implications in cancer.
From: Concepts of extracellular matrix remodelling in tumour progression and metastasis
Post-translational modification | Protein targets | Effectors | Cancer types | Associated changes in cancer |
|---|---|---|---|---|
Hydroxylation | Collagen | Procollagen-lysine 1, 2-oxoglutarate 5-dioxygenases (PLODs) | Many types, including bladder254, lung255, and breast cancers256, and renal cell carcinoma257 | Increased expression of PLODs in cancer and stromal cells increases collagen cross-linking and correlates with poor survival. PLOD2 is induced by hypoxic conditions71. |
Collagen | Prolyl-4-hydroxylase subunit alpha-1 (P4HA) | Breast cancer | Inhibition of collagen hydroxylation increases breast cancer-derived lung metastasis in mice258. | |
Cross-linking | Collagen, elastin | Lysyl oxidase (LOX) and lysyl oxidase homologues (LOXLs) | Many types, including colorectal, pancreatic, breast, lung, and prostate259 | Overexpression of LOX and LOXLs increases fibrosis and ECM stiffness and promotes tumourigenesis and metastasis259. |
Fibronectin, HSPB, fibrinogen, collagen VI | Transglutaminases | Many types, including PDAC, glioblastoma, melanoma260, and breast cancer261 | Overexpression of TG2 in cancer cells and metastatic cancer cells262 increases ECM cross-linking, affects mechanical properties and cell–matrix signalling68. | |
Glycosylation | Fibronectin | Glycosyltransferases and glycosidases | Urothelial carcinoma263 | Increased fibronectin glycosylation is correlated with increased invasiveness of urothelial carcinoma263 and enhanced EMT in human prostate cancer cell lines264. |
αvβ3 and αvβ6 integrins | Glycosyltransferases and glycosidases | Breast cancer | Inhibition of glycosylation increases the invasion properties of metastatic cells265. | |
Phosphorylation | Fibronectin | Casein kinase II-like protein kinase | Many types266 | Phosphorylated fibronectin increases mechanical cell functions and cell traction forces for attachment266 and occurs at growth factor binding sites267. |
Many targets including MMPs and laminin A1 | Vertebrate lonesome kinase (VLK) and extracellular serine/threonine protein kinase (FAM20C) | Currently poorly understood268 | Extracellular kinases phosphorylate ECM and ECM-associated components, which can potentially alter downstream kinase signalling pathways268,269. | |
Sulphation | Glycosaminoglycans (GAGs) | Sulfotransferases and heparanase | Many types, including breast, ovarian, colorectal, prostate, and gastric cancers270 | Changes in the degree of sulphation and/or the pattern in chondroitin sulphates and heparan sulphates in glycosaminoglycans are associated with different cancers by changing cell–cell and cell–matrix signalling270,271,272. |
Citrullination | Collagen | Protein arginine deiminase 4 (PAD4) | Liver metastases of colorectal cancer | Promotes liver metastases of colorectal cancer215. |
Isomerization | C-terminal telopeptide of type I collagen | Non-enzymatic | Breast and prostate cancer | High levels of non-isomerised C-telopeptide of collagen I (α-CTX-I) are indicative of high ECM turnover in bone metastases220. |
Carbamylation | Collagen | Non-enzymatic | Currently poorly understood | Increased carbamylation decreases stability of collagen I triple helices and affects their degradation by MMPs273. Carbamylated collagen type I affects cancer cell migration274. |
Glycation | Collagen | Non-enzymatic | Currently poorly understood | Glycated collagen type I affects cancer cell migration274. |
