Table 1.

Post-translational modifications of ECM and ECM-associated molecules and their implications in cancer.

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 signalling270–272.
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.