Table 1.
ECM fragments affect the main hallmarks of cancer progression.
| ECM bioactive fragments | Parent molecule | Generating enzymes | Receptors | Biological activity |
|---|---|---|---|---|
| Collagen fragments | ||||
| Type IIB procollagen NH2 propeptide | Type IIB collagen | ADAMTS-3 (20) | αvβ3, αvβ5 integrins (21) | ↗ EC and tumor cell death (chondrosarcoma, cervical and breast cancer) (21) through programmed cell necrosis (22) |
| Arresten (α1 chain NC1 domain) | Type IV collagen | Cathepsin S (23) MT1-MMP, MT2-MMP (24) |
α1β1 integrin (25, 26) | ↘ Angiogenesis and tumor growth (melanoma, glioblastoma, colorectal and lung cancer, squamous cell carcinomas) (25) ↘ FAK/c-Raf/MEK-1/2/ERK-1/2/p38 MAPK pathways in EC↗ EC apoptosis through bcl-xl/bax ratio modulation (25) |
| Canstatin (α2 chain NC1 domain) | Type IV collagen | Cathepsin S (23) MT1-MMP, MT2-MMP (24) |
α1β1, αvβ3, αvβ5 integrins (27) | ↘ Angiogenesis and tumor growth (ocular, lung, breast, oral squamous cell, esophageal carcinoma, gastric, ovarian, pancreatic, prostate, and colorectal cancer (28) ↘ VEGF-A/VEGFR-1-2 signaling pathway in squamous cell carcinoma (29) ↗ Apoptosis in cancer cell and EC through bcl-2bcl-xl/bax ratio modulation (30) ↘ Caspase 8 and 9 activation in EC (27) |
| Tumstatin (α3 chain NC1 domain) | Type IV collagen | MMP-9 (31) | αvβ3, αvβ5 integrins (32) | ↘ Angiogenesis and tumor growth (melanoma, glioma, osteosarcoma, breast, colon, prostate and lung cancer, gastric, hepatocellular, and squamous cell carcinoma (33, 34) |
| 54–132 amino-acid sequence | 54–132 amino-acid sequence:↗ G1 arrest, ↗ caspase-3 activation and ↘ FAK/PI3K/Akt/mTOR pathway in ECs (35) | |||
| 185–203 amino-acid sequence | 185–203 amino-acid sequence :↘ melanoma and EC migration through a decrease in MMP-2, uPA, t-PA (36) | |||
| Tetrastatin (α4 chain NC1 domain) | Type IV collagen | αvβ3 integrin (37) | ↘ Tumor growth (melanoma, glioma, osteosarcoma, breast, colon, prostate and lung cancer, gastric, hepatocellular and squamous cell carcinoma (37–40) ↘ FAK/PI3K/Akt pathway and ↘ MMP-2 in tumor cells (37, 38) |
|
| Lamstatin (α5 chain NC1 domain) | Type IV collagen | ↘ Angiogenesis (41) and lung cancer growth (42, 43)Unknown molecular mechanism | ||
| Hexastatin (α6 chain NC1 domain) | Type IV collagen | ↘ Angiogenesis and tumor growth (Lewis lung carcinoma and spontaneous pancreatic insulinoma) (44)Unknown molecular mechanism | ||
| Vastatin (NC1 domain of collagen VIII alpha 1 chain) | Type VIII collagen | ↘ EC proliferation and tumor growth and metastasis in murine hepatocellular carcinoma models (45) ↘ PcK1, JAG2, and c-Fos, ↘ Notch/AP-1 pathway (46) |
||
| Restin (NC10 domain of collagen XV) | Type XV collagen | ↘ EC migration, renal carcinoma growth (47) and breast cancer metastasis (48) ↘ ATF3 activity by direct interaction (49) ↘ EMT through p-73 binding, mir-200a/b increase and ZEB1/2 inhibition in breast cancer cells (48) |
||
| Endostatin (20-kDa C-terminal fragment of collagen XVIII) | Type XVIII collagen | α5β1 integrin; caveolin-1 (50) | ↘ Angiogenesis, lymphangiogenesis and tumor growth (51) ↗ Src-kinase pathway, ↘ RhoA GTPase activity; ↘ Ras/c-Raf/p38/Erk-1 pathway in EC (52, 53) |
|
| Frizzled domain (FZC18): ↘ Wnt/β-catenin pathway (54) | ||||
| NC1 XIX | Type XIX collagen | Plasmin (55) | αvβ3 integrin (56) | ↘ Melanoma cell migration, invasion, tumor growth and angiogenesis (56, 57) ↘ MMP-14 (57) in melanoma↘ FAK/PI3K/Akt/mTOR pathway in melanoma cells (57) |
| Elastin fragments | ||||
| VG-6 (VGVAPG) | Elastin | Proteinase 3, cathepsin G (58), MMP-7,9,12 (59), neprilysin (60) | ERC, αvβ3 and αvβ5 integrins, galactin-3 (61), RPSA (62) | ↗ Angiogenesis (63) and tumor growth in melanoma models (62, 64, 65) ↗ MT1-MMP, ↗ PI3K/Akt/NO synthase, ↗ NO/cGMP/Erk1/2 pathways in EC (66) ↗ IL-1β through NF-κB pathway in melanoma cell (67) ↗ MMP and plasminogen activation cascades in cancer cells |
| AG-9 (AGVPGLGVG) | Elastin | Proteinase 3, cathepsin G (58), MMP-7,9,12 (59), neprilysin (60) | RPSA (62) | ↗ Tumor growth in a melanoma model (62) ↗ Tumor cell migration, invasion through MMP and plasminogen activation cascades |
| Laminin fragments | ||||
| IKVAV (α1 chain fragment) | Laminin-111 | α3β1 and α6β1 integrins (68) | ↗ Angiogenesis, tumor growth, and metastasis (68) ↗ bone marrow mesenchymal stem cell proliferation by activating MAPK/ERK1/2 and PI3K/Akt signaling pathways (69) ↗ t-PA in melanoma cells (68) |
|
| AG73 (RKRLQVQLSIRT from α1 chain) | Laminin-111 | Syndecans 1, 2, and 4 (68) | ↗ Angiogenesis and tumor growth (68) ↗ Rac1 and ERK1/2 signaling pathways (70) |
|
| YIGSR (β1 chain fragment) | Laminin-111 | 67 KD receptor (68) | ↘ Tumor growth and metastasis (68) Unknown mechanism |
|
| C16 (KAFDITYVRLKF from γ1 chain) | Laminin-111 | αvβ3 and α5β1 integrins (68) | ↗ Tumor growth (68) ↗ MMP-9 production in melanoma cells (68) |
|
| γ2 chain N-terminal fragment | Laminin 332 | MMP-2, cathepsin S, MT1-MMP (71) | α3β1 integrin, CD-44 (71) | ↗ Angiogenesis, tumor growth and metastasis (71) Unknown mechanism |
| α3 chain C-terminal fragment | Laminin 332 | Plasmin, MMP-2, MT1-MMP, C-proteinase, mTLD, BMP-1 (71) | α3β1 and α6β1 integrins (71) | ↗ Angiogenesis, tumor growth (71) Unknown mechanism |
| A5G27 (RLVSYNGIIFFLK from α5 chain) | Laminin 511 | Cell surface glycans (72) | ↘ Breast tumor cell proliferation↗ 4T1.2 experimental pulmonary metastasis (72) Unknown mechanism |
|
| Fibronectin fragments | ||||
| Anastellin (type III module) | Fibronectin | ↘ Angiogenesis, tumor growth and metastasis (73) ↗ p38 MAPK activation in EC (74) |
||
| Proteoglycans fragments | ||||
| Metastatin | Aggrecan | ADAMTS (75) | ↘ Growth, migration, angiogenesis of melanoma and prostate cancer (76) Unknown mechanism |
|
| EndorepellinLG3 fragment (C-terminal fragment of Endorepellin) | Perlecan | MMP-7 (77)Cathepsin L and BMP-1-Tolloid-like proteases (78) | α2β1 integrin (79) | ↘ EC proliferation and migration, angiogenesis, tumor growth (78–84) ↘ VEGF-A/VEGFR pathway in EC (79) ↗ autophagy through Peg3 activation in EC (79, 85) |
| Versikine | Versican | ADAMTS (86) | TLR2 (34) | ↗ Immunogenicity in myeloma (87, 88) ↗ IL-1β, IL-6 expression by myeloma-associated macrophages through both Ppl2 kinase-dependent or -independent pathways (88) |
| Lumcorin (SSLVELDLSYNKLKNIP)L9M (ELDLSYNKLK) Lumikine/LumC13 (YEALRVANEVTLN) | Lumican | α2β1 integrin (89), MMP-14 (90, 91), ALK5/TGFβR1 (92) | ↘ Growth, migration, angiogenesis in melanoma and breast cancer (93–96) ↘ FAK/Akt/ERK pathway↘ MMP-14 proteolytic activity (90, 97) ↗ keratocytes migration (92, 98) |
|
| Synstatins | ||||
| SSTN 92-119, SSTN 82-130, SSTN 210-240 | Syndecan-1 | αvβ3, αvβ5 and α3β1 integrins, HER2, VEGFR2 (co-receptors of ectodomain) (34, 99–103) |
↘ Angiogenesis in breast cancer (104–106)Depend on HER2- and EGFR-coupled mechanism (104) | |
| SSTN87-131 | Syndecan-4 | EGFR, α3β1 integrin (co-receptors of ectodomain) (34) | ↘ Cell motility (104)Depend on HER2- and EGFR-coupled mechanism (104) | |
| Glypican fragments | ||||
| Glypican-3 derived peptide | Glypican-3 | Wnt | ↗ Cell proliferation, migration and invasion in hepatocellular carcinoma (107) ↗ Wnt/β-catenin, Hedgehog, and YAP pathway (108–110) ↗ Macrophage recruitments in tumor (108) ↗ EMT (108) |
|
| Has | ||||
| HA oligosaccharides | HA | CD44 (111) | Alters tumor growth, metastatic potential, and progression in prostate, colon, breast, and endometrial cancers (112, 113, 165)LMW HA promotes angiogenesis (114)HMW HA decreases angiogenesis, induces EMT (114) | |
4E-BP1 protein, eukaryotic initiation factor 4E-binding protein 1; ADAMTS, a disintegrin and metalloproteinase with thrombospondin motifs; AP-1, activator protein 1; ATF, activating transcription factor; ALK5, TGFβ type I receptor kinase; BMP, bone morphogenetic protein; cGMP, cyclic guanosine monophosphate; EC, endothelial cell; ECM, extracellular matrix; EGFR, epidermal growth factor receptor; EMT, epithelial–mesenchymal transition; ERC, elastin receptor complex; ERK, extracellular signal-regulated kinase; FAK, focal adhesion kinase; HA, hyaluronan; HER2, human epidermal growth factor receptor-2; HMW-HA, high-molecular-weight HA; IL, interleukin; JAG2, jagged canonical Notch ligand 2; LMW-HA, low-molecular-weight HA; MAPK, mitogen-activated protein kinase; MEK, MAPK/ERK kinase; MMP, matrix metalloproteinase; mTLD, mammalian Tolloid; mTOR, mammalian target of rapamycin; NF, nuclear factor; NO, nitric oxide; PI3K, phosphoinositide 3-kinase; RPSA, ribosomal protein SA; TLR, Toll-like receptor; t-PA, tissue-type plasminogen activator; uPA, urokinase-type plasminogen activator; VEGF, vascular endothelial growth factor; VEGFR, vascular endothelial growth factor tyrosine kinase receptor; TGFβ, transforming growth factor β.