Table 1.

Examples of extracellular matrix ECM components and ECM modifying enzymes that have been reported to be up/down-regulated in gliomas. In the last column, a few examples of therapies targeting these proteins are given.

Factor	Function	Up/Down Regulated in Glioma [References]	Therapies Targeting These Proteins [References]
ADAMs 8, 9, 10, 17, 19	extracellular disintegrin and metalloproteases	up-regulated [39]	ADAM 10 and 17 [40]
ADAM-22	inhibitor of astrocyte proliferation	downregulated in high-grade gliomas [41]	over-expression of miR-145 targets, among other genes, also ADAM-22 [42]
ADAMTS-4 and ADAMTS-5	degrade lectican and small leucine-rich repeat families of proteoglycans	expression correlates with glioma invasiveness [43]	no example of specific targeting found
Cathepsin B and D	extracellular proteases	upregulated in high-grade gliomas [44,45,46,47]	tivozanib diminished glioblastoma multiforme (GBM) cell invasion by impairing the proteolytic cascade of cathepsin B/urokinase-type plasminogen activator (uPA)/matrix metalloproteinase-2 (MMP-2) [48]
CCN1	heparin-binding protein; interacts with the integrins α-v β-3 and α-6β-1 and increases the migration of glioma cells	highly up-regulated in primary gliomas and invasive glioblastoma cell lines [49]	potential therapy based on oncolytic HSV1 (OV) [50]
Collagen Type IV	the major structural component of basement membranes	up-regulated [51]	the lysyl oxidase inhibitor β-aminopropionitrile disrupts collagen structure in the tumor and inhibits tumor angiogenesis and glioblastoma multiforme growth in a mouse orthotopic brain tumor model [52]
Hyaluronan	the major component of the brain ECM	up-regulated in primary brain tumors [53] It stimulates secretion of matrix metalloproteases	hyaluronidase can improve penetration of therapeutic agents into brain tumors [54]
Matrix metalloproteinase (MMP)-1	interstitial collagenase	expression increases with WHO grade [55]	a collection of new drugs targeting matrix metalloproteases have been tested in vitro. Among them: 2-Amino-2-[2-(4-octylphenyl)]-1,3-propanediol hydrochloride (FTY720) [56], chlorotoxin [57], ellagic acid [58], fucoxanthin [59], caffeic acid [60]. Moreover, silencing of specific genes appears as a promising tool for inhibiting growth and invasiveness of glioma cells, by reducing expression of matrix metalloproteases [61,62]
MMP-2	gelatinase activity	highly upregulated, secreted, activated [63,64,65]
MMP-3	broad substrate specifity	highly upregulated, secreted, activated [66]
MMP-7	broad substrate specifity	highly upregulated, secreted, activated [67]
MMP-9	gelatinase activity	highly upregulated, secreted, activated [64,65]
MMP-11	does not degrade laminin, fibronectin and elastin; has a strong activity on serine protease inhibitor α1-antitrypsin and insulin-like growth factor binding protein-1 (IGFBP-1)	expression increases with WHO grade [55]
MMP-12	degrades soluble and insoluble elastin, type IV collagen, fibronectin, fibrillin-1, laminin, vitronectin, chondroitin sulfate and heparin sulfate proteoglycans, MMP2/3 activation	elevation of MMP-12 by tenascin-C in glioma [68]
MMP-19	degrades various ECM components including collagen type IV, nidogen-1, fibronectin, tenascin-C isoform, aggrecan and laminin-5-gamma-2-chain	expression increases with WHO grade [55]
MMP-26	degrades type IV collagen, fibronectin, vitronectin, alpha 1-antitrypsin (A1AT), insulin-like growth factor-binding protein 1 (IGFBP) and activates MMP9	significantly up-regulated [69]
(MT1)-MMP/MMP-14	involved in the maturation of active MMP-2	highly upregulated, secreted, activated [70]	no example of specific targeting found
Tenascin-C	plays a crucial role in angiogenesis, proliferation and cell migration	up-regulated [71,72]	a peptide that bound to tenascin C has been isolated by phage display peptide library. The selected peptide specifically recognized tenascin C protein in xenograft mouse tissue [73]
Tenascin-R	influences cell adhesion, neural cell migration, cell-matrix interaction and axon outgrowth	increasingly down-regulated with glioma progression: (in grade IV glioblastoma only a weak TN-R expression is detected [72]	no example of specific targeting found
TIMP-1	natural inhibitor of MMPs	higher levels in GBM compared to lower grade glioma [74]	2-Amino-2-[2-(4-octylphenyl)]-1,3-propanediol hydrochloride (FTY720) [56]
Thrombospondin 1 (TSP-1)	Implicated in cancer cell, adhesion, migration, invasion, inhibition of angiogenesis	may decrease with tumor grade [75]	no example of specific induction found