Matrix metalloproteinase protein inhibitors: highlighting a new beginning for metalloproteinases in medicine

Figures & data

Table 1 MMPs aid cancer progression and are a quintessential partner for malignancy

MMPs	Cancer type	Molecular insight	References
Collagenases
MMP-1	Breast cancer	Reduced level is associated with decreased TGF-α release and phospho-EGFR expression accompanied by reduced cell migration. Overexpression increases brain metastases	24,25
	Lung cancer	Double KO mice show decreased susceptibility to carcinomas induced by chemical carcinogens, and MMP-1 modulates the polarization of a Th1/Th2 inflammatory response	26
MMP-13	Breast cancer	In bone metastases, tumor cells activated MMP-13 expression, which leads to pre-osteoclast differentiation	27
	Head and neck squamous cell carcinoma	Promote VEGF-A release resulting in tumor angiogenesis	28
	Melanoma	Induce amoeboid cell migration in an MAP-kinase-independent manner through EGFR stimulation	29
	RCC	RCC cell lines show a TGF-β 1-mediated induction of expression	30
MMP-8	Colorectal cancer	Associated with elevated blood neutrophil count, distant metastases, and decreased BMI	31
	Cutaneous squamous cell carcinomas	Upregulated in peritumoral inflammatory cells, but found associated with a possible anti-lymph node metastasis protective property	32,33
Gelatinases
MMP-2	Chondrosarcoma	Cysteine-rich WISP-1 enhances the migration by increased expression through the α5β 1 integrin receptor, FAK, MEK, ERK, p65, and NF-κB signal transduction pathways	34
	Gastric cancer	Valuable negative prognosis marker, primarily contributed by cancer cells	35
	Non-small cell lung cancer	GOLPH3 transcription factor is a negative marker of tumor progression and mediates metastasis through MMP-2 and MMP-9	36
	Oral squamous cell carcinoma	CAFs produced MMP-2 that induced keratinocyte discohesion and epithelial invasion in a TGF-β-dependent manner	37
	Prostate cancer	MCP-1 of adipocyte origin enhances growth and invasion via MMP-2 action	38
MMP-9	Breast cancer	Downregulation of SCC-S2, an NF-κB-inducible transcription factor associated with enhanced invasiveness, coincided with the decreased expression of MMP-9 and MMP-1 High expression of MMP-2 and MMP-9 in carcinoma cells, not in stromal cells, is related to high transcription factor AP-2. Positive stromal MMP-9 expression is related to HER2 overexpression in ER-positive disease.	39 40
MMP-9	Breast cancer	Resulted in the activation of αvβ3 integrin. Expression of activated αvβ3 in cells showed enhanced migration toward vitronectin and fibrinogen	41
		NDRG2 expression mediates increase in BMP-4 levels and reduces metastasis via suppression of MMP-9	42
	Colorectal cancer	Neutrophil-derived MMP-9 releases biologically active VEGF165 from the ECM cells by cleaving heparan sulfates leading to angiogenesis	41
	Gastric cancer	KiSS-I (human melanoma metastasis suppressor gene) suppresses proliferation and metastasis by reduced MMP-9 levels via restricted NF-κB binding to its promoter region	43,44
		Expression promoted by neurotensin and causes cell migration via the ERK pathway	45
Stromelysins
MMP-3	Hepatocarcinoma	Metastasis is upregulated via concomitant MMP-3 and MMP-9 action induced by CypA (a member of peptidyl prolyl isomerases)	46
	Larynx cancer	PLGF causes expression of MMP-3 via ERK/MAPK signaling pathway believed to play an important role in metastasis	47
	Pancreatic ductal adenocarcinoma	Co-expressed with K-Ras in pancreatic ductal adenocarcinoma and is associated with Rac1b, leading to stimulation of metaplasia and immune infiltration of stroma	48
	Prostate cancer	CAF ER-α functions through a CAF–epithelial axis of interaction and downregulates MMP-3. Abrogation of ER-α leads to reduced MMP-3 expression and cell migration	49
MMP-10	Colorectal cancer	Produced predominantly by infiltrating myeloid cells in both murine and human colitis DSS model, and the absence of the enzyme leads to bad inflammation score and an onset of dysplasia	50
	Lung cancer	Required for maintenance of a stem-like cell population, presenting itself as a potent drug target in this system	51
MMP-11	Breast cancer	Gli1, an established oncogene, upregulates MMP-11 expression and increases potency toward an invasive phenotype in ER-a-negative breast cancer cell lines	52
		MMP-11^+ mononuclear inflammatory cells form metastases along with concomitant high levels of ILs (IL-1, IL-5, IL-6, and IL-17) and IFN-β and NF-κB as well as exhibit an increased CD68^+/(CD3^+CD20^+) cell ratio at their invasive front	53
Matrilysin
MMP-7	Colorectal cancer	Its ability to shed Fas ligand helps to select cancer cells with reduced sensitivity to apoptosis, thereby permitting an environment of genetic instability Invading and metastasized tumors show increased activity and increased metastatic lesions	54 55
MMP-7	Pancreatic ductal adenocarcinoma	Stat3 signaling enforces MMP-7 expression, and MMP-7 deletion leads to reduced primary tumor progression and metastasis	56
	Ovarian cancer	MSLN, in tissues with a poor clinical outcome, induces MMP-7 expression, which is believed to be through the activation of MAPK/ERK and JNK signal transduction pathways	57
	Prostate cancer	Helps avoid anoikis and increases invasive phenotype by shedding E cadherin and subsequent detachment from cadherin-catenin complex	58
MT
MMP-14	Breast cancer	KLF8 activates MMP-14 downstream, and cell surface presentation of it depends on FAK expression and activity	59
		MMP-14 blockade decreases TGF-β, polarizes macrophages to an antitumor phenotype, increases iNOS, improves tumor perfusion, reduces primary tumor growth, and enhances response to radiation therapy	60
		Stromal abundance and tumor progression is stimulated by TGF-β secreted by MCF-7 cells acting in a paracrine manner	61
Others
MMP-12	Colorectal carcinoma	An inverse correlation exists with the depth of the intestinal wall invasion, the lymphatic invasion, and the vascular invasion and MMP-12 levels indicating probable protective effect	62
MMP-19 and	Melanoma	Increased expression coincides with ceased expression of E-cadherin pointing toward a role post-EMT	63
MMP-12

Abbreviations: AP, activator protein; BMI, body mass index; BMP-4, bone morphogenetic protein-4; CAFs, cancer-associated fibroblasts; CypA, cyclophilin A; DSS, dextran sulfate sodium; FAK, focal adhesion kinase; ECM, extracellular matrix; EGFR, epidermal growth factor receptor; ER, estrogen receptor; EMT, epithelial–mesenchymal transition; GOLPH3, Golgi phosphoprotein-3; HER2, human epidermal growth factor receptor 2; IFN, interferon; IL, interleukin; iNOS, inducible nitric oxide synthase; KLF8, Krüppel-like factor 8; KO, knockout; MCP-1, monocyte chemotactic protein-1; MMP, matrix metalloproteinase; MSLN, mesothelin; MT, membrane type; NDRG2, N-myc downstream-regulated gene 2; PLGF, placental growth factor; RCC, renal cell carcinoma; TGF, transforming growth factor; VEGF-A, vascular endothelial growth factor.

Figure 1 MMPs contributing to disease progression in inflammation as well as cancer of lungs (A) and the gut (B) can be targeted with specific selective inhibitors of high affinity.

Abbreviations: ECM, extracellular matrix; IBD, inflammatory bowel disease; MMP, matrix metalloproteinase; TACE, tumor necrosis factor-alpha converting enzyme; TNFα, tumor necrosis factor α.

Figure 2 Engineering approaches for MMPs inhibition with TIMPs.

Notes: (A) Illustration of MMP-2 activation by the TIMP-2/MMP-14 complex and MMP inhibition strategy using N-TIMP-2. (B) Schematic illustration of YSD system; the protein of interest is fused to AGA2p, which binds to AGA1p on the cell surface through disulfide bonds. Expression is detected via a fluorescently labeled antibody targeting the c-myc epitope. Fluorescent antibodies or other labeling methods also detect the binding of the target protein. Flow cytometry screens are performed on the YSD library in order to collect the high-affinity binders.
Abbreviations: C, C-terminal domain of tissue inhibitors of metalloproteinase 2; HA, hemagglutinin; MMP, matrix metalloproteinase; N, N-terminal domain of tissue inhibitors of metalloproteinase 2; N-TIMP-2, N-terminal tissue inhibitors of metalloproteinase 2; TIMP, tissue inhibitor of metalloproteinases; YSD, yeast surface display.