Edited by: Erika Ruiz-Garcia, National Institute of Cancerology (INCan), Mexico
Reviewed by: Linda C. Meade-Tollin, University of Arizona, United States; Ronca Roberto, University of Brescia, Italy
This article was submitted to Molecular and Cellular Oncology, a section of the journal Frontiers in Oncology
†These authors have contributed equally to this work
This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
During angiogenesis, new vessels emerge from existing endothelial lined vessels to promote the degradation of the vascular basement membrane and remodel the extracellular matrix (ECM), followed by endothelial cell migration, and proliferation and the new generation of matrix components. Matrix metalloproteinases (MMPs) participate in the disruption, tumor neovascularization, and subsequent metastasis while tissue inhibitors of metalloproteinases (TIMPs) downregulate the activity of these MMPs. Then, the angiogenic response can be directly or indirectly mediated by MMPs through the modulation of the balance between pro- and anti-angiogenic factors. This review analyzes recent knowledge on MMPs and their participation in angiogenesis.
Currently, cancer research is focused on understanding the functional mechanisms underlying cell transformation and tumor progression that can be used to develop new markers and therapies (
On the other hand, angiogenesis, in which MMP participation is well-recognized, was found to be involved in cancer metastasis over 45 years ago. Interest in angiogenesis related to cancer arose in 1968 when it was highlighted that tumors secrete a diffusible substance that stimulates angiogenesis (
Given the relevance of MMPs in diseases such as cancer, this work presents the most representative studies on the subject. We emphasize the role of cytokines and growth factors inducing EMT in various types of cancer together with the role of MMPs. We also analyzed the carcinogenic and angiogenic processes, and with the participation of MMPs, cytokines, and immune system cells in these processes along with the regulation, activation, and signaling pathways of MMPs in cancer cells.
MMPs, also known as matrixins, are members of the metzincin protease superfamily of zinc-endopeptidases.They display a specific proteolytic activity against a broad range of substrates located on the ECM. Other members of the superfamily include A Disintegrin and metalloproteinases (ADAMs), and ADAMs with thrombospondin motifs (ADAMTSs), which contain a conserved methionine (Met or M) residue adjacent to the active site (
Structure and architectures of MMPs. The selected Protein Data Bank (PDBs) structures are comprehensive (when possible) full-length peptides found in the available coordinates files, all structures were overlapped at similar positions. For every structure, the propeptide domain and triple-helical collagen peptide appear in yellow, while the catalytic domains (right) appear in black, and hemopexin domains (left) in white.
Evolutionary relationship of the catalytically domain of MMP family. Additionally, the main substrates are mentioned. MMPs classification is based on a phylogenetic tree of the catalytic domains reported (
All MMPs are produced as proenzymes and require a proteolytic cleavage under physiological conditions to promote the release of the propeptide domain (zymogen activation) and generate mature MMPs (
Moreover, the MMP catalytic domain of the metzincin clan of metalloendopeptidases shares a general zinc-binding signature as core of the catalytic reactivity; the signature conserved sequence is the H-E-X-X-H-X-X-G-X-X-H/D region. Additionally, the conserved M residue of the superfamily is located on the methionine containing turn (Met-turn) which is part of the catalytic region and likely has structural-stability functions; nevertheless, the strict conservation of this residue remains unclear (
Angiogenesis is a process by which new blood vessels or capillaries grow from the preexisting vasculature, and it is necessary for diffusion of nutrients and delivery of oxygen for tissue metabolism or cells involved in wound healing, myeloid and stromal cells. New blood vessels require the dismantling of endothelial lined vessels via the “sprouting” of endothelial cells (ECs), expanding the vascular tree (
Collagenases (MMP-1, −8, and −13) are proteins associated with angiogenesis, and their loss leads to the irreversible rupture of the matrix. Type IV collagen participates in cell endothelial migration in the interstitial stromal spaces. It is known that the tissue inhibitors of metalloproteinases (TIMP-1, TIMP-2, TIMP-3, and TIMP-4) regulate them, playing a key role in angiogenesis regulation by inhibiting neovascularization (
In adults, angiogenesis is initiated only under inflammation or hypoxic conditions (
On the other hand, several studies have established the importance of transmembrane receptors and ligands participating in cell differentiation. Their role in endothelial sprouting during angiogenesis has recently been studied. ECs express several Notch receptors (such Notch1 and Notch4), as well as the Notch1 protein and Notch ligand delta-like 4 (DLL4), which are important signals for vascular development (
As previously mentioned, angiogenesis is a normal development and part of the healing process; however, it is key to tumor branching and arborization under pathological conditions such as cancer. The formation of new vascular networks promotes the growth, maintenance, and spread of cancer (
The accelerated growth of the tumor leads to hypoxic tumor microenvironment, interstitial hypertension, and acidosis. To reverse these adverse physicochemical changes, VEGF-C and VEGF-D are synthesized by the activation of VEGFR-3/2, triggering a rise in diameter and density of the peritumoral lymphatic vessels, favoring the propagation of tumor cells toward sentinel lymph nodes (
It is well known that MMPs have been implicated in angiogenesis regulation as well as in the anomalous relationship between cancer and the related processes of angiogenesis, vasculogenesis and lymphangiogenesis. MMPs also have a role in the immune system action in cancer development and progression (
Immune system proteins associated to MMPs in angiogenesis and cancer.
IL-1α, IL-3, VEGF, GCSF and GM-CSF | Secretion of proteins (IL-1α, IL-3, VEGF, GCSF, GM-CSF) under Hypoxia stress increase efficiency for induction of angiogenesis | Human A431 squamous carcino cells |
Hypoxia increase secretion: MMP-13. Hypoxia increase secretion: MMP-3, MMP-9 and MMP-13 | ( |
IL-1βTNF- α | IL-1β as inductor shows a slight dose-dependent increasing secretion of MMP-2. TNF-α as inductor shows a slight dose-dependent increasing secretion of MMP-9. A curious fact, retinoic acid strongly inhibited MMP-2 secretion | Human Glioblastoma T-98G cell line | MMP-2 and MMP-9 | ( |
IL-1β | IL-1β induced MMP-2 and MMP-9 expression and activities mediated NK-kB activation, whereas melatonin suppresses it | Human Gastric adenocarcinoma MGC803cell line and Human Gastric cancer SGC-7901 cell line | MMP-2 and MMP-9 | ( |
IL-1β | IL-1β/p38/AP-1(c-fos)/MMP-2 and MMP-9 pathway play an important role in metastasis in gastric cancer | Human Gastric cancer cell lines MKN45 and AGS | MMP-2 and MMP-9 increase gene expression and protein expression in response to IL-1β treatment | ( |
IL-1β | The STAT3 signaling is present in myeloid cells in human cancer angiogenesis and it is required for the cellular migration. The activity of STAT3 in tumor-associated myeloid cells participate in the elevated gene transcription of VEGF, bFGF, IL-1β MMP-9, CCL2 and CXL2 | Murine Tumor-infiltrating myeloid cells | MMP-9 is elevate by the STAT3 activity | ( |
IL-5 | L-5 increased migration and MMP-9 expression via activation of transcription factors NF-κB and AP-1, and induced activation of ERK1/2 and Jak-Stat signaling in both cells. IL-5Rα, inhibition, suppressed migration, ERK1/2, NF-κB, AP-1 activation and MMP-9 expression. MMP-2 expression remains without changes | Human Bladder carcinoma cell lines: 5637, T24 and HT1376 | MMP-2 and MMP-9 | ( |
IL-22 (IL-10 family member) and IL-22R1 | Promotes gastric cancer cell invasion through STAT3 and ERK signaling in MKN28 |
Human Gastric cancer cell lines MKN28 and SGC-7901 | IL-22 upregulate the gene expression of MMP-7 and MMP-13 in MKN28 |
( |
IL-10 | IL-10-stimulated macrophages polarized to M2 phenotype (low IL-12, IL-6 expression and IL-10 high expression) significantly increased AGS and RKO cells Invasion radio. Conditioned medium from IL-10-stimulated macrophages (M2) induced in AGS cell motility, migration and mediated angiogenesis | Human Diffuse gastric carcinoma cell line: AGS |
MMP-2 and MMP-9 elevated expression and activities on AGS cells with conditioned medium from IL-10-stimulated macrophages (M2) | ( |
IL-8 (CXCL8) |
Breast cancer cells secreting high levels of RANTES, CCL2 and G-CSF showing a potential capability to recruit monocytes and to instruct them to secrete high levels of IL-1β and IL-8, and MMP-1, MMP-2 and MMP-10 | Patient samples diagnosed with ductal carcinoma. Monocytic |
MMP-1, MMP-2 and MMP-10 | ( |
IL-8 (CXCL8) | Co-cultured ovarian cancer stem-like cells with macrophages (derived from THP-1 cells) polarized to M2 phenotype increased IL-10, VEGF, MMP-9 and IL-8 secretion, and CD163 and STAT3 expression. THP-1 cell conditioned medium plus IL-8 induced stemness in SKOV3 cells involving IL-8/STAT3 signaling. | Human SKOV3-derived ovarian cancer stem-like cells. | MMP-9 | ( |
IL-8 (CXCL8) | Recruited B cells mediated IL-8/androgen receptor and MMP signals in bladder cancer could enhance invasion and metastasis | Bladder tumor specimens were collected from 24 patients |
MMP-1 and MMP-9 | ( |
IL-8 (CXCL8) | Human Oral squamous cell carcinoma cells SCC-25, OSC-20 and SAS cells | MMP-1, MMP-2, MMP-7, MMP-9 and MMP-10 are up-regulated after 72 hours of |
( |
|
IL-8 (CXCL8) | IL-8 directly enhances endothelial cell survival, proliferation, MMP production and modulate angiogenesis | Human Umbilical Vein Endothelial Cell and dermal microvascular endothelial cells | MMP-2 and MMP-9 mRNA expression was increased in cells treated with 10 and 100 ng/ml IL-8. The Culture supernatant showed high level of both active MMPs | ( |
IL-8 (CXCL8) |
IL-8, IL-9, MMP-2 and MMP-9 secreted by Falconi Anemia Cells are expressed under the control of NF-kB/TNF-α signaling pathways. These secretory factors are effective on promoting proliferation, migration, invasion of surrounding tumor cells | Falconi Anemia Cells (EUFA274, EUFA274Rev, EUFA450, EUFA450RevR, |
MMP-2 MMP-7 and MMP-9 are overexpressed | ( |
IL-8 (CXCL8) |
Self-conditioned medium collected from A549 cells was treated with neutralizing antibodies against IL-1β, IL-8, and VEGF and used in A459 cells. The inhibition of motility and invasion in A549 cells were observed, the effect was higher in IL-8 and VEGF neutralizing medium | A549 (human lung adenocarcinoma), MCF-7 (breast adenocarcinoma) and HT-29 (colon carcinoma) | MMP-2 activity was detected in Self-conditioned medium collected from A549 cells | ( |
IL-8, VEGF, angiogenin, and NKG2D | Lung tumor–associated NK cells (TANKs) of peripheral blood and tumor-infiltrating NK cells (TINKs) induced functional angiogenesis-associated behaviors of endothelial cells |
Human Lung tumor–associated NK cells (TANKs) of peripheral blood and tumor-infiltrating NK cells (TINKs) of patients with colorectal cancer | MMPs down-regulate the activator NKG2D, a surface marker for NK cell activation, in TANKs. Which is correlated with increased release of MMP-9, TIMP-1 and TIMP-2. | ( |
IL-8, IL-6, IL-1a, IL-1RA, GM-CSF, CCL5 (RANTES), TNF-α, VEGFA | Different lines cells from similar tumors show a varied secreted immunological biomarker profiles. Although almost every cells lines express the eight cytokines, apparently the metastatic stage, cellular origin, the site and the genome differences plus, an uncertain passage number of the cell lines, cause different profiles: SCC25 express mostly VEGFA and CCL5; SCC19 express mostly VEGFA, IL-6 and IL-8; SCC92 mostly express TNF-α IL-6, IL-1α and IL-8; SCC99 express mostly IL-8 | Human Head and neck squamous cell carcinoma lines: SCC4, SCC15, SCC25, SCC84 and SCC92 are from the oral cavity; while SCC19 and SCC99 are from the oropharynx | MMP-1, MMP-7 and MMP-9 are higher expressed on SCC25. Others cell lines express different MMP profiles: SCC99 mostly express MMP-1 and MMP-9; SCC15, SCC19 and SCC84 mostly express MMP-7 and MMP-9; SCC4 and SCC92 mostly express MMP-9 | ( |
IL-8 | IL-8 and MMP-9 are co-expressed on MCF-7 cell line induced by TPA (a carcinogen). Orientin downregulates signal PKCα /ERK and blocks the nuclear translocation of AP-1 and STAT3 causing an attenuation of IL-8 and MMP-9 induced by TPA treatment, but only affected the migration and invasion of ER-positive MCF-7 cells | Human Breast cancer cell line MCF-7 estrogen receptor positive | MMP-9 | ( |
IL-8, IL-6 | MMP expression is regulated by cancer cell density via the signaling of IL-6 and IL-8. The synergistic signaling of IL-6 and IL-8 regulates the production of MMPs through the JAK/STAT signaling pathway | Human Fibrosarcoma HT1080 cells and breast carcinoma MDA-MB-231 cels | HT1080 in high cell density not only expresses MMP-1, MMP-2 and MMP-3 mainly but also MMP-11 and MMP-14 |
( |
IL-6 | In macrophages, the homeo-domain protein Six1 overexpression was able to induce IL-6 up-regulation and increase activity of STAT3 in Hepatocellular carcinoma cells. Macrophages Six1 upregulate IL-6 and MMP-9 and can stimulate cancer cell invasion by elevating MMP-9 expression | Human Leukemic monocyte cell line: THP-1; Human hepatoma cell line: A59T; and hepatocellular carcinoma cell line: HepG2 |
MMP-9 | ( |
IL-6 | IL-6 regulates MMP expression via proximal GAS-like STAT binding elements (SBEs). IL-6 lead the formation of a complex STAT1/AP-1 | Patient colon tumor tissue |
MMP-1 and MMP-3 | ( |
IL-6 | IL-6/ NOS2 inflammatory signals regulate MMP-9 and MMP-2 dependent metastatic activity | Nasopharyngeal carcinoma from patients | MMP-9 and MMP-2 | ( |
IL-6 | IL-6 secreted by astrocytes induce upregulation of MMP-14 increasing migration and invasion of Glioma cell lines | Human Glioma cell lines U251 and A172 |
MMP-14 (MT1-MMP) | ( |
IL-11 | IL-11 promoting chronic gastric inflammation and associated tumorigenesis mediated by excessive activation of STAT3 and STAT1 | Gastric tumor gp130 Y757F/Y757F mice model | Upregulate the gene expression of MMP-13 | ( |
IL-11 | Under hypoxia conditions all cell lines upregulate gene expression and protein production of IL-11 |
Human Breast cancer cell line: MDA-MB-231; colorectal carcinoma cell line: HCT116; non-small lung carcinoma: H1299; malignant melanoma cell line: A375 and hepatocellular carcinoma cell line: HepG2 | Upregulate the gene expression of MMP-2, MMP-3 and MMP-9 | ( |
IL-12 | IL-12 treatment inhibited lung tumor growth, resulting in the long-term survival of lung cancer-bearing mice. Further examination revealed that IL-12 rapidly activated NK cells to secrete IFN-γ, resulting in the inhibition of tumor angiogenesis and MMP-9 transcript level decreased |
Murine breast cancer HTH-K (syngeneic breast carcinoma), injected in C57BL/6 mice to generate an orthotopic lung cancer model | L-12 prevented blood vessel regrowth and inhibit MMP-9 | ( |
IL-17 | In breast tumors was observed the presence of IL-17 strongly positive cells within the scattered tumor-associated inflammatory infiltrate. IL-17 addition to breast cancer cell lines promoted significant invasiveness | Human Archival paraffin-embedded sections of 19 primary invasive breast tumors (15 Grade III and four Grade II). Human Breast cancer cell lines: MDA-MB231 and MDAMB435 cell lines | Selective antagonists for MMP-2/MMP-9 or MMP-3 suppressed the stimulatory effect of IL-17 on breast cancer invasion. However, IL-17 does not affect secretion of these MMPs | ( |
IL-17 | High salt synergizes with sub-effective IL-17 to induce breast cancer cell proliferation mediated activation of SIK3 (a G0/G1-phase inductor) by mTOR complex. SIK3 induce expression of CXCR4 through MMP-9 activation | Human Breast cancer cells lines: |
MMP-9 | ( |
IL-17 | MMP-7 mediates IL-17's function in promoting prostate carcinogenesis through induction of EMT, indicating IL-17-MMP-7-EMT axis as potential targets for developing new strategies in the prevention and treatment of prostate cancer | Murine Prostate cancer cell lines (LNCaP, C4-2B and PC-3). PB-Cre4 mice | MMP-7 | ( |
IL-17B, IL-17RB | IL−17B dose dependently promoted the invasion, growth and migration of thyroid cancer cells. IL-17RB induced ERK1/2 activation pathway and increased MMP-9 expression |
16 paired Human thyroid cancer tissues |
MMP-9 | ( |
IL-17 | IL-17A treatment promotes OE19 cell migration and invasion, upregulates MMP-2 and MMP-9 expression, increase ROS production, IκB-α phosphorylation and NF-κB nuclear translocation. IL-17 cause these effects through ROS/NF-κB/MMP-2/9 signaling pathway | Human Esophagus adenocarcinoma |
MMP-2 and MMP-9 | ( |
IL-18, IL-10 and TNF- α | IL-18 and IL-10 synergistically act to amplify OPN and thrombin production, which in turn augments M2 macrophage polarization. M2 Macrophages and endothelial direct cell- cell interaction resulting in excessive angiogenesis | Mouse leukemic monocyte Mphi cell line RAW264.7 and Mouse endothelial cell line b.End5 | Stimulation of RAW264.7 cells with TNF- α increases MMP-2 and MMP-9 gene expression |
( |
IL-32α | IL-32 stimulation in MG-63 cells shown, dose-dependently promoted the invasion and motility of osteosarcoma cells and induced the activation of AKT in a time-dependent manner. IL-32 stimulation increased the expression and secretion of MMP-13 | Human MG-63 osteosarcoma cell line | MMP-13 | ( |
IL-33 | IL-33 increases the abilities of proliferation, migration and invasion of melanoma cells and Vasculogenic mimicry tube formation through ST2. IL-33 induces the production of MMP-2/9 via ERK1/2 phosphorylation | Human Melanoma of patients | MMP-2 and MMP-9 | ( |
IL-33 | IL-33 significantly promoted cell invasion and migration and induced the expression of MMP-2 and MMP-9 via ST2 and AKT pathway | Human Lung cancer cell lines: A549 and NCI-H1299 | MMP-2 and MMP-9 | ( |
IL-33, IL1RL1 (IL-1-R4) | IL-33 expression in the tumor epithelium of adenomas and carcinomas and expression of the IL-33 receptor, its receptor IL1RL1 in the stroma of adenoma and both the stroma and epithelium of human colorectal cancer |
Human colorectal cancer and mouse model of intestinal tumorigenesis | MMP-1 and MMP-3 | ( |
IL-35 | IL-35 can induce N2 neutrophil polarization (protumor phenotype) by increasing G-CSF and IL-6 production, and promote |
Murine H22 hepatocarcinoma cell |
MMP-9 | ( |
IL-35 | Significantly lower expression of IL-35 was also observed in Hepatocellular carcinoma patients. IL-35 over-expression in HepG2 cells significantly upregulated HLA-ABC and CD95, reduced activities of MMP-2 and MMP- 9, and decreased cell migration, invasion and colony formation capacities | Hepatocellular carcinoma from 75 patients and Human Hepatocellular carcinoma cell line HepG2 | MMP-2 and MMP-9 | ( |
IL-37 | Transfected cells A549 overexpressing IL-37 cause low gene expression of MMT-9, PCNA, Ki-67, Cyclin D1 and CDK4, but elevated expression of caspace-3 and caspace-9. IL-37 inhibits the proliferation, migration and invasion of human lung adenocarcinoma A549 cells as well as the chemotaxis of Treg cells and promotes apoptosis of A549 cells | Murine Lung adenocarcino line cells A549. Xenograft mouse models. | MMP-9 | ( |
CXCR4 | Lymph node metastatic Hepatocarcinome Hca-F exosomes (contain elevated CXCR4) promote migration and invasion in HcaP cells elevating the secretion of MMP-9, MMP-2 and VEFG-C | Murine hepatocarcinoma cell lines Hca-F and Hca-P | MMP-2 and MMP-9 | ( |
TNF- α | Tumor necrosis factor-α (TNF-α) induce a dose-dependent increase in MMP-9 activity HT1376 cells, through ERK1/2 and P38 MAP kinase activity and activation of the transcription factors NF-kB, AP-1 and SP-1 | Human Bladder carcinoma cell line, HT1376 | MMP-9 induced by TNF-α thought the NF-kB, AP-1 and Sp-1 cis-elements of the gene promoter mediated regulation ERK1/2 and p38 MAP kinase | ( |
TNF- α | TNF-α secretion from cancer cell line increased expression of MMP-2 and MMP-9 and increased TNF-α production. A TNF-α/TNF-R1/NF-kB system signaling pathway generated a highly metastatic cancer cells. TNF-α-triggered NF-κB activation to upregulation of active MMP released from the cancer cells | Human Oral squamous cell carcinoma SAS cell line. Metastatic cervical lymph nodes and metastatic lung cell lines induced by a SAS injected in the tongue of mouse | MMP-2 and MMP-9 | ( |
TNF- α | Aberrant TNF-α signaling promotes cancer cell motility, invasiveness, and enhances cancer metastasis mediated NF-kB signaling. TNF-α-induced expression and stabilization of C/EBPb depends on p38MAPK activation, but not on NF-kB activity. C/EBPβ and its downstream MMP-1 and MMP-3 are required for TNF-α-induced cancer cell migration. TNF-α activates multiple signaling pathways, including NF-kB and C/EBPβ to promote cancer cell migration. TNF-α treatment significantly increased the number of migrated MDA-MB-231 and MDA-MB-435 cells in a dose-dependent manner | Human Breast cancer lines cells: MDA-MB-231 and MDA-MB-435 | MMP-1 and MMP-3 mediate TNF-α-induced cell migration downstream of C/EBPb | ( |
TNF- α | AMB cells stimulation with TNF-α increased IL-6 and MMP-9 mRNA expressions, via NF-kB activation. Furthermore, TGF-β and IFN-c increased TNF-α-mediated expressions of MMP-9 and IL-6 mRNA, while those responses were suppressed by NF-kB inhibitor | Ameloblastoma cells (AMB) cultures from patients were inmortalized using hTERT vector | MMP-9 | ( |
Proteins associated with MMPs in angiogenesis on cancer.
L1 adhesion molecule /CD171 | Constitutive cleavage of L1 proceeds in exosomes mediated by a disintegrin and MMP10, under apoptotic conditions multiple MMP are involved | Human ovarian carcinoma cells OVMz | ADAM10 | ( |
PIGF | Knockdown of PlGF in spheroid body cells reduced |
Human Spheroid cells from gastric adenocarcinoma MKN-45 and GS cells lines | MMP-2 and MMP-9 activities | ( |
VEGFR2 blockade | Brain tumor vessels: Vascular stabilization by increases pericyte coverage, up-regulation of angiopoitin-1 and collagenase IV activity provides and oxygenated environment through the degrades pathologically thick basement membrane by MMPs activation | Human Orthotopic glioblastoma obtained by xenografts on mouse of U87 gliomas tumors | MMPs−2 and MMP-9 | ( |
VEGF | In colorectal liver metastasis, the high expression of stroma-derived MMP-12 and VEGF correlated with a dismal prognosis | Colorectal liver metastasis of patients | MMP-12 | ( |
Angiopoietin-2 | In colorectal lung metastases, the high stromal expression: MMP-1-2,-3 is indicator for a more favorable clinical outcome, whereas high expression of stromal angiopoietin-2 is associated with a reduced cancer-specific survival and an independent prognostic marker for cancer-specific survival in lung metastasis | Colorectal lung metastasis of patients | MMP-1, MMP-2 and MMP-3 | ( |
Chemokines related to the immune system and ENPP3, BNIP3, AZGP1 and PIGR | Stage II colorectal cancer. Poor prognosis is associated with low expression of the genes PIGR, CXCL13, MMP3, TUBA1B, CXCL10, and high expression of SESN1, AZGP1, KLK6, EPHA7, SEMA3A, DSC3 ENPP3, BNIP3 and ENPP3 | Human Stage II colorectal cancer | MMP3 | ( |
MIF | Increased expressions of both MIF and MMP-9 were significantly associated with microvessel density of tumor, but only dual high-expression of MIF and MMP-9 was in relation to tumor invasion and tumor recurrence | 67 intracranial meningioma |
MMP-9 | ( |
TGF-β | TGF-β-pretreated A549 cells increased migration and invasiveness, decreased expression of E-cadherin, tight-junction proteins and increased expression of N-cadherin and vimentin. TGF-β-mediated exosomes and might function by increasing the expression of MMP-2 | Human Carcinoma lung A549 cell line | MMP-2 | ( |
TGF-β, IL-1α | Production of IL-1a by pancreatic stellate cells induce alterations in MMP and TIMP profiles and activities, upregulating MMP-1 and MMP-3. TGF-β counteracted the effects of IL-1α on pancreatic stellate cells downregulating and reestablishing MMP and TIMP profiles | Pancreatic Stellate Cells from patients with pancreatic ductal adenocarcinoma | MMP-1 and MMP-3 | ( |
EGR1 | EGR1 mediates hypoxia-induced SIRT1 transcriptional repression, and the acetylation of NF-kB and the activation of MMP-2 and MMP-9 | Human HCT 116 and SW480 Cell colorectal cancer cells line | MMP-2 and MMP-9 | ( |
CHI3L1 (Chitinase 3-like protein 1) | CHI3L1 promotes the metastasis of gastric and breast cancer cells, interacts with the IL-13Rα receptor on the plasma membrane of gastric cancer cells. Even more, CHI3L1 activates MAPK signaling pathway in gastric and breast cancers and the activator protein-1 (AP) transcriptional activity in cancer cells | Gastric cancer cells: MKN-45, AGS, MGC-803 and HGC-27. Breast cancer cells: MDA-MB-231, MDA-MB-435 and MDA-MB-468. Melanoma cells (A375) | MMP-1, MMP-2, MMP-3, MMP-7, MMP-9, MMP-12 | ( |
Angiogenesis studies using MMP-8 and MMP-2 knock-out mice, show an
Among the most studied MMPs participating in angiogenesis is the MMP-14 (MT1-MMP). It significantly contributes to angiogenesis regulation by cleaving ECM molecules as a matrix-degrading enzyme (
MT1-MMP functions and mechanism.
Soluble MMP expression and its effects on cancer stabilization/proliferation are intimately linked via vascular angiogenesis mechanisms that are now well recognized. In this regard, MMP-1 expression has been reported to contribute to the progression of Head and neck squamous cell carcinomas (HNSCC) and the suggest metastatic phenotype of human breast and colorectal cancers, among others (
Many studies have been published describing the relationship between MMP-2 expression and tumor angiogenesis. One of the earliest reports indicates that IL-8, an angiogenic factor, induces MMP-2 expression and activity in melanoma cells, enhancing their invasion (
On the other hand, MMP-9 promotes endothelial cell migration and triggers the angiogenic switch by releasing VEGF during carcinogenesis (
Studies have revealed that, both MMP-2 and MMP-9 can degrade type IV collagen and are frequently elevated in human cancer. Additionally, a cooperative effect of MMP-2 and MMP-9 was demonstrated in an
Many other MMPs have also been implicated in the incipient establishment of cancer angiogenesis (
It has been widely accepted that MMPs likely play antagonistic roles in regulating cancer angiogenesis. MMP-7 and MMP-9 may be involved in the blockage of cancer angiogenesis by cleaving plasminogen and generating angiostatin molecules (
Membrane type 1 matrix metalloproteinase (MT1-MMP) is considered a key mediator of cancer progression and metastasis. The overexpression of MT1-MMP in malignant breast cells significantly enhances VEGF production via the Akt and mTOR signaling pathways activated by the MT1-MMP–VEGFR-2–Src complex, which promotes tumor growth and angiogenesis (
On the other hand, the proteolytic cleavage of semaphorin 4D into its soluble form by MT1-MMP provides a novel molecular mechanism to control tumor-induced angiogenesis in HNSCC (
Moreover, MT4-MMP expression correlates with EGFR activation, which triggers an angiogenic switch through its catalytic activity and induces the dissemination of cancer cells by disturbing the vessel integrity of the primary breast tumor and promoting hematogenous but not lymphatic metastasis (
It is known that uncontrolled angiogenesis, anomalous ECM turnover, decreased growth, and cell migration, as well as inflammatory response, are the result of an imbalance between MMPs activity and their inhibitors, which may be associated with different diseases. Several specific signals are responsible for coordinating the formation, growth, remodeling, and stabilization of blood vessels. It is recognized that excessive growth-promoting signal cues lead to pathological angiogenesis and cancer (
In the tumoral microenvironment, there is a complex and dynamically interacting areas involving stromal cells (fibroblasts, myofibroblasts, neuroendocrine cells and immune cells), blood vessels, lymphatic network, and ECM (
The presence of secreted extra-cellular vesicles (exosomes) has recently gained importance within the tumor microenvironment (
Since they are diverse, MMPs influence multiple cellular processes, such as the inflammatory process regulating barrier function and the activity of inflammatory cytokines and chemokines. Chemoattractant proteins such as MCP-1, MCP-2, MCP-3, and MCP-4 are targets for MMP activity, as result the modified MCPs changing their activity from agonist to antagonist and causing inflammation. Inflammation produces immune tolerance and leads to specific micro-environment conditions, exploited by tumors to evade immune cells and enhance progression, angiogenesis and metastasis (
Several studies, both clinical and experimental, have shown that elevated MMP (including MT1-MMPs) levels are associated with the modulation of tumor progression. In brain tumors, growth factors and cytokines modulate the activity of several MMPs. Additionally, it has been observed that MMP-2-positive tumor cells in patients are correlated with low mean survival (
Furthermore, in the context of immune cells, there are tumor-associated cells that contribute to the synthesis and upregulation of MMPs (
Furthermore, accumulated evidence shows that primary tumors can recruit immune cells, such as MMP-9 positive neutrophils, B cells, and M2 polarized macrophages to produce tumor-associated immune cells, which are known to contribute to neovascularization by supplying MMP-9 and other MMPs (
Finally, the molecular role of MMPs in the immune system and cancer is to modulate a series of latent signaling proteins located in ECM, including cytokines and growth factors such as quiescent TGF-β forming a complex with TGF-β-binding protein-1 in ECM. Thus, TGF-β modulates MMP expression, resulting in a bidirectional regulatory loop enhancing TGF-β signaling and promoting cancer progression (
Accordingly, immunomodulatory mechanisms of MMPs, cytokines, receptors, and growth drivers are involved in the development and progression of several types of cancer.
MMPs and their inhibitors TIMP, control a wide variety of physiological processes. They constitute promising pharmaceutical targets for inhibition and other metastatic processes.
Currently, monoclonal antibodies are possible candidates to inhibit the activity of MMPs (MMP−14,−12,−9, and−2). However, studies have only managed to identify antibodies against MMP-9 activity, which has biological functions and not for the MMP−14,−12, and−2 (
Recently, the effect of MMP-2 gene silencing in normal and MCF-7 cells exposed to the irradiation has been studied. It is known that this MMP leads to the degradation of basement membranes; however, the differential response to DNA damage silencing the MMP-2 gene in normal and MCF-7 cells may be attributable to ROS generation (
All these studies represent advances in cancer drug development and cancer therapy, with a focus on the control of MMPs and the proteins with which they form complex networks of multifunctional interactions to modulate the signaling pathways that deviate during the development of metastatic cancer. Importantly, the emerging combined clinical therapy mitigates the side effects of existing treatments and raises the anticancer efficacy of chemotherapeutic drugs.
In this work, we have highlighted the role that MMPs play in the cancer and its interaction with growth factors, inhibitor proteins, and the EMT process. The activity of MMPs is involved in the degradation, remodeling, and exchange of ECM, which, under normal physiological conditions, contributes to homeostasis as part of an extensive network of extracellular tissue modulation. In cancer, homeostasis is modified, leading to localized abnormal physiological conditions that modify this extensive network of extracellular tissue modulation.
The increase in MMP activities, as an abnormal process, is a way of producing/inducing an erroneous metabolic cascade. Erroneous metabolic cascades are signals that trigger the emergence of complex abnormal cell pathways, which give rise to tumor/cancerous phenotype cells. In this regard, the transformation into tumor/cancerous phenotypes suggests an exacerbated adaptive survival process. MMPs are not the only elements of this extensive network of extracellular tissue modulation; others such as TIMP proteins, which modulate MMPs, ADAMs and ADAMTSs (
Although the information on the role of MMPs in cancer is very broad and the way these proteins are expressed is well known, we observed a significant lack of data at the fine level of the relationship between MMPs and the continuity of both the normal and altered signals that positively modulate the carcinogenic process. MMPs produce modulatory elements that remain unclear and, considering that the ECM is a complex array of proteins, fibers, and carbohydrates in different tissues, there may be several variants that generate the loss of homeostasis, causing the diverse cancerous processes observed.
In the angiogenesis process, MMPs are well-known key factors involved in ECM degradation that induce angiogenesis initiation in both physiological and pathological processes. However, the experimental evidence thus far demonstrates that MMPs also play a decisive role in the activation of pro-angiogenic and, in some cases, anti-angiogenic factors in cancer tissues. Thus, MMPs can be considered angiomodulators, which could control new vessel formation necessary for cancer growth, progression, and spread. Therefore, we speculate that MMPs participate in cancer angiogenesis in a cell context-dependent manner.
Most of the experimental data regarding MMP participation in cancer development, vascular endothelium processes, other epithelia (such as periodontal), and inflammatory processes allow us to assume that MMPs are proteins that carry out a type of external cellular regulation/signaling on the ECM. These proteins possess a different regulatory action mechanism that is complementary to other mechanisms such as ligand-receptor signaling pathways. The MMP mechanism is based on editing macromolecules by proteolysis, mainly anchored to the ECM.
It is evident that the proportion of MMPs and other macromolecules (cytokines, grown factors, fibers such as integrins, polysaccharides, and others) in the ECMs of different tissues in normal conditions are metabolically, micro-environmentally, and epigenetically balanced for their functions in each type of tissue. There are tissue-specific proportions, although ECMs have a high degree of heterogeneity.
Inspecting our concept of MMP participation in ECM in the literature, we found an excellent review of ECM with similar concepts (
On the other hand, EMT is a biological process aimed producing mesenchymal phenotype cells from epithelial cells. Its inverse process, mesenchymal-epithelial transition (MET), is carried out with the participation of ECM elements. EMT and MET lead to normal tissue regeneration and fibrosis [EMT type 2, according to Kalluri (
Evidence suggests that tumor cells induce the uncontrolled upregulation of MMPs, producing a large number of stimulating factors that disrupt EMT and immunological processes that prevent tumor cell elimination and migration. The upregulation progresses to generating anomalous tissue-specific type signals.
It is known that tumor cells have extensive heterogeneity in their metabolism and phenotype relative to normal tissue across cancer types. Furthermore, these abnormal signals coming from the tumor cells are tissue-specific, leading to the adaptation to the microenvironment where they developed. Finally, an interesting observation of the MMP family is the large, robust specificity profile, which suggests that its role is controlled in a tissue-specific manner; that is, MMP types are expressed accordingly to the regulatory proteins needed for the tissue.
However, more research efforts are needed to determine when abnormal signals begin, what the determinants are, and how microenvironmental tissue-specific conditions can lead a cell to change its metabolism and phenotype. In addition, the question remains: When does the high expression problem of MMPs become a problem metabolically? Although MMPs do not seem to be the cause of the appearance of tumor cells, they induce tumor development because they are targets to regulate development, contributing to increased invasiveness and growth of metastatic tumors.
MA-S conceived the idea and scripted the basis of the manuscript. RA and MA-S had equal contributions and a role in the design, analysis, and writing of the article. RA contributed in entirety to the design of the
The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.