· Anything that stimulates the rate of mitosis. This is because a cell is most susceptible to mutations when it is replicating its DNA during the S phase of the cell cycle.

· Certain hormones (e.g., hormones that stimulate mitosis in tissues like the breast and the prostate gland).

· Chronic tissue injury (which increases mitosis in the stem cells needed to repair the damage).

· Agents that cause inflammation (which generates DNA-damaging oxidizing agents in the cell).

· Certain other chemicals; some the products of technology

· Certain viruses.

Figure: 1 Molecular Biology of cancer

Figure: 2 Morphological changes of cancer cells

Figure: 3 Developmental Stages of Cancer

Matrix metalloproteinases (MMPs):

Matrix metalloproteinases (MMPs) are zinc-dependent endopeptidases. Other family members are adamalysins, serralysins, and astacins. The MMPs belong to a larger family of proteases known as the metzincin superfamily. Collectively they are capable of degrading all kinds of extracellular matrix proteins, but also can process a number of bioactive molecules. They are known to be involved in the cleavage of cell surface receptors, the release of apoptotic ligands (such as the FAS ligand), and chemokine in/activation. MMPs are also thought to play a major role on cell behaviors such as cell proliferation, migration (adhesion/dispersion), differentiation, angiogenesis, apoptosis and host defense. They were first described in vertebrates (1962), including Homo sapiens, but have since been found in invertebrates and plants. They are distinguished from other endopeptidases by their dependence on metal ions as cofactors, their ability to degrade extracellular matrix, and their specific evolutionary DNA sequence.^6-8

Figure: 4 Structural Domains of Matrix Metalloproteinases

Table: 1 Classifications of Matrix Metalloproteinesis^9-10

Sub Group MMP Nomenclature

Interstitial collagenases

MMP-1

MMP-8

MMP-13

Collagenase-1

Collagenase-2

Collagenase-3

Gelatinase

MMP-2

MMP-9

Gelatinase-A

Gelatinase-B

Strimelysins

MMP-3

MMP-10

MMP-11

MMP-12

Strimelysin-1

Strimelysin-2

Strimelysin-3

metalloelastase

Metrilysins

MMP-7

MMP-26

Metrilysin-1

Metrilysin-2, Endometase

Membrain type MMP

MMP-14

MMP-15

MMP-16

MMP-17

MMP-24

MMP-25

MMP-23

MT1-MMP

MT2-MMP

MT3-MMP

MT4-MMP

MT5-MMP

MT6-MMP

CA-MMP

Others

MMP-18

MMP- 19

MMP-20

MMP-21

MMP-22

MMP-27

MMP-28

Collagenase-4

RASI-1

Enamelysin

CMMP

Epilysin

The proteolytic activity is delicately regulated by transcriptional regulation, proenzyme activation, and inhibition of pro MMP activation and MMP activity. In addition, chemical agents (e.g. organomercurials), oxidative stress, serine proteinases such as plasmin and trypsin, and other MMPs such as MT-MMP activate each other in a complex network. Microenvironmental changes including low pH and heat treatment can also cause activation. Activation of MMPs is stepwise in many cases and can be initiated by other already activated MMPs or by several serine proteinases that can cleave peptide bonds within the MMP prodomain. In addition, bacterial proteinases can activate primps. ^11-12

Figure: 5 Activation of MMP

The function of MMPs is very complicated and subtle. They are involved in normal physiological processes as well as in pathological processes. Physiological processes include the normal turn bover and maintenance of ECM proteins in connective tissue and BM and also in tissue remodelling and embryogenesis. Moreover, MMPs are engaged in the cell-cell and cell-matrix signaling. MMPs are able to modulate the activity of a variety of nonmatrix proteins. MMP-7 for instance is responsible for the activation of prodefensin in the small intestine, there by participating in the bacterial defense process. Several MMPs, including MMP-1, -2, -3, -11, and -7 can modulate the activity of many growth factors, cytokines, chemokines, and adhesion receptors through proteolytic cleavage. Fragments of matrix proteins can act as chemo attractants. MMPs can also process pro-inflammatory mediators, defensins, complement components, cell adhesion molecules, and cell surface receptors participating in cell signaling and innate immunity. Certain MMPs, such as MMP-8, MMP-9, and MMP-7, can exert anti-inflammatory or defensive characteristics. The cellular sources of different MMPs have been investigated widely. MMPs are usually derived from different pulmonary inflammatory cells, such as alveolar macrophages, neutrophils, and eosinophils, in addition to resident cells including. Bronchial epithelial cells, Clara cells, alveolar type II cells, fibroblasts, smooth muscle cells, and endothelial cells. The expression rates of MMPs differ between stimulated and nonstimulated conditions.^13-14

Matrix metalloproteinases have multiple important roles in cancer development:¹⁵^-17

(1) MMPs cause tumor cell initiation and growth. MMP3 has pre-neoplastic activity and is correlated in cancer cell malignant phenotype.

(2) MMPs are crucial in degradation of basement membrane and extra cellular matrix that are fundamental for cancer cell invasion, and metastasis establishment.

(3) MMPs are related to tumor angiogenesis. MMP-2 is responsible for laminin-5 degradation.

(4) MMPs are associated with breast physiological development in which MMP-9 stimulates increased cell proliferation, branching and morphogenesis by TNFα.

(5) MMP-9 is also important for cancer cell migration and it cooperates with αvβ3 integrin ¹⁸.

(6) MMPs are correlated with cell proliferation. They release growth factors that are important for cancer and mammary gland cell multiplication.

(7) MMPs are important in apoptosis. They are reported to initiate apoptosis by causing loss of contact of cells to the basement membrane. TIMP1 and TIMP2 are thought to decrease apoptosis.¹⁹

MMP localization in tumors:

The morphological localization of MMPs intra tumoral in breast cancer has been the subject of numerous studies. Different studies have sometime-contradictory data on the location of MMPs. Some co-localize MMP with neoplastic epithelial cells whereas others associated them with different components of the neoplastic stroma. Therefore, according To some reports, MMP-2 can be observed in stromal tumor fibroblasts and well differentiated invasive cancer cells in the neoplastic cell plasma membrane in peri tumor stromal cells and/or angiogenic blood vessels. MMP-9 has been associated with neoplastic cell plasma membrane, non-neoplastic ducts and acini, epithelial cells and macrophages, stromal fibroblasts and endothelial cells, tumor-infiltrating stromal cells, including neutrophils, macrophages, and vascular pericytes. Expression for MMP-3 was observed both in tumor and stroma cells. Normal breast epithelia were weakly positive for MMP-3-mRNA. tumor cells and peri tumor stroma showed low MMP-3 transcript levels, especially in medullary carcinomas. There is therefore a need to determine the exact location of MMPs in the different types of cells that compose the tumor in order to understand more about the way MMPs influence the invasive and metastatic process. We observed staining for MMP-2, -3 and -9 in the cytoplasm of neoplastic epithelial cells in all neoplastic sites evaluated (mammary gland, lung, omentum, pancreas, heart, kidney and brain). MMP 2 and MMP 9 also stained stromal fibroblasts. Staining was also observed normal epithelium and macrophages within metastatic foci.²⁰

MMPs and tumor stroma interaction:

Tumor environment is very important for expression and activities of MMPs. For instance IL12, a cytokine observed in the extracellular matrix, can enhance the activity of MMPs. In the tumor cell-cell interactions, pericellular environment and products of degradation of the extracellular matrix are important for MMP production and activation. Tumor cells also interact with stromal cells or cell-bound factors that stimulate the production of MMPs. Among these factors, extracellular matrix metalloproteinase inducer (EMMPRIN) stimulates in vitro production of MMPs. EMMPRIN is present at the surface of both tumor epithelial and peri tumoral stromal cells. Stromal cells do not expressed EMMPRIN, but this molecule is bound to stromal cells via a superficial specific receptor. MMP3 and MMP-2 are expressed predominately in peri tumoral fibroblasts. MT-MMP1 is produced in fibroblasts and is a major activator of MMP-2 this suggests that the stroma component is fundamental for MMP production. MT1-MMP is anchored to the cell surface and acts as a receptor for TIMP2 that binds to MT1-MMP through his N terminal domain. This binary complex acts then as a receptor for pro-MMP-2. TIMP2 C-terminal binds to pro-MMP-2 and MT1-MMP cleaves then pro-MMP-2 causing the formation of an intermediate species. Stromal fibroblasts at the tumor invasion front are thought to produce the bulk of MMP-2.Tumor cells usually express low constitutive levels of MMP-2. Stromal cells have strong but short induction of MMP-2. This very high and complex regulation of the expression of MMPs represents a host response to the tumor and neoplastic cell interaction with the tumor stromal component is fundamental for cancer invasion and metastasis.²¹

Figure: 6 Effect of MMPs in metastesis development

The role of MMPs in diseases:

Excessive expression of MMPs contributes to the pathogenesis of different pulmonary and non pulmonary diseases. They are believed to play a role in the pathogenesis through degradation of ECM and BM. BM protein degradation might cause influx of inflammatory cells and perturbation of the epithelial/endothelial structure, whereas degradation of elastin and collagen could predispose to airspace enlargement. Aberrant expression of MMPs has been associated with many destructive diseases including lung diseases, arthritis, periodontal diseases, atherosclerotic rupture, aortic aneurysm, and tumor progression. Lung diseases, with excessive amounts of MMPs include equine and human COPD, human asthma, bronchiectasis, and various interstitial diseases.²²

MMP-2 and MMP-9 (gelatinases) MMP-2 and MMP-9 belong to the group of gelatinases. Their key feature is that they readily digest the denaturated collagens, gelatins. These MMPs have some differences in their capacity to cleave different types of collagens; MMP-2, but not MMP-9, can degrade native type I and II collagens. MMP-9, also known as gelatinase-B, is secreted from cells in a glycosylated 92-kDa form and activated thereafter to 77- to 82-kDa and 68-kDa forms by a protease cascade. The most efficient activators of MMP-9 are probably human trypsin-2 together with MMP-3. Dimeric forms of the 220-kDa proMMP-9 are commonly found. The protein sequence of canine MMP-9 displays similarities with human (79.6%), rat (72.0%), rabbit (80.6%) and bovine (82.3%) sequencies (Yokota et al. 2001). MMP-9 has been located in many different inflammatory cells such as macrophages, neutrophils, mast cells, and eosinophils. Pulmonary resident cells do not produce MMP-9 in the normal lung but can express various MMP-9 species under stimulation. In these resident cells, MMP-9 is expressed in bronchial epithelial cells, Clara cells, alveolar type II cells, fibroblasts, smooth muscle cells, endothelial cells, and submucosal cells. MMP-9 plays a key and pivotal role in gelatine and type IV collagen degradation but also has many other substrates such as elastin, collagen V, VII, X, XI, XIV, and fibronectin. MMP-9 participates in basal cell migration, ECM component digestion, and activity modulation of other proteases and cytokines. MMP-2, or gelatinase-A, a 72-kDa gelatinase in its latent form, is converted into 59- to 62-kDa forms during activation (Birkedahl-Hansen et al. 1993). The canine N-terminal amino acid sequence has been found to be 87% identical to human MMP-2. MMP-2 is not readily activated by serine proteinases including trypsin-2 and plasmin; instead, the main activation of proMMP-2 takes place on the cell surface mediated by MT-MMPs with the assistance of tissue inhibitor of matrix metalloproteinase 2 (TIMP-2). Macrophages as well as pulmonary structural cells, such as fibroblasts, pneumocytes, epithelial, and endothelial cells, synthesize MMP-2. MMP-2 shares mostly substrate specificities with MMP-9 but can also digest type I and II collagens similarly to the classical collagenases (MMP-1, -8, and -13). Elevated levels of MMP-9 have been reported in such pulmonary diseases as asthma, adult respiratory distress syndrome (ARDS), human and equine COPD, and bronchiectasis. In normal, healthy resting tissues, the production of MMP-9 is at a low level. MMP-9 has been proposed to merely modulate enzymes and cytokines to fine-tune both destruction and repair, and may even have a beneficial function in a subset of cells in the disease process, therefore not being heavily involved heavily in the ECM destructive processes. While few studies have focused on the role of MMP-2, its contribution has nevertheless been shown in inflammatory human lung diseases. Increased levels of either MMP-2 or activated forms of MMP-2 have been found in lung diseases including experimental silicosis, COPD, bronchiectasis, asthma, and ARDS. Similar to MMP-9, MMP-2 has also been reported to act as an effector and down regulator in inflammation, for instance, demonstrated that MMP-2 can diminish inflammation.^23-25

Figure: 7 Domain structure of the MMP-2.

Pre: signal sequence; Pro: propeptide with a free zinc-ligating thiol (SH) group; Zn: zinc-binding site; II: collagen-binding fibronectin type II inserts; H: hinge region;

The hemopexin/vitronectin-like domain contains four repeats with the first and last linked by a disulfide bond.

MMP-2 is a Zn^{+2 dependent endopeptidase, synthesized and secreted in zymogen form}. The nascent form of the protein shows an N-terminal signal sequence ("pre" domain) that directs the protein to the endoplasmic reticulum. The pre domain is followed by a propeptide-"pro" domain that maintains enzyme-latency until cleaved or disrupted, and a catalytic domain that contains the conserved zinc-binding region. A hemopexin/vitronectin-like domain is also seen, that is connected to the catalytic domain by a hinge or linker region. The hemopexin domain is involved in TIMP (Tissue Inhibitors of Metallo-Proteinases) binding, the binding of certain substrates, membrane activation, and some proteolytic activities. It also shows a series of three head-to-tail cysteine-rich repeats within its catalytic domain. These inserts resemble the collagen-binding type II repeats of fibronectin and are required to bind and cleave collagen and elastin. The regulation of MMP-2 activity occurs at many levels, of which regulation through TIMP-2 and its cell surface receptor, MT1-MMP (MMP14) is critically decisive. At higher levels of TIMP-2, MT1-MMP forms a ternary complex with MMP-2 through, leaving no free MT1-MMP receptors, thereby inhibiting the activation of pro-MMP-2 by MT1-MMP. But at lower levels of TIMP-2, due to availability of free MT1-MMP, MT1-MMP mediated activation of MMP-2 is observed. Further data also indicates that expression of TIMP-2, MMP-2 and MT1-MMP (MMP-14) is co-regulated transcriptionally, demonstrating an intricate network of regulation. Pro-MMP-2 activation is also seen by complex signaling induced by ECM proteins like osteopontin, various cytokines for example IL-8 in endothelial cells and other factors.^26-28

Expression: MMP-2 is tightly regulated at the transcriptional and post-transcriptional levels.

Localisation: Peri/extracellular

Function: Primary function is degradation of proteins in the extracellular matrix. It proteolytically digests gelatin (denatured collagen), and types IV, V, VII, IX and X collagen. Physiologically, MMP-2 in coordination with other MMPs, play a role in normal tissue remodeling events such as embryonic development, angiogenesis, ovulation, mammary gland involution and wound healing. MMP-2 is also involved in osteoblastic bone formation and/or inhibits osteoclastic bone resorption.^29-31

Homology: Homology in amino acid sequence is seen with the other members of Metalloproteinase family especially with MMP-9.

Inhibition of MMPs:

Physiological inhibition of MMPs:

The activity of MMPs can be inhibited by endogenous or exogenous synthetic inhibitors. The endogenous inhibitors are known as TIMPs, and to date four TIMPs (TIMP-1, TIMP-2, TIMP-3, and TIMP-4) have been identified in vertebrates. They play a key role in maintaining the delicate balance between ECM deposition and degradation in different physiological processes. TIMPs appear in most tissues and body fluids, but TIMP-3 is the only member of the TIMP family which is found exclusively in the ECM. TIMPs inhibit the active enzyme as well as regulate the activation process of MMPs. They form tight bonds with the activated MMPs, resulting relatively heat-, and proteolytic-resistant complexes. TIMP-1 and -2 inhibit the activity of most MMPs, with the exception of MT1-MMP. TIMP-2 is a ten times more effective inhibitor of MMP-2 and MMP-9 than TIMP-1, and TIMP-1 is two times more effective against MMP-1 than against other MMPs. TIMP-1 forms complexes preferentially with proMMP-9, and TIMP-2 and -4 with proMMP-2 (Goldberg et al. 1989). TIMP-3 inhibits activity of MMP -1, -2, -3, -9, and -13. TIMP-4 inhibits the activity of MMP-2 and MMP-7 more potently than that of MMP -1, -3, and -9. Recent studies have revealed that these proteins can also exhibit biological activities that affect cell proliferation and survival. These activities are distinct from their interactions with MMPs or inhibition of MMPs. The predominant nonspecific serum inhibitor is 2-macroglobulin, which is also responsible for regulating various other proteinases, especially serine proteinases.^32-34

Synthetic inhibitors of MMPs:

Synthetic exogenous MMP inhibitors, such as GalardinTM, MarimastatTM, BatimastatTM, and the gelatinase-selective CTTHWGFTLC-peptide, are the target of much research activity, particularly in the pharmaceutical field. Extensive investigations have examined their biological activities in tumor growth, invasion, metastasis, and angiogenesis as well as in the diagnosis and treatment of inflammatory diseases. Doxycycline and nonantimicrobial tetracycline derivatives (chemically modified tetracyclines, CMT) possess anticollagenase activity. CMTs have been tested in vitro also in pulmonary epithelial lining fluid in equine COPD. Despite tremendous efforts over the last decade with multiple inhibitor classes, simple, safe, and effective drugs for inhibiting. Individual MMPs have not yet emerged. The only inhibitor in clinical use is low-dose or sub antimicrobial dose doxycycline which has been shown to be beneficial as adjunctive medication in human periodontal diseases.^35-36

Future Treatment:

The treatment of glioblastomas requires a multidisciplinary approach that takes the presently incurable nature of the disease into consideration. Treatments are multimodal and include surgery, radiotherapy and chemotherapy. Current recommendations are that patients with glioblastomas should undergo maximum surgical resection, followed by concurrent radiation and chemotherapy with the novel alkylating drug temozolomide. This is then to be followed by additional adjuvant temozolomide for a period of up to 6 months. Major advances in surgical and imaging technologies used to treat glioblastoma patients are described. These technologies include magnetic resonance imaging and metabolic data that are helpful in the diagnosis and guiding of surgical resection. However, glioblastomas almost invariably recur near their initial sites. Disease progression usually occurs within 6 months and leads rapidly to death. A number of signaling pathways can be activated constitutively in migrating glioma cells, thus rendering these cells resistant to proapoptotic insults, such as conventional chemotherapies. Therefore, the molecular and cellular therapies and local drug delivery that could be used to complement conventional treatments are described, and some of the currently ongoing clinical trials are reviewed, with respect to these new approaches.³⁷

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Received on 31.07.2011

Modified on 20.08.2011

Accepted on 05.09.2011

Research J. Science and Tech. 3(5): Nov.-Dec. 2011: 301-307