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 Table of Contents  
REVIEW ARTICLE
Year : 2013  |  Volume : 9  |  Issue : 3  |  Page : 356-363

Matrix metalloproteinases and their tissue inhibitors in gastric cancer as molecular markers


1 Ecology and Health Laboratory, Institute of Public Health, University of Veracruz, Xalapa, Veracruz, Mexico
2 Department of Gastroenterology Dr. Miguel Dorantes Mesa Hospital, Xalapa, Veracruz, Mexico
3 Digestive Physiology and Gastrointestinal Motility Laboratory, Institute of Medical and Biological Research, University of Veracruz, Veracruz, Mexico

Date of Web Publication8-Oct-2013

Correspondence Address:
Clara L Sampieri
Institute of Public Health, University of Veracruz Luis Castelazo Ayala Avenue, Xalapa, Veracruz, CP 91190
Mexico
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0973-1482.119302

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 > Abstract 

Gastric cancer is a complex disease that involves a range of biological individuals and tumors with histopathological features. The pathogenesis of this disease is multi-factorial and includes the interaction of genetic predisposition with environmental factors. Gastric cancer is normally diagnosed in advanced stages where there are few alternatives to offer and the prognosis is difficult to establish. Metastasis is the leading cause of cancer deaths. Identification of key genes and signaling pathways involved in metastasis and recurrence could predict these events and thereby identify therapeutic targets. In this context, the extracellular matrix metalloproteinases (MMPs) and their inhibitors (TIMPs) represent a potential prognostic tool, because both genetic families regulate growth, angiogenesis, invasion, immune response, epithelial mesenchymal transition and cellular survival. Proteolytic parameters based on MMP/TIMP expression could be useful in the identification of patients with a high probability of developing distant metastases or peritoneal dissemination for each degree of histological malignancy. It is also probable that these parameters can allow improvement in the extent of surgery and dictate the most suitable therapy. We reviewed papers focused on human gastric epithelial cancer as a model and focus on the potential use of MMPs and TIMPs as molecular markers; also we include literature regarding gastric cancer risk factors, classification systems and MMP/TIMP regulation.

Keywords: Gastric cancer, matrix metalloproteinases, tissue inhibitors of matrix metalloproteinases, molecular markers


How to cite this article:
Sampieri CL, León-Córdoba K, Remes-Troche JM. Matrix metalloproteinases and their tissue inhibitors in gastric cancer as molecular markers. J Can Res Ther 2013;9:356-63

How to cite this URL:
Sampieri CL, León-Córdoba K, Remes-Troche JM. Matrix metalloproteinases and their tissue inhibitors in gastric cancer as molecular markers. J Can Res Ther [serial online] 2013 [cited 2019 Nov 13];9:356-63. Available from: http://www.cancerjournal.net/text.asp?2013/9/3/356/119302


 > Introduction Top


Gastric cancer is the second highest cause of cancer related death, with incidence being highest in China, Japan, Eastern Europe and Latin America. [1] Stomach cancer is characterized by late clinical presentation, rapid prognosis and poor survival. [2] In advanced gastric cancer cases complete surgical resection, gastrectomy, remains the only curative method but in general, five-year survival following surgery is poor. [3]

Development, Progression and Molecular Prognosis of Gastric Cancer

Established gastric cancer risk factors are diverse and can be grouped as follows:

  • Nutritional: high consumption of salt, smoked food, hot spicy dishes, nitrite-rich food or water, high carbohydrate and fat ingestion, and low consumption of milk, fruits, fresh vegetables, selenium, vitamins A, C and E. [4]
  • High consumption of tobacco and alcohol, although these gastric cancer risks remain controversial. [5],[6]
  • Bacterial and viral infections: Helicobacter pylori infection has been associated with intestinal type gastric cancer; this bacteria is considered as a Group I carcinogen by the World Health Organization (WHO). [7],[8] In addition, mycoplasma [9] and Epstein-Barr [10] virus infections have been associated with gastric tumorgenesis.
  • Precursor conditions: some histological changes in healthy gastric mucosa significantly increase the risk of gastric adenocarcinoma, including chronic atrophic gastritis, [11] adenomatous polyps, [12] Barrett΄s esophagus, [13] intestinal metaplasia, [14] dysplasia, [15] and Ménétrier disease. [16]
  • Accumulation of genetic modifications: including tumor suppressor gene inactivation of p53, [17] adenomatous polyposis coli (APC), [18] Rb genes, [19] E-cadherin, [20] deleted in colorectal cancer (DCC) gene, [21] oncogene activation of c-erb-B2, [22] K-ras, [23] K-sam, c-myc, c-met, [24] and microsatellite alterations. [25]
Gastric cancers constitute a highly heterogeneous group of tumors in terms of biological behavior and epidemiology. In general, patient outcome is difficult to predict using classifications. However, diverse classifications have been proposed in order to identify the morphological variability and correlate to prognosis:

  • The Borman classification of advanced gastric cancer carcinomas divides tumors into four groups; I) Mainly exophytic growth, usually broad-based polypoid tumors with a protruding, papillary, cauliflower-shaped or villous surface; II) Carcinomas with a central, bowl-shaped ulceration and elevated margins; III) Centrally ulcerating carcinomas without ridged, elevated margins and indistinctly delineated from its surroundings; and IV) Diffuse tumors with infiltration of the gastric wall. [26]
  • The Lauren classification distinguishes two groups of tumors; intestinal and diffuse. [27] The intestinal type is characterized by cohesive neoplasic cells forming gland-like tubular structures, tends to occur in older men, and is associated to a defined pattern of histological changes in healthy gastric mucosa. [27],[28] In the diffuse type, neoplasic cell cohesion is absent, so that individual cells infiltrate and thicken the stomach wall without forming a discrete mass. [27] In the intestinal type, the macroscopic margins correspond approximately to microscopic spread, whereas in the diffuse type, poorly differentiated cancer can extend submucosally far beyond its macroscopic borders. [27]
  • The Ming classification is based on patterns of growth and invasiveness; expanding and infiltrative types. Expanding carcinomas grow en masse and by expansion, resulting in the formation of discrete tumor nodules, whereas infiltrative carcinoma tumor cells invade individually. [29]
  • The Goseki classification combines two morphological characteristics; the degree of differentiation of the glandular tubules and the amount of mucus in the cytoplasm. Categorization is made into four groups; I) Well tubular differentiation and poor mucus in cytoplasm; II) Well tubular differentiation and rich mucus in cytoplasm; III) Poor tubular differentiation and poor mucus in cytoplasm and IV) Poor tubular differentiation and rich mucus in cytoplasm. [30]
  • The WHO classification is based on predominant histological pattern. Tubular adenocarcinomas contain prominent dilated or slit-like and branching tubules. Papillary adenocarcinomas are well differentiated cancers with elongated finger-like processes lined by cylindrical or cuboidal cells supported by fibrovascular connective tissue cores. Mucinous adenocarcinomas contain more 50% extracellular pools, when present scattered signet-ring cells do not dominate the histological picture. In signet/ring cell carcinomas, more than 50% of the tumor consists of isolated or small groups of malignant cells with intracytoplasmic mucin. [31]
  • The TNM classification is an anatomically-based system that records the primary and regional nodal extent of the tumor and the presence or absence of metastases. This system has been found to be the most reliable prognostic indicator of clinical outcome, albeit with a discrete contribution. Each individual aspect of TNM is termed a category: T describes the primary tumor site, N the regional lymph node involvement and M the presence or otherwise of distant metastatic spread. Based on these categories, the TNM classification groups gastric cancer patients into clinical stages. [32]
Despite the existence of several classification systems, significant advances in curative surgeries, and the development of therapies such as adjuvant chemotherapy, and biological and radiation therapy, most gastric cancer patients suffer from local and distance recurrence. This may be due to high biological heterogeneity of the gastric tumors, complex pathogenesis networks and histological classification difficulties. An integrated molecular profile might therefore assist in predicting outcomes more accurately in order to provide appropriate treatment for these patients. Research efforts in clinical cancer research must be directed towards the identification of clusters of predictor genes, as a key tool in the establishment of molecular systems for gastric cancer staging. Knowledge regarding differences in gene expression profiles between normal gastric mucosa, precursor conditions and malignant tissue, including expression signatures for progressive stages, is central to elucidating regulatory pathways involved in gastric cancer development and progression. Stage-defining genes are thus associated with the biological behavior of the tumor, contributing to the definition of survival rates in those patients. The incorporation of gene expression profiles and pathological features can lead to the development of prognostic scoring systems for each degree of histological malignancy. [33] It is also conceivable that molecular staging systems for gastric cancer may allow improvement in the selection of patients for adjuvant and neoadjuvant therapy, targeted therapy design, drug delivery pathway, surgical resection design and improved prognostication to facilitate the decisions of both clinician and patient.

The development of molecular biology has enhanced our understanding of gastric cancer, although their molecular mechanisms are still unknown. Some interesting molecules have been suggested as prognosis markers in these patients, including cell adhesion molecules, such as E-cadherin, [34] tumor suppressor genes, for example, p53, [35] cell growth factors and their receptors, such as epidermal growth factor receptor (EGFR) [36] and extracellular matrix remodeling genes, matrix metalloproteinases (MMPs) and their natural inhibitors, the tissue inhibitors of the metalloproteinases (TIMPs). However, most of these molecules have failed to become popular as prognostic tools in gastric cancer, probably due to limitations in reliability, sensitivity and specificity, problems than could be solved by methods to optimize reproducibility: avoiding sampling variability, increasing the sample size of tumors, extending the number of genes analyzed and creating partnership platforms to study multicenter trials. Increasing the molecular information obtained from tumors and their microenvironments improves the precision with which treatment can be administered.

Hence, in addition to their ability to degrade extracellular matrix (ECM) and basement membrane, and participate in growth regulation, angiogenesis, invasion, immune response, survival and epithelial mesenchymal transition, [37] the proteolytic parameters of MMPs and TIMPs may be suitable as prognosis tools in guiding operative treatment such as extent of surgery and use of appropriate therapy.


 > Materials and Methods Top


For online tables we reviewed Medline using the following keywords: a) metalloproteasa b) tissue inhibitor of metalloprotease and c) gastric cancer, using as limits: English and Spanish language. Then the abstracts were carefully reviewed in order to verify: a) study model (human) b) epithelial gastric cancer and c) statistical analysis regarding association of gene expression with clinicopathological features and/or classification systems. For the introductory part of this review we included key papers focused on gastric cancer risk factors, classification systems and MMP/TIMP regulation.

Matrix Metalloproteinases

The MMPs are a family of 24 zinc-dependent endopeptidases in humans that degrade components of ECM. The MMP genes are distributed widely among human chromosomes, although there is a cluster at 11q22 containing nine genes. [38] MMPs participate in several normal and pathological processes, and their activity is mainly modulated by the action of the TIMPs. [39] Structurally, MMPs are divided into eight classes: five are secreted and three are membrane type (MT-MMP). [40] According to substrate preferences, MMPs can be divided into six groups: collagenases (MMP-1,-8,-13), gelatinases (MMP-2,-9), stromelysins (MMP-3,-10,-11,-19), matrilysins (MMP-7,-26), MT-MMPs (MMP-14,-15,-16,-17,-23,-24,-25), and a heterogeneous group (MMP-12,-20,-21,-27,-28). [41],[42]

Because MMPs exhibit degradative actions against multiple substrates and influence many biological functions, their expression and activity is strictly controlled both temporally and spatially. [43] The mechanisms that control MMP activity operate in coordination to ensure that these proteases are present in the pericellular location of the correct cell type, at the right time and in the necessary amount. [42] However, malignant tumors have developed strategies to avoid these regulatory mechanisms and produce the dysregulated proteolytic activity that accompanies cancer invasion and metastasis, with conspiratorial help by surrounding stromal components. [44] The spread of cancer cells is a multi-step process and many of the stages of tumor invasion require degradation of the ECM and the connective tissue surrounding tumor cells. [45]

The MMPs are up regulated in almost every type of human cancer; in some cases their expression profile can indicate the degree of tumor progression. [46] This is important since metastasis is the principal event leading to death in patients with cancer. [47] In this context, a synthetic MMP inhibitor called marimastat has been evaluated in a pilot study of inoperable gastric cancers patients. In terms of results, the drug may have produced alterations in hepatic metabolism and despite the reduced dose, about one-third of the patients developed arthralgia/myalgia, events that are normally rapidly reversible on discontinuation of the drug. After 4 weeks of treatment, endoscopy showed 10 out of 31 patients had increased the fibrotic cover of the tumor, 8 showed decreased hemorrhagic appearance, and at least 2, where histology was assessable, showed evidence of increased stromal fibrotic tissue. [48] Following this study, a randomized trial with 369 advanced gastric patients was conducted; this trial reported a significant benefit in progression/free survival maintained over a further 2 years of follow-up, 10% of patients treated with marimastat were withdrawn from the study due to musculoskeletal pain. This study was the first demonstration of the therapeutic benefit of MMP inhibitors, particularly in a subset of patients who had already received chemotherapy. [49]

Regulation of Matrix Metalloproteinases

Regulation of MMP activity can occur at different levels: gene transcription, post-transcriptional mRNA stabilization, translational efficiency, enzyme compartmentalization and secretion, and proenzyme activation and inhibition which are mediated mainly by TIMPs and the membrane-anchored glycoprotein reversion-inducing cysteine-rich protein with Kazal motifs (RECK). Transcription, proenzyme activation and inhibition are likely the principal levels that regulate MMP activity. [42],[50]

There are several complex mechanisms by which cells regulate transcription of MMP genes. [51] Most MMPs are not expressed under normal quiescent conditions, but their transcription is usually induced in tumor and host cells by a wide variety of soluble factors. These soluble factors are produced by the stroma, infiltrating defense cells, or by the tumor cells. [44] However, some MMP genes tend to be constitutively expressed and thus non-inducible, [52] while others are tissue specific, for example MMP20 which is expressed exclusively in the pulp tissue of developing teeth. [53]

The soluble factors that stimulate MMP expression include cytokines and growth factors, such as interleukins, [54] epidermal growth factor (EGF), [55] nerve growth factor (NGF), [56] vascular endothelial growth factor (VEGF), [57] fibroblast growth factor (FGF), [58] transforming growth factor-b (TGF-b), [59] nuclear factor-kB (NF-kB), [60] and extracellular matrix metalloproteinase inducer (EMMPRIN). [61] In addition to soluble factors, changes in cell shape, mechanical [62] and oxidative stress [63] may also result in MMP induction.

Another important mechanism that affects MMP transcription occurs by the presence of single nucleotide polymorphisms (SNPs) in their promoter regions, which may create or abolish transcription factor binding sites thereby modify MMP transcriptional activity. [64] In this regard, it has been reported that MMP7 -181A/G polymorphism is a candidate marker for predicting individuals who are at higher risk of developing gastric cancer in the Japanese [65] and Chinese [66] populations. A SNP in the promoter region of MMP9 -1562 C/T is associated with the invasive phenotype of gastric cancer in Japan. [67] Moreover, when protein polymorphisms of MMP-9: R279Q and P574R were studied in China, [68] the investigators reported significant associations between both SNPs and lymph node metastasis, but not the invasion of gastric cancer. On the other hand, it has been reported that a single adenine insertion/deletion in the MMP3 promoter region causes transcriptional elevation; but this SNP is not associated with a risk of development and lymphatic metastasis in gastric cardia adenocarcinoma in Chinese population. [69]

The MMPs, like other proteolytic enzymes, are synthesized as inactive zymogens and their activation mechanisms are often the result of a complex proteinase cascade focused on the immediate pericellular space. [42] Although most MMPs are activated outside the cells following their secretion, as latent zymogens, other MMPs such as MT-MMPs, [70] MMP-11 [71] and MMP-23 [72] are activated by intracellular protein convertases before they reach the cell surface or are secreted.

Activity of MMPs is controlled by diverse endogenous inhibitors. The principal inhibitor of MMPs in plasma is the abundant protein a2-macroglobulin, [73] whereas TIMPs are the primary and best known MMP inhibitors in tissues. Once a2-macroglobulin binds to a MMP, the complex is removed by scavenger receptor-mediated endocytosis. [73] Thrombospondin-2, in a similar manner to that of a2-macroglobulin, interacts with pro-MMP-2 generating a complex which is removed by endocytosis. [74] By contrast, thrombospondin-1 binds pro-MMP-2 [75] preventing their activation. This ability of thrombospondin-1 to inhibit pro-MMP-2 and pro-MMP-9 has been implicated in the suppression of tumor growth. [76]

Human TIMPs are a family of four secreted proteins whose primary function is to limit the degradative actions of MMPs. TIMPs interact via their N-terminal domain with all MMP active sites to reversibly block proteolytic activity. [39] TIMP-1, -2 and -4 are soluble proteins, while TIMP-3 is associated with the ECM. [77] TIMPs inhibit the activity of all MMPs with the exception of certain MT-MMPs that are poorly or non-inhibited by TIMP-1. [78]

Matrix Metalloproteinases and their Tissue Inhibitors in Gastric Cancer

Studies regarding regulation of MMPs, reviewed in, [79] and TIMPs in gastric cancer (see online tables) have suggested that these molecules could be useful as markers of depth of invasion, metastasis and peritoneal dissemination; all of which are key parameters in defining patient treatment, despite the wide heterogeneity of gastric tumors, that in the general intestinal type tends to metastasize via both hematogenous and lymphatic routes, while the diffuse type commonly produces peritoneal dissemination or lymph node metastasis, rarely hematogenous. [80]

Interestingly, depending on the technique employed such as RT-PCR, Northern blotting, Immunohistochemistry or ELISA and the categories used to classify expression in gastric cancer tumor specimens, authors have associated the expression of certain MMPs and TIMP-2 with Borman, [81] Lauren [82],[83],[84],[85],[86],[87] and TNM classifications (see online tables). Full validation of these molecules into translational clinical research would be a benefit for a potentially curative treatment guide. Moreover, some studies suggest that MMPs and TIMPs have the ability to predict the prognosis of gastric cancer prognosis (see below).

Finally, we review studies that have reported an association between MMP/TIMP expression and survival, depth of invasion, lymph node metastasis, distant metastasis and peritoneal dissemination in gastric cancer patients. Using diverse techniques, authors have proposed that expression of MMP2, [88],[89] MMP7, [82] MMP-9, [87] MMP13, [88] MMP14,[83],[90] MMP-28 [91] and TIMP-1 [92] in tumor specimens; MMP7 in peritoneal lavage [93] and MMP-9 [94] and TIMP-1 [95] in plasma are associated with poor prognosis in gastric cancer. Through immunohistochemistry, this association is also found for MMP-7, [96] but not for MMP-2 and MMP-9. [85],[97] In contrast, elevated levels of MMP12 (mRNA/protein) in tumor specimens are associated with better prognosis. [98]

By means of RT-PCR technology, authors have reported that MMP7[99] and MMP14[90] are associated with depth of invasion: this correlation also is found using immunohistochemistry analysis for MMP-7. [100] For MMP-1,-2,-9,-11,-28, TIMP-1 and TIMP-2 there have also been reported associations with depth of invasion; however, some studies are conflictive or cannot be directly compared (see online tables).

Using RT-PCR technology in tumor specimens [83] and Quantitave real-time PCR (qPCR) in bone marrow and peripheral blood samples, [101] a correlation has been found between expression of MMP14 and lymph node metastasis. By means of RT-PCR [93] and ELISA, [96],[102] MMP7 expression has been associated with lymph node metastases in peritoneal lavage of gastric patients and in tumor specimens, respectively, however, this correlation is not found using RT-PCR in tumor specimens. [96] MMP2 expression assessed by in situ hybridization (ISH) has shown negative correlation with lymph node metastasis, a result not produced by immunohistochemistry study. [98] Expression of MMP9 (mRNA/protein), MMP-11, TIMP-1 and TIMP-2 have been correlated with lymph node metastasis or N classification, but again some reports are conflictive or cannot be fully compared (see online tables).

Expression in tumors of MMP9,[103] MMP-11 [104] and TIMP-1 [95] by ISH, immunohistochemistry and ELISA, respectively, have been associated with distant metastasis. Likewise, elevated levels of MMP-2 and TIMP-2 have been correlated to distant metastasis in serum samples. [105]

The incidence of high levels of MMP14 in bone marrow and peripheral blood detected by qPCR has been correlated with peritoneal dissemination. [101] The expression of MMP7 (mRNA/protein) in tumor specimens detected by RT-PCR and immunohistochemistry has also been associated with this parameter. [96] Interestingly, MMP7 expression detected by RT-PCR in peritoneal lavage of gastric cancer patients is also associated with peritoneal metastases. [93] However, non-association of MMP-7 in tumors with peritoneal metastasis has also been reported. [102] High levels of TIMP-1 in plasma samples, [106] detected by ELISA, have been reported to be associated with peritoneal dissemination, but not high levels in tumor specimens. [92] Finally, MMP-1 in tumor specimens [107] and in serum samples [108] has been shown to be non-correlated to peritoneal dissemination.


 > Conclusion Top


It is well established that correct staging of cancer patients is crucial for improved prognosis, the power of molecular diagnostics and prognosis is only beginning to be applied for the benefit of public health and promises to make major contributions. Due to high pathological complexity in gastric cancer; however, few molecular markers are clinically useful at present for guiding treatment. In patients with newly diagnosed tumors, it is essential to know the probable subsequent formation of metastasis; this knowledge allows patients with localized disease to avoid over-treatment and its associated undesirable side effects while patients with advanced cancer can equally avoid under-treatment. The combination of proteolytic gene expression profiles and clinicopathological factors may thus provide an insight into tumor biology and guide clinicians with respect to management strategy. In this regard, in multivariate analysis, MMP and TIMP profiles in gastric cancer may constitute an additional tool to aid in revealing tumor behavior. Hence, gene expression profiles allow characterization of differentially expressed genes and those that are considered to be key determinants of cellular type phenotype and function. The application of MMP and TIMP profiles may therefore have the potential to predict the future development of metastasis. These MMP and TIMP profiles studies should be follow recommendations of BRISQ [109] (Biospecimen Reporting for Improved Study Quality) and REMARK [110] (Reporting Recommendations for Tumor Marker Prognostic Studies) in order to have a reliable assessment of study quality and adequate interpretation.


 > Acknowledgement Top


National Council of Science and Technology of Mexico (CONACyT: 85675 and 79628).

 
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