Role of matrix metalloproteinases and their inhibitors in tumor invasion and metastasis

The role of various matrix metalloproteinases (MMP)—such as gelatinases, stromelysins, matrilysin, collagenase-3, and membrane-bound MMP (MB-MMP)—in tumor invasion and metastasis is discussed. Data suggesting significance for malignant growth of the expression level of these enzymes and also of their activators and inhibitors are presented. It is concluded that at different stages of tumor progression the activity of different MMPs is displayed, which is regulated by various growth factors and oncogenes. Different malignancies are characterized by changes in activities of specific MMPs. Data are presented which show significance of the ratio between the MMP activity and that of tissue inhibitors of metalloproteinases (TIMP) in tumor invasion and metastasis, especially in connection with a dual role of TIMP as both MMP inhibitors and activators.     

The role of microRNAs in prostate cancer migration,invasion, and metastasis

Prostate cancer (PCa) is considered the most prevalent malignancy and the second major cause of cancer-related death in males from Western countries. PCa exhibits variable clinical pictures, ranging from dormant to highly metastatic cancer. PCa suffers from poor prognosis and diagnosis markers, and novel biomarkers are required to define disease stages and to design appropriate therapeutic approach by considering the possible genomic and epigenomic differences. MicroRNAs (miRNAs) comprise a class of small noncoding RNAs, which have remarkable functions in cell formation, differentiation, and cancer development and contribute in these processes through controlling the expressions of protein-coding genes by repressing translation or breaking down the messenger RNA in a sequence-specific method. miRNAs in cancer are able to reflect informative data about the current status of disease and this might benefit PCa prognosis and diagnosis since that is concerned to PCa patients and we intend to highlight it in this paper.     

Genome-wide expression analysis suggests a crucial role of dysregulation of matrix metalloproteinases pathway in undifferentiated thyroid carcinoma

Background

Thyroid cancer (TC) is the most common malignant cancer of the Endocrine System. Histologically, there are three main subtypes of TC: follicular, papillary and anaplastic. Diagnosing a thyroid tumor subtype with a high level of accuracy and confidence is still a difficult task because genetic, molecular and cellular mechanisms underlying the transition from differentiated to undifferentiated thyroid tumors are not well understood.A genome-wide analysis of these three subtypes of thyroid carcinoma was carried out in order to identify significant differences in expression levels as well as enriched pathways for non-shared molecular and cellular features between subtypes.

Results

Inhibition of matrix metalloproteinases pathway is a major event involved in thyroid cancer progression and its dysregulation may result crucial for invasiveness, migration and metastasis. This pathway is drastically altered in ATC while in FTC and PTC, the most important pathways are related to DNA-repair activation or cell to cell signaling events.

Conclusion

A progression from FTC to PTC and then to ATC was detected and validated on two independent datasets. Moreover, PTX3, COLEC12 and PDGFRA genes were found as possible candidates for biomarkers of ATC while GPR110 could be tested to distinguish PTC over other tumor subtypes. The genome-wide analysis emphasizes the preponderance of pathway-dysregulation mechanisms over simple gene-malfunction as the main mechanism involved in the development of a cancer phenotype.

Electronic supplementary material

The online version of this article (doi:10.1186/s12864-015-1372-0) contains supplementary material, which is available to authorized users.     

Advances in assays of matrix metalloproteinases (MMPs) and their inhibitors

Matrix metalloproteinases (MMPs) play an important role in many physiological and pathological processes. To assay the activities of MMPs is important in diagnosis and therapy of the MMPs associated diseases, such as neoplastic, rheumatic and cardiovascular diseases. Several assay systems have been developed, which include bioassay, zymography assay, immunoassay, fluorimetric assay, radio isotopic assay, phage-displayed assay, multiple-enzyme/multiple-reagent assay and activity-based profiling assay. The principle, application, advantage and disadvantage of these assays have been reviewed in this article.     

The role of microRNAs in ovarian cancer initiation and progression

Epithelial ovarian cancer (EOC) has the highest mortality rate of all gynaecological cancers. One of the greatest impediments to improving outcome is an incomplete understanding of the molecular underpinnings of EOC pathogenesis and progression. Recent studies suggest that microRNAs (miRNAs) are involved in ovarian tumorigenesis and cancer development. Several miRNA profiling studies have identified some consensus aberrantly expressed miRNAs in EOC tissues, and these EOC-related miRNAs may play critical roles in the pathogenesis and progression of EOC. Moreover, some of the miRNAs may have diagnostic or prognostic significance. In this review, recent progress to reveal the role of miRNAs in EOC will be addressed, and a model for miRNA functions in ovarian cancer initiation and progression will be proposed.     

Altered matrix metalloproteinase expression associated with oncogene-mediated cellular transformation and metastasis formation

Matrix metalloproteinase expression was examined in a series of mammalian cell lines of varying degrees of malignant progression. The expression of MMP-2 and MMP-9 was found to correlate with ras-mediated cellular transformation and as a function of malignant potential. Altered MMP-2 and MMP-9 expression was found to correlate also in other oncogene transformed cell lines and the level of expression of both MMP-2 and MMP-9 correlated with metastatic potential. Increased expression of both MMP-2 and MMP-9 was also found in cells which constitutively over-express MAP kinase kinase suggesting that one of the consequences of the persistent activation of the MAP kinase pathway is elevated expression of MMP-2 and MMP-9. Additionally, this study demonstrated a correlation between the expression of MMP-3 (stromelysin-1) and the level of ras expressed in cells and with the cells' ability to form tumors and with malignant potential. The existence of a novel 80 kDa caseinase activity which correlates with ras expression and the ability of the cell to form tumors was also demonstrated. The growth status of transformed cells was also found to be important in determining the expression of MMP-2 mRNA but not MMP-9 mRNA expression, and this expression was cell-type specific. This study also demonstrates that oncogenes can interact to influence and to determine the nature of the matrix metalloproteinases expressed and that this interaction results in a tumorigenic phenotype and, most importantly, contributes to the metastatic phenotype. Alterations in the expression and the regulation of MMPs, particularly MMP-2 and MMP-9, constitute an integral part of the altered growth regulatory program found within transformed cells and in particular, in transformed cells capable of malignant progression.     

基质金属蛋白酶及其组织抑制剂研究进展

基质金属蛋白酶家族是细胞外基质降解过程中的重要酶类,组织金属蛋白酶抑制剂是基质金属蛋白酶的天然抑制物。研究证实,细胞外基质中基质金属蛋白酶及其组织抑制剂的失衡与多种病理机制有关,尤其与肿瘤的侵袭和转移密切相关。本就基质金属蛋白酶及其组织抑制剂的性质、结构以及功能进行了综述。     

The role of inflammation and its related microRNAs in breast cancer: A narrative review

Breast cancer is recognized as the most common type of cancer among women with a high rate of mortality all over the world. Over the past years, growing attention has been regarded to realize more about the mechanisms underlying the disease process. It is revealed that the progression of breast cancer may be strongly linked to chronic inflammation owing to the role of inflammatory factors in genetic instability and subsequent cancer predisposition. Although the association between breast cancer and inflammatory pathways has been well-defined now, only recent evidence pointed towards the inflammation-related microRNAs (miRNAs) as potential biomarkers and therapeutic targets involved in the crosstalk of multiple pathways during breast cancer development. Moreover, the practical interactions between these miRNAs and inflammatory factors are also a little characterized. In this review, we intended to describe the effects of predominant inflammatory pathways such as cytokines, phosphoinositide 3-kinase/protein kinase B, and nuclear factor kappa B in association with tumor promoting and tumor suppressing miRNAs on breast cancer progression. Providing new studies in the field of combining biomarkers for early diagnosis, prognosis, and monitoring breast cancer are very important. Notably, understanding the underlying mechanisms of miRNAs as a possible link between inflammation and tumorigenesis may offer a novel insight for combating this epidemic.     

LINC01133 inhibits breast cancer invasion and metastasis by negatively regulating SOX4 expression through EZH2

Mounting evidence highlights long non‐coding RNAs (lncRNAs) as crucial regulators in multiple types of biological processes and contributing to tumourigenesis. LINC01133, located in chromosome 1q23.2, was a recently identified novel lncRNA with a length of 1154nt. It was involved in the development of colorectal cancer and non‐small cell lung cancer. However, its clinical relevance, biological functions and potential molecular mechanism in breast cancer are still unclear. In this study, we found that the LINC01133 expression was significantly down‐regulated in breast cancer samples and was associated with progression and poor prognosis of breast cancer. Further experiments demonstrated that overexpression of LINC01133 inhibited invasion and metastasis in breast cancer both in vitro and in vivo. Mechanistic investigations revealed that LINC01133 repressed SOX4 expression by recruiting EZH2 to SOX4 promoter. Moreover, rescue experiments further confirmed that LINC01133 functional acted as an anti‐oncogene, at least partly, via repressing SOX4 in breast cancer. Taken together, these findings imply that LINC01133 could serve as a novel prognostic biomarker and potential therapeutic target for breast cancer.     

The role of matrix metalloproteinases (MMPs) and their inhibitors (TIMPs) in the development of esophageal cancer

Esophageal cancer (EC) is one of the most aggressive malignant tumors of the gastrointestinal tract. There are two distinct histological types of EC: esophageal squamous cell carcinoma and adenocarcinoma of the esophagus. Etiologic factors and the patterns of incidence of both subtypes are different. Matrix metalloproteinases (MMPs) and their tissue inhibitors (TIMPs) play an important role in esophageal carcinogenesis. Gellatinases MMP-2 and MMP-9 are able to degrade collagen IV from basement membranes and extracellular matrix which is related to tumor progression, including invasion, metastasis, growth and angiogenesis. It has been shown that increased expression of MMPs plays a crucial role in the development of several human malignancies, including esophageal cancer. The activity of MMPs is regulated by their endogenous natural inhibitors (TIMPs). Among these, the roles of TIMP-1 and TIMP-2 in EC development, tumor progression and formation of metastases have been most extensively characterized and best recognized.     

microRNAs in breast cancer: regulatory roles governing the hallmarks of cancer

A large number of etiological factors and the complexity of breast cancers present challenges for prevention and treatment. Recently, the emergence of microRNAs (miRNAs) as cancer biomarkers has added an extra dimension to the ‘molecular signatures’ of breast cancer. Bioinformatic analyses indicate that each miRNA can regulate hundreds of target genes and could serve functionally as ‘oncogenes’ or ‘tumour suppressor’ genes, and co‐ordinate multiple cellular processes relevant to cancer progression. A number of studies have shown that miRNAs play important roles in breast tumorigenesis, metastasis, proliferation and differentiation of breast cancer cells. This review provides a comprehensive overview of miRNAs with established functional relevance in breast cancer, their established target genes and resulting cellular phenotype. The role and application of circulating miRNAs in breast cancer is also discussed. Furthermore, we summarize the role of miRNAs in the hallmarks of breast cancer, as well as the possibility of using miRNAs as potential biomarkers for detection of breast cancer.     

MiRNA在乳腺癌转移中的作用

乳腺癌是女性高发的恶性肿瘤之一,远处转移是患者致死的最重要原因。目前乳腺癌转移的具体机制尚未明确。乳腺癌转移相关微RNA(microRNA,miRNA)的发现,为我们研究乳腺癌转移提供了新的思路。miRNA参与包括乳腺癌细胞的生长、凋亡、迁移、侵袭等肿瘤发生、发展过程,进而实现对乳腺癌转移的调控。有些miRNA在乳腺癌转移过程中起促进作用;有些则起抑制作用;还有一些miRNA的功能存在争议。本文将主要着眼于近年来发现的这几类miRNA在乳腺癌转移中所起的作用,并对其将来在乳腺癌诊断、预后判断及治疗中的应用做一综述。     

Exonuclease 1 expression is associated with clinical progression,metastasis, and survival prognosis of prostate cancer

Prostate cancer (PCa) is the most prevalent malignancy and the second leading cause of cancer-related deaths in the male population in western countries, and we explored the association between exonuclease 1 (EXO1) expression and clinical progression, metastasis (Met), and survival prognosis of PCa. EXO1 expression of high/low-metastatic patient-derived xenografts model was investigated and clinical correlation and prognosis outcomes were validated. EXO1 in high-metastatic models was significantly increased compared with low-metastatic lines. In memorial sloan-kettering cancer center (MSKCC) cohort, EXO1 expression positively correlated with PCa Met, and patients with high EXO1 had poor biochemical recurrence-free survival in primary PCa cohort. Validation in The Cancer Genome Atlas primary cohort indicated EXO1 expression was significantly associated with lymph node Met and disease-free survival. The overexpression of EXO1 is significantly associated with PCa poor survival outcome, and is a promising biomarker for PCa, especially for primary PCa. A prospective study is clearly needed to validate these findings.     

Functional role of matrix metalloproteinases (MMPs) in mammary epithelial cell development

The extracellular matrix (ECM) is an important regulator of mammary epithelial cell (MEC) function and is remodeled by matrix metalloproteinases (MMPs). To investigate the significance and regulation of MMP activity in normal MEC, we utilized a primary culture model in which rat MEC were grown three dimensionally within a reconstituted basement membrane (RBM) in defined serum-free medium. Zymograms of culture medium demonstrated that five major gelatinases of 97, 80, 74, 69, and 65 kDa were secreted by MEC and were distinct from gelatinases of RBM origin. Based on molecular weight, p-aminophenylmercuric acid activation, immunoblotting with MMP-specific antibodies, inhibition by EDTA, a peptide containing the prodomain sequence of MMP (TMRKPRCGNPDVAN) and two synthetic MMP inhibitors (BB-94 and CGS 27023A), these were classified as inactive and active forms of MMP-9 and MMP-2. The maximal MMP activities occurred when MEC were in a rapid proliferation and branching phase and declined after they underwent functional differentiation. Known regulators of MEC growth and differentiation were evaluated for their ability to modulate gelatinase activity in primary culture. Secretion of one or both MMPs was inhibited by EGF, TGFalpha, prolactin, and hydrocortisone and stimulated by progesterone. Furthermore, the functional significance of MMPs was demonstrated since three MMP inhibitors blocked branching morphogenesis elicited by the absence of hydrocortisone. Additionally, two synthetic MMP inhibitors not only inhibited epithelial cell growth but also inhibited normal alveolar development of the MEC. Finally, these drugs were found to enhance MMP secretion from MEC, although the activity of the secreted MMPs was inhibited as long as the drug was present.     

基质金属蛋白酶在乳腺癌上皮间质转化中的作用

基质金属蛋白酶(matrix metalloproteinase,MMP)能够分解并修饰细胞外基质及细胞连接,促进上皮细胞从周围组织中分离出来。在乳腺癌中MMP表达量升高,刺激肿瘤发生,引起癌症细胞的入侵和转移。上皮细胞-间质细胞转化(epithelial-mesenchymal transition,EMT)的激活与肿瘤的发生也有关。最近的研究表明MMP在乳腺的发育和致病的EMT过程中充当促进因子和介质的角色。本文主要概括最新的关于MMP是如何调节乳腺癌细胞的运动、入侵和EMT所驱动的乳腺癌发育的研究,为更好地理解MMP在乳腺癌发病过程中的作用提供依据。     

Matrix metalloproteinases and their expression in mammary gland

The matrix metalloproteinases (MMPs) are a family of zine-dependent endopeptidases that play a key role in both normal and pathological processes involving tissue remodeling events.The expression of these proteolytic enzymes is highly regulated by a balance between extracellular matrix (ECM) deposition and its degradation,and is controlled by growth factors,cytokines,hormones,as well as interactions with the ECM macromolecules.Furthermore,the activity of the MMPs is regulated by their natural endogenous inhibitors,which are members of the tissue inhibitor of metalloproteinases (TIMP) family.In the normal mammary gland,MMPs are expressed during ductal development,lobulo-alveolar development in pregnancy and involution after lactation.Under pathological conditions,such as tumorigenesis,the dysregulated expression of MMPs play a role in tumor initiation,progression and malignant conversion as well as facilitating invasion and metastasis of malignant cells through degradation of the ECM and basement membranes.     

Roles of matrix metalloproteinases in development,immunology, and ovulation in fruit Fly (Drosophila)

Matrix metalloproteinase (MMP), a protease enzyme, participates in proteolytic cleavage of extracellular matrix proteins from Drosophila and mammals. But, recent studies have revealed other physiologically important roles of MMP in Drosophila. MMP contributes to cardioblast movement and distribution of collagen proteins during cardiogenesis in developing Drosophila. Tissue remodeling, especially tracheal development is also maintained by MMP. MMP regulates certain immunological functions in Drosophila such as wound repairing, plasmatocyte assemblage at the injured site of the basement membrane and glial response to axon degeneration in Drosophila nervous system. But, the contribution of MMP to tumor formation and metastasis in Drosophila has made it an interesting topic among researchers. Ovulation and egg laying are also found to be affected positively by MMP in Drosophila.     

Production of matrix metalloproteinases in specific subpopulations of human-patient breast cancer invading in three dimensional culture system

This article aims at investigating the effect of production of matrix metalloproteinases (MMP) in human breast cancer tissues by means of three dimensional culture system. Thirty-nine tumour samples were taken from breast cancer patients. The tumour blocks were cultured on sponge gel using the three dimensional culture system. Breast cancer cells began shedding into the culture medium after 24 hours of culture. The cells were stained with trypan blue dye to assess viability on days 2, 4, 6 and 8. The culture medium was collected at these time points and tested for matrix metalloproteinases (MMP) 1,2,3 and 9 activities. There was a progressive increase in migration of cancer cells into the gel and culture medium from day 2 to day 8 and the interval difference was statistically significant (F ratio=4.06; p=0.008). The levels of all the MMPs tested were also significantly raised (P<0.05 for all the MMPs tested). When the levels of MMPs were correlated with the metabolic activities in the gel, medium and tumour block, cells in block show no correlation whereas cells in gel correlated significantly with MMP-1 and MMP-3. Cancer cells in the culture medium correlated with MMP-9. In conclusion, there is a progressive migration of cancer cells outside the tumour block. The migration into the gel and culture medium is associated with progressive and differential production of MMPs. It is likely that the three dimensional culture model assists in the selection of different subpopulations of cancer cells with different invasion properties as exemplified by the differential production of MMP.