Elsevier

Biochimie

Volume 87, Issues 3–4, March–April 2005, Pages 287-297
Biochimie

Gelatinases (MMP-2 and -9) and their natural inhibitors as prognostic indicators in solid cancers

https://doi.org/10.1016/j.biochi.2005.01.014Get rights and content

Abstract

Neoplastic growth and dissemination involve increased proteolytic activity that is able to escape the regulative elements. Matrix metalloproteinases (MMPs), particularly gelatinases A and B (MMP-2 and -9), play a role in tumor invasion and angiogenesis, and they participate in cancer progression in several neoplasias. The expression of tissue inhibitors of gelatinases, TIMPs-1 and -2, has also been shown to be associated with the clinical course in some cancers. The prognostic value of these markers, however, seems to vary a great deal in different neoplastic diseases. In this review, the impact of the gelatinases and their inhibitors on the clinical course in several solid cancers is evaluated based on the growing data from recent clinical studies. The clinical data most often explore the overexpression of mRNA or immunoreactive protein in tumor tissue, or measure the concentration of the circulating proteinase or its inhibitor in pretreatment or follow-up serum samples. The growing amount of recent clinical data suggests that the impact of gelatinases on treatment decisions should be tested in clinical trials.

Section snippets

Gelatinases and their inhibitors in breast carcinoma

Breast cancer is the most common female malignant tumor in the western world. The overall prognosis of breast cancer patients has improved during the last decade. Despite the fact that this neoplasia is potentially fatal, several patients still have a more indolent clinical course of the disease, and these patients often have favorable survival. Many biological factors associated with progression or aggressive behavior of cancer have been identified to help distinguish the aggressive disease,

MMP-2 and -9 in gynecological neoplasias

Preclinical studies have linked the activity of the matrix metalloproteinases with aggressive behavior in ovarian carcinoma [8], [9], [47]. Metalloproteinases and their mRNA have been localized both to tumor cells and to stromal fibroblasts in ovarian carcinoma [48]. It is possible that ovarian cancer cells are dependent on stromal interactions in their MMP expression [8], [9]. Cultured ovarian cancer cells are able to maintain MMP-2 expression after primary cultures when MMP-9 expression

Gelatinases and their inhibitors in prostatic neoplasia

In preclinical studies, MMP-9 has been linked to the ability of cultured prostate carcinoma cells to produce lung metastases in animal models [64]. It is probable that both MMP-2 and -9 play a role in prostate cancer cell invasion [65] as well as in prostate cancer-induced angiogenesis [66]. The gelatinases associate with the progression of prostatic neoplasia in several clinical studies [67], [68], [69], [70]. The MT1-MMP and MMP-2 immunolocalization have been shown to change during the

Metalloproteinases and their inhibitors in bladder and renal carcinomas

Many preclinical studies have explored the role of the metalloproteinases in cancer invasion by using bladder transitional cell carcinoma cells as a model. Recent clinical studies have confirmed the preclinical findings suggesting that gelatinases seem at least to be linked with the progression of transitional cell carcinoma of the bladder. Inverse association with TIMP-2 and survival has been shown in bladder cancer by Grignon et al. (1996) [74]. The expression of MMP-2, MT1 MMP as well as

Markers of matrix degradation in lung carcinoma

Lung carcinoma is a common and very aggressive neoplasm including histologically different entities with unfavorable prognosis. The number of studies suggesting that MMPs may be involved in lung cancer progression is increasing. Bronchopulmonary carcinomas overexpress the mRNA for MMP-2, MT1-MMP and MMP-11, especially when presenting with a malignant phenotype and high tumor stage [81]. The MMP-2 and -9 have been associated with increased tumor spread and poor prognosis in lung cancer [82], [83]

Gelatinases in head and neck carcinomas

Head and neck cancers consist of a heterogeneous group of neoplasias, 90% of which are squamous cell carcinomas (HNSCC). Clinical stage at the time of diagnosis and anatomic region are naturally the most important predictors of survival, but the clinical behavior of these tumors varies and might be attributed to the biological factors involved in growth and invasion. Elevated levels of the immunoreactive protein for MMP-2 and -9 have been detected in nearly 40% of HNSCC tumors [89]. MMP-9, but

MMPs and their inhibitors in gastrointestinal cancers

Both MMP-2 and -9 have been shown to correlate with malignant behavior in various gastrointestinal tumors. In colorectal carcinoma, positive correlation has been reported between high expression of MMP-2 or TIMP-2 and advanced stage [92], [93] as well as between MMP-9 mRNA and early relapse or poor survival [94]. The TIMP-1 also seems to associate with aggressive phenotype in colorectal carcinoma, circulating TIMP being high in patients presenting with lymph node or liver metastases of

MMP-2 and -9 in melanoma

Different murine and human melanoma cell lines and tumors have been widely used as preclinical models in studying invasion and metastasis in general. These studies address the role of different MMPs in melanoma progression. Cultured melanoma cells have been shown to produce at least MMP-1, -2, -3 and -9, and the MMP-activity has been correlated with melanoma invasion [102], [103], [104], [105], [106]. The expression of MMP-2 and -9 as well as the invasion and attachment is modified in cultured

Gelatinases in brain neoplasias

The treatment of the most aggressive forms of brain tumors still poses a challenge. In spite of the development of new drugs, the prognosis of aggressive gliomas is still poor. New options for treatment would thus be welcome. It is typical that brain neoplasms vary in their ability to invade surrounding tissues and recur after radical treatment. The most malignant brain tumors (glioblastoma multiforme) are fairly resistant to therapy and cause death in due course, while low malignancy tumors

Summary

Clinical data in several solid cancers show that gelatinases generally associate with aggressive clinical course of the disease. However, the impact of this association seems to vary in different solid cancer diseases. Given the fact that there is a great deal of variation in both the biological features and the clinical course between the distinct neoplastic diseases, it is surprising that particularly MMP-2 seems to associate with an aggressive clinical course in a large variety of solid

References (128)

  • A. Talvensaari-Mattila et al.

    Preoperative serum MMP-9 level is prognostic in breast carcicnoma

    Cancer Lett.

    (2005)
  • L. Nakopoulou et al.

    Correlation of tissue inhibitor of metalloproteainse-2 with proliferative activity and patients' survival in breast cancer

    Mod. Pathol.

    (2002)
  • T.N. Young et al.

    A plasma membrane-associated component of ovarian adenocarcinoma cells enhances the catalytic efficiency of matrix metalloproteinase-2

    J. Biol. Chem.

    (1995)
  • M. Takemura et al.

    Type IV collagenase and tissue inhibtor of metalloproteinase in ovarian cancer tissue

    Int. J. Gyn. Obstet.

    (1994)
  • A. Westerlund et al.

    Gelatinase A immunoreactive protein in ovarian lesions—prognostic value in epithelial ovarian cancer

    Gynecol. Oncol.

    (1999)
  • A. Talvensaari-Mattila et al.

    Matrix metalloproteinase 2 immunocreative protein appears early in cervical epithelial dedifferentiation

    Gynecol. Oncol.

    (1999)
  • B. Davidson et al.

    MMP-2 and TIMP-2 expression correlates with poor prognosis in cervical carcinoma—a clinicopathologic study using immunohistochemistry and mRNA in situ hybridization

    Gynecol. Oncol.

    (1999)
  • B. Davidson et al.

    Expression of matrix metalloproteinase-9 in squamous cell carcinoma of the uterine cervix—clinicopathologic study using immunohistochemistry and mRNA in situ hybridization

    Gynecol. Oncol.

    (1999)
  • J.S. Ross et al.

    Prognostic significance of matrix metalloproteinase 2 and tissue inhibitor of metalloproteinase 2 expression in prostate cancer

    Mod. Pathol.

    (2003)
  • K. Vasala et al.

    Matrix metalloproteainse-2 immunocreactive protein as a prognostic marker in bladder cancer

    Urology

    (2003)
  • M.M. Walther et al.

    Progelatinase A mRNA expression in cell lines derived from tumors in patients with metastatic renal cell carcinoma correlates inversely with survival

    Urology

    (1997)
  • S. Ylisirniö et al.

    Serum type I collagen degradation markers, ICTP and crosslaps, are factors for poor survival in lung cancer

    Anticancer. Res.

    (1999)
  • S. Curran et al.

    Matrix metalloproteinases in tumour invasion and metastasis

    J. Pathol.

    (1999)
  • A.F. Chambers et al.

    Changing views of the role of matrix metalloproteinases in metastasis

    J. Natl. Canc. Inst.

    (1997)
  • N. Fujimoto et al.

    Interaction between tissue inhibitor of metalloproteinases-2 and progelatinase A: immunoreactivity analysis

    Biochem. J.

    (1996)
  • V.-M. Kähäri et al.

    Matrix metalloproteinases and their inhibitors in tumour growth and invasion

    Ann. Med.

    (1999)
  • D.E. Gomez et al.

    Tissue inhibitors of metalloproteinases: structure, regulation and biological functions

    Eur. J. Cell Biol.

    (1997)
  • E. Miyagi et al.

    Marked induction of gelatinases, especially type B, in host fibroblasts by human ovarian cancer cells in anthymic mice

    Clin. Exp. Metastasis

    (1995)
  • T. Itoh et al.

    Reduced angiogenesis and tumour progression in gelatinase A-deficient mice

    Cancer Res.

    (1998)
  • B. Hibner et al.

    BAY 12-9566, a noverl, biphenyl matrix metalloproteinase inhibitor, demonstrates anti-invasive and anti-angiogenic properties

    Proc. Am. Assoc. Cancer Res.

    (1998)
  • T. Kurizaki et al.

    Relationship between matrix metalloproteinase expression and tumor angiogenesis in human breast carcinoma

    Oncol. Rep.

    (1998)
  • G.P. Amorino et al.

    Interactions of monocytic cells with human endothelial cells stimulate monocytic metalloproteinase production

    Am. J. Pathol.

    (1998)
  • A. Talvensaari-Mattila et al.

    MMP-2 immunocreative protein, a marker of aggressiveness in breast carcinoma

    Cancer

    (1998)
  • A. Scorilas et al.

    Overexpression of matrix-metalloproteinase-9 in human breast cancer: a potential favourable indicator in node-negative patients

    Br. J. Cancer

    (2001)
  • A.N. Mirza et al.

    Prognostic factors in node-negative breast cancer: a review of studies with sample size more than 200 and follow-up more than 5 years

    Ann. Surg.

    (2002)
  • M.G. Daidone et al.

    Laminin receptors, collagenase IV and prognosis in node negative breast cancers

    Int. J. Cancer

    (1991)
  • A. Talvensaari-Mattila et al.

    MMP-2 positivity and age less than 40 years increase the risk for recurrence in premenopausal patients with node-positive breast carcinoma

    Breast Cancer Res. Treatm.

    (1999)
  • A. Talvensaari-Mattila et al.

    Matrix metalloproteinase-2 (MMP-2) is associated with the risk for a relapse in postmenopausal patients with node-positive breast cardinoma treated with antiestrogen adjuvant therapy

    Breast Cancer Res. Treatm.

    (2001)
  • R. Hirvonen et al.

    Matrix metalloproteinase-2 (MMP-2) in T1-2N0 breast carcinoma

    Breast Cancer Res. Treat.

    (2003)
  • A. Talvensaari-Mattila et al.

    Matrix metalloproteinase-2 (MMP-2) is associated with survival in breast carcinoma

    Br. J. Cancer

    (2003)
  • A. Sivula et al.

    Association of cyclooxygenase-2 and matrix metalloproteinase-2 expression in human breast cancer

    Breast Cancer Res. Treat.

    (2005)
  • S. Leppä et al.

    A high serum matrix metalloproteinase-2 level is associated with an adverse prognosis in node-positive breast carcinoma

    Clin. Cancer Res.

    (2004)
  • A.G. Remacle et al.

    Assay of matrix metalloproteinase types 1, 2, 3 and 9 in breast cancer

    Br. J. Cancer

    (1998)
  • S.M. Ranuncolo et al.

    Plasma MMP-9 (92 kDa-MMP) activity is useful in the follow-up and in the assessement of prognosis in breast cancer patients

    Int. J. Cancer

    (2003)
  • G. Gianell et al.

    Gelatinase levels in male and female breast cancer

    Biochem. Biophys. Res. Commun.

    (2002)
  • L.M. Coussens et al.

    Inflammation and cancer

    Nature

    (2002)
  • L. Van't Veer et al.

    Gene expression profiling predicts clinical outcome of breast cancer

    Nature

    (2002)
  • A. Hansen Ree et al.

    High levels of messenger RNAs for tissue inhibitors of metalloproteinases (TIMP-1 and TIMP-2) in primary breast carcinomas are associated with development of distant metastasis

    Clin. Cancer Res.

    (1997)
  • L. Nakopoulou et al.

    Enhanced mRNA expression of tissue inhibitor of metalloproteinase-1 (TIMP-1) in breast carcinomas is correlated with adverse prognosis

    J. Pathol.

    (2002)
  • K. McCarthy et al.

    High levels of tissue inhibitor of metalloproteinase-1 predict poor outcome in patients with breast carcinoma

    Int. J. Cancer

    (1999)
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