Expression and clinical significance of matrix metalloproteinase-2 and matrix metalloproteinase-9 in oral squamous cell carcinoma
Introduction
Oral squamous cell carcinoma (OSCC), the sixth most common cancer, is characterized by a high degree of local invasiveness and a high rate of metastasis to cervical lymph nodes, but a low rate of metastasis to distant organs. Death as a result of cancer is often the result of local recurrence or regional and/or systemic metastasis. Thus, metastasis are a major problem in successful cancer treatment, and it is believed that they begin early in the growth of the primary tumor.1
The process of metastasis consists of series of tumor–host interactions that involve multiple extracellular matrix degrading enzymes, including serine proteinases, cysteine proteinases, and matrix metalloproteinases (MMPs).2 MMPs play an important role in the malignant behavior of the neoplasm. They are a family of Zn2+-dependent proteinases that can degrade all components of extracellular matrix (ECM).3 This family of endopeptidases is associated with ECM degradation in physiological and pathological conditions such as embryonic development, wound healing, angiogenesis, arthritis, inflammation, and tumor metastasis.4 They are classified into four groups according to their substrate specificity: collagenases (MMP-1, -8, and -13), gelatinases (MMP-2 and -9), stromelysins (MMP-3, -10, and -11), and membrane-type MMPs (MT-MMPs) (MMPs 14–17, 24, and 25). Alignment of the amino acid sequences between these enzymes shows that there is a high degree of homology between the enzymes in each group (about 80%) and between groups (about 50%).5 MMPs are produced by cancer cells or through the induction of surrounding stromal cells. This suggests that tumor cells are capable of utilizing MMPs produced by stromal cells and indicates an active role for stroma in tumor invasion.5
To successfully establish a metastasis, the first step is active migration of cancer cells from their tissue of origin and involves the degradation of the underlying basement membrane, which is made up of matrix macromolecules such as type IV collagen, laminin, and heparan sulfate proteoglicans. Thus, this membrane constitutes the first barrier to tumor invasion and because one of its major constituents is type IV collagen, the gelatinases (MMP-2 and MMP-9) are thought to play an important role in its degradation because of their ability to cleave this type of collagen. Most of the MMPs except MT-MMPs and MMP-11 (stromelysin 3) are secreted as inactive zymogens and are activated extracellularly or pericellularly by serine proteinases, such as trypsin, plasmin, and neutrophil elastase6 that cleave their amino-terminal domains. Similarly to other MMPs, MMP-2 is secreted in an inactive zymogen form (pro-MMP2), but its conversion to an active form (active-MMP2) is due to membrane type 1-metalloproteinase (MT1-MMP or MMP-14).7 In fact, pro-MMP-2 binds to TIMP-2 in combination with MT1-MMP on the cell surface, forming a ternary complex. Then, pro-MMP-2 in the complex is activated by adjacent MT1-MMP that is free from TIMP-2.8 Together with the degradation of the basement membrane, cancer expansion requires the induction of angiogenesis in the malignant tissue to provide nourishment for proliferating cancer cells.1 Schnapper et al.9 have demonstrated the importance of type IV collagenases in new blood vessel formation.
Neck lymph node metastasis are found in approximately 50% of patients with OSCC treated by neck dissection,10 and is considered to be the most important clinical prognostic factor in these patients. Although treatment guidelines are based on tumor site, node and distant metastasis (TNM system), they do not always predict clinical outcome accurately, because patients of the same TNM groups have different survival rates. As a consequence, from a prognostic point of view, it is of paramount importance for the clinician to know the invasiveness of the cancer and the likelihood of metastasis. The expressions of MMP family members in OSCC have been reported. Specifically, previous studies have shown that MMP-2 (72-kDa type IV collagenase or gelatinase A)11, 12, 13 and MMP-9 (92-kDa type IV collagenase or gelatinase B)13 are expressed in OSCC. However, the correlation of their expressions with clinical and histopathological features is still controversial.
Studies that elucidate the mechanism of metastasis of cancers may result in the development of treatments which will decrease, or even inhibit this process, improving the survival rate of patients. The purpose of this study was to investigate the expression of MMP-2 and MMP-9 in a series of 68 OSCC, and to evaluate the implications of their expression on clinicopathologic factors, principally on prognosis, using immunohistochemistry.
Section snippets
Patients
This study is based on a retrospective cohort of 68 patients suffering from a primary OSCC who were diagnosed at the Department of Oral and Maxillofacial Surgery, Asturias University Hospital, Oviedo, Spain, between January of 1990 and December of 1992. Inclusion criteria were surgical treatment performed according to standard procedures and consisting of the resection of the primary tumor and a radical or selective ipsi- or bilateral neck dissection, complete clinicopathologic data and
Immunohistologic expression of MMP-2 in primary OSCC and regional lymph node metastasis
Immunoreactivity for MMP-2 was detected in 19 of 68 cases (28%) and primarily in cancer nests of the advancing front of neoplastic tissue (Fig. 1). Of these 19 cases, 3 cases (4.4%) strongly expressed MMP-2; 5 (7.4%) showed immunostaining between 10% and 50% of cancer cells, and finally, 11 (16.2%) expressed less than 10% of positive cell staining. The remaining 49 cases (72%) were negative for MMP-2. Of the 23 cases with lymph node metastasis, 8 cases (34.8%) expressed MMP-2, with 2 (8.7%)
Discussion
Matrix metalloproteinases (MMPs) are a family of proteases commonly expressed in invasive tumors and adjacent stroma, and it is thought that they play an important role in tumor invasion and metastasis. Initially, a carcinoma develops within the epithelium, confined by the basement membrane. This structure has several components (laminin, type IV collagen, and heparan-sulphate proteoglycan) and its degradation is an essential step for progression from carcinoma in situ to invasive carcinoma.
Acknowledgments
The auhors thank Ms. Aurora Fernández García for technical assistance. We are grateful to Dr. Jonas Hannestad (Department of Psychiatry, Duke University) for help in reviewing the manuscript for English syntax. This work was supported by a grant for scientific research from the Ministry of Health, Spain (Instituto de Salud Carlosiii, PI020137).
References (35)
- et al.
Matrix metalloproteinases and oral cancer
Oral Oncol.
(1999) - et al.
Expression of matrix metalloproteinase-2 and -9 in oral squamous cell carcinomas with regard to the metastatic potential
Oral. Oncology
(2000) - et al.
Activation of matrix metalloproteinase-2 in head and neck squamous cell carcinoma: studies of clinical samples and in vitro cell lines co-cultured with fibroblasts
Cancer Lett.
(2000) - et al.
Clinical significance of expression of membrane type 1 matrix metalloproteinase and matrix metalloproteinase-2 in human head and neck squamous cell carcinoma
Hum. Pathol.
(2000) - et al.
Type I collagen degradation by invasive oral squamous cell carcinoma
Oral. Oncol.
(2000) - et al.
Matrix metalloproteinase 2 and matrix metalloproteinase 9 expression in human oral squamous cell carcinoma and the effect of protein kinase C inhibitors: preliminary observations
Oral. Surg. Oral. Med. Oral. Pathol. Oral. Radiol. Endod.
(2003) - et al.
Survival and patterns of recurrence in 200 oral cancer patients treated by radical surgery and neck dissection
Oral. Oncol.
(1999) - et al.
Molecular aspects of tumor cell invasion and metastasis
Cancer
(1993) - et al.
Biology and biochemistry of proteinases in tumor invasion
Physiol. Rev.
(1993) - et al.
Tumor cell interactions with the extracellular matrix during invasion and metastasis
Annu. Rev. Cell. Biol.
(1993)
The matrix degrading metalloproteinases
Bioessays
Activation mechanisms of matrix metalloproteinases
Biol. Chem.
A matrix metalloproteinase expressed on the surface of invasive tumor cells
Nature
Expressions of matrix metalloproteinases in early-stage oral squamous cell carcinoma as predictive indicators for tumor metastasis and prognosis
Clin. Cancer Res.
Type IV collagenases and TIMPs modulate endothelial cell morphogenesis in vitro
J. Cell. Physiol.
The inhibitory effect of matrix metalloproteinase inhibitor ONO-4817 on lymph node metastasis in tongue carcinoma
Anticancer Res.
Expression of matrix metalloproteinase-2 related to lymph node metastasis of oral squamous cell carcinoma. A clinicopathologic study
Am. J. Clin. Pathol.
Cited by (125)
Molecular biological findings of ameloblastoma
2021, Japanese Dental Science ReviewArtificial Intelligence in Cancer: Diagnostic to Tailored Treatment
2020, Artificial Intelligence in Cancer: Diagnostic to Tailored TreatmentHemidesmosomal linker proteins regulate cell motility, invasion and tumorigenicity in oral squamous cell carcinoma derived cells
2017, Experimental Cell ResearchImmunolocalization of epithelial cell adhesion molecule and matrix metalloproteinase.9 in oral epithelial dysplasia and oral squamous cell carcinoma
2023, Journal of Cancer Research and Therapeutics