Tissue Inhibitor of Matrix Metalloproteinase-1 Is Prognostic in Head and Neck Squamous Cell Carcinoma: Comparison of the Circulating and Tissue Immunoreactive Protein

Abstract

Purpose:Tissue inhibitors of metalloproteinases (TIMP) are capable of inhibiting the matrix metalloproteinases, but they also possess other biological functions. Little is known about the role of TIMP-1in the progression and spreading of cancer cells among patients with head and neck squamous cell carcinoma (HNSCC). In this study, the pretreatment serum levels of TIMP-1or the overexpression of TIMP-1 immunoreactive protein in the primary tumor was correlated to the clinical course in patients with HNSCC. Experimental Design:TheTIMP-1immunoreactive protein was studied in 74 cases representing HNSCC. The tissue immunoreactive protein was evaluated from paraffin-embedded tumor sections in 68 cases using immunohistologic staining with a specific antibody, and in 68 cases the pretreatment serum levels of TIMP-1 were quantitatively measured by ELISA assay. The results were compared with the clinicopathologic factors of the disease and the patients'outcome. Results: A positive correlation was found between the size of the primary tumor (T) and the circulating TIMP-1 level (P = 0.021) or the positive immunoreaction of TIMP-1 in tumor (P = 0.039). The 5-year cause-specific survival was significantly lower in patients presenting with a high serum TIMP-1 level than in those with a low level of TIMP-1 (38% versus 64%, P = 0.034). They also had an unfavorable 5-year relapse-free survival rate (37% versus 56%, respectively). Similarly, the expression of TIMP-1 in tumor was prognostic for shortened survival, the 5-year cumulative relapse-free survival being 42% in patients with a TIMP-1^positive tumor versus 75% in cases with a negative tumor (P = 0.035). TissueTIMP-1positivity also seemed associated to the cause-specific survival (P = 0.075) and to be connected with later lymph node or hematogenic relapses. Conclusions:This study shows for the first time that both circulating and tissueTIMP-1 immunoreactive protein predicts the clinical course and dissemination in HNSCC, suggesting that TIMP-1 might be related to both tumor growth and metastasis in HNSCC.

Plasma levels of MMPs and TIMP-1 in urinary bladder cancer patients

“…In patients with head and neck squamous cell cancer. the level of TIMP-1 in tissues and serum are associated with unfavorable prognosis (Ruokolainen et al, 2005). Our present study demonstrates that levels of TIMP-1 are significantly elevated in plasma (by 1.7-and 1.8-fold) in patients with stage IV and III UBC, respectively, compared to controls.…”

Expression of angiogenic growth factors in laryngeal carcinoma

“…A study by Li et al (28) that investigated the expression of FGF-BP in HNSCC in 35 primary (8 from the larynx, 11 from the oral cavity, 4 from the pharynx, 5 from the neck, 3 from the nasal cavity and 4 from the face) and 8 metastatic specimens, as well as 7 control tissues, identified an increased expression of FGF-BP in primary and metastatic tissue specimens compared to adjacent control tissue and concluded that an increased FGF-BP expression is associated with angiogenesis by measuring microvessel count. Ruokolainen et al (12) observed that pre-treatment serum levels of TIMP-1 (n=68) and TIMP-1 in the tumour tissue (n=74) were positively correlated with the size of the tumour. However, in accordance with the present findings, no positive correlation was observed between tissue TIMP-1 positivity or serum TIMP-1 levels and disease stage or tumour grade.…”

“…Chen et al (11) investigated the expression of angiogenic factors in tumour tissue, HNSCC cell lines and serum, and established that IL-8, VEGF and GM-CSF produced by HNSCC are consistent with the pathology of the neoplasm. In addition, Ruokolainen et al (12) reported circulating and tissue TIMP-1 to be associated with a shortened cause-specific and relapse-free survival of HNSCC patients. In accordance with the present study, a previous study suggested a role for angiogenin in HNSCC, demonstrating an increased expression measured by immunohistochemistry, in situ hybridization, or serum concentration in numerous malignancies, including breast, cervical, gastric, hepatic, renal, prostate, pancreatic, endometrial and colorectal cancer, leukemia, lymphoma, melanoma and osteosarcoma (13).…”

Lack of prognostic value of MMP-9 expression and immunohistochemically defined germinal center phenotype in patients with diffuse large B-cell lymphoma treated with modern chemotherapy with or without CD20 antibody

“…Tissue inhibitors of matrix metalloproteinases (TIMPs) are molecules, that are able to inhibit the activities of all MMPs, but they also have several other functions independent of the MMP inhibition, such as effects on angiogenesis, growth, and apoptosis [5]. MMP-2, MMP-9, TIMP-1, and TIMP-2 have been demonstrated to exhibit prognostic value in several solid cancers [6][7][8][9][10]. It has also been reported both by us and other authors, that high MMP-9 protein expression is an indicator for an adverse prognosis in patients with DLBCL treated mainly with CHOP-type chemotherapy [11,12].…”