Alteration of MMP-2 and -14 expression by imatinib in HPV-positive and -negative squamous cell carcinoma

Abstract

Abstract. Head and neck squamous cell carcinoma (HNSCC)is an aggressive epithelial malignancy. It is known to be the most common neoplasm appearing in the upper aerodigestive tract. The poor 5-year survival rate has remained unchanged in the last decades even though improved techniques in surgery, radiation and chemotherapy have been established. In contrast to the overall decreasing incidence of head and neck cancer in the US, the incidence of HPV-associated oropharyngeal cancer is increasing, indicating the importance of viral etiology. Furthermore, growth and invasion of HNSCC are strongly influenced by the extracellular matrix (ECM). Matrix metalloproteinases (MMP) have been shown to play key roles in the remodeling of the ECM. Imatinib (STI 571) was originally designed to inhibit the BCR-ABL tyrosine kinase in chronic myeloid leukaemia. But it also has an inhibitory impact, e.g., on the protein-tyrosine-kinase (PTK) receptor c-kit and on its PTK activity in HNSCC. In this study, we incubated the HNSCC cell lines HNSCC 11A and 14C and the p16-positive SCC line CERV196 with increasing concentrations of imatinib or carboplatin. After an incubation time of up to 10 days, we evaluated MMP-2 and -14 expression by ELISA techniques and immunohistochemistry. MMP-2 and -14 expression was demonstrated in all incubated tumor cell lines. Especially incubation with imatinib resulted in a significant decrease in MMP expression in incubated cell lines. Our results indicate that the expression of MMP-2 and -14 is suppressed in the presence of imatinib. Thus, imatinib may exert in part its inhibitory effect on malignant cell growth via the blockage of the signal transduction of PTK receptors. Further studies are warranted, especially keeping in mind the moderate toxicity of imatinib.

Human Papillomavirus Modulates Matrix Metalloproteinases During Carcinogenesis: Clinical Significance and Role of Viral Oncoproteins

“…Kuasne et al (67) found that MMP-1 expression is a predictive marker for metastasis in lymph nodes in penile cancer via the PPARG, VEGF and EGFR pathways. In line with these findings, the receptor tyrosine kinase (RTK) inhibitor imatinib was able to reduce the expression of MMP2 and MMP14 in a cervical cancer cell line in vitro, suggesting MMP upregulation in this context may be, at least, partly, mediated by RTKs (68). On the other hand, a similar effect was observed on two HPV-negative cell lines representing head and neck squamous cell carcinomas in the same study, suggesting that such regulatory mechanisms are not specific for HPV-related cancers but may be present in SCCs at large.…”

Interaction of a CD44+ head and neck squamous cell carcinoma cell line with a stromal cell-derived factor-1-expressing supportive niche: An in vitro model

“…The localization of CSC candidates at the border of the tumor is feasible, as this is where invasion and tumor growth occurs. Invasiveness and metastasis of a tumor also depends on the capacity to cut and rebuild the extracellular matrix (25,26). Malignant cells infiltrate healthy tissue by degrading components of the extracellular matrix, breaking down vessel borders and therefore generating metastases in distant organs.…”

“…Malignant cells infiltrate healthy tissue by degrading components of the extracellular matrix, breaking down vessel borders and therefore generating metastases in distant organs. A number of tumor types have been shown to involve the presence of matrix metalloproteinases, including HNSCC (24,26,27). …”

Functional effects of SDF-1α on a CD44+ CXCR4+ squamous cell carcinoma cell line as a model for interactions in the cancer stem cell niche

“…In this study, we showed that polarization and formation of filopodia and a prominent uropod were increased in CD44 + CXCR4 + UM-SCC 11A cells in a dose-dependent manner by SDF-1α. This effect can probably be attributed to cytoskeleton rearrangements of actin-containing protrusions (51,52) and this also might be influenced by extracellular factors such as matrix metalloproteinases (52)(53)(54). In general, the formation of podia is said to be concomitant with cell adhesion to the microenvironment, especially the cellular microenvironment surrounding them (18).…”