New Insight of Matrix Metalloproteinases in Colorectal Cancer: The Good, Bad and Ugly

Abstract

MMPs are produced by a number of numerous cell types. Their main function is to degrade the various components of the extracellular matrix (ECM) of mammalian system. Recent studies showed the significance of MMPs as regulators of extracellular matrix signalling networks. Due to the broad spectrum of their substrate specificity, MMPs contribute to the homeostasis of many tissues and participate in several physiological processes, such as bone remodelling, angiogenesis, immunity and wound healing. MMP activity is tightly regulated at the transcriptional level as well as by the endogenous tissue inhibitors of metalloproteinases (TIMPs). Dysregulation of MMP activities leads to pathological situations such as arthritis, inflammation and cancer, thus emphasize MMPs as promising therapeutic targets. Colorectal cancer (CRC) is the third and second cancer for incidence and mortality worldwide, and is becoming prevalent in developing countries. The family of matrix metalloproteinases (MMPs) plays a critical role in the initiation and progression of CRC. MMPs have been detected in CRC patients, and the expression of most of them correlates with a poor prognosis. Moreover, many studies have explored the inhibition of MMPs and targeted therapy for CRC, but there is not enough information about the role of MMPs in the malignancy. In this review, the role of MMPs in colorectal cancer and its pathogenesis has been discussed. Many researchers have demonstrated that MMPs and TIMPs are especially important in the process of tumour invasion, progression and the metastasis of colorectal cancer (CRC). It has been proposed that MMPs and TIMPs might play a part not only in tumour invasion and initiation of metastasis but also in carcinogenesis from colorectal cancer. Overexpression of MMPs and TIMPs are associated with increased survival in colorectal cancer, presumably as a result of an inhibitory effect on angiogenesis. Based on the assumption that MMPs were responsible for metastasis, several orally active, low molecular weight inhibitors of MMPs (MMPIs) have been developed. These MMPIs have been effective in controlling cancer progression in animals, but have failed to prolong survival in clinical trials in patients with advanced cancer. MMPIs have not yet been evaluated in patients with colorectal cancer