Role of the extracellular matrix: Enzyme activities and metastasis

Abstract

The local milieu of malignant tumor cells has key roles in cancer progression. A major component of the niche is the extracellular matrix (ECM), a complex interdigitating meshwork of macromolecules with multiple biophysical and biochemical characteristics. Although tightly controlled during normal tissue development and homeostasis, the ECM is mostly deregulated and becomes disorganized in cancer. Abnormal ECM has an impact on cancer progression by promoting tumor malignancy and metastatic dissemination. Importantly, the altered ECM in tumor is associated with deregulated ECM-regulating enzymes (matrix metalloproteinases, lysyl oxidase, urokinase plasminogen activator, and cysteine cathepsin). Excess expression of ECM-regulating enzymes alters behavior of cancer cells in the tumor niche, and its sustained upregulation results in the progressive breakdown of normal ECM which is replaced by tumor-derived ECM, thereby allowing tumor malignancy and cancer cell dissemination. Thus, ECM-regulating enzymes act as essential mediators of deregulating and disorganizing ECM. In this chapter, we will review and discuss how ECM-regulating enzymes generate disruption of ECM homeostasis and contribute to cancer progression, especially cancer metastasis.