Abstract
Proteases play a crucial role in the progression and metastasis of ovarian cancer. Pericellular protein degradation and fragmentation along with remodeling of the extracellular matrix (ECM) is accomplished by numerous proteases that are present in the ovarian tumor microenvironment. Several proteolytic processes have been linked to cancer progression, particularly those facilitated by the matrix metalloproteinase (MMP) family. These proteases have been linked to enhanced migratory ability, extracellular matrix breakdown, and development of support systems for tumors. Several studies have reported the direct involvement of MMPs with ovarian cancer, as well as their mechanisms of action in the tumor microenvironment. MMPs play a key role in upregulating transcription factors, as well as the breakdown of structural proteins like collagen. Proteolytic mechanisms have been shown to enhance the ability of ovarian cancer cells to migrate and adhere to secondary sites allowing for efficient metastasis. Furthermore, angiogenesis for tumor growth and development of metastatic implants is influenced by upregulation of certain proteases, including MMPs. While proteases are produced normally in vivo, they can be upregulated by cancer-associated mutations, tumor–microenvironment interaction, stress-induced catecholamine production, and age-related pathologies. This review outlines the important role of proteases throughout ovarian cancer progression and metastasis.
Highlights
Ovarian cancer (OvCa) is the deadliest gynecological cancer, with an overall five year survival rate of only 48.8% [1]
Serine, and metallo-proteases are the main subclasses of proteases which contribute to cancer progression and metastasis [5]
OvCa carcinomas have been shown to develop from two precursor cells: the ovarian surface epithelium (OSE) and the fallopian tube epithelium (FTE) [29]
Summary
Ovarian cancer (OvCa) is the deadliest gynecological cancer, with an overall five year survival rate of only 48.8% [1]. Spreading OvCa cells must penetrate the mesothelial cell layer and invade into the sub-mesothelial extracellular matrix (ECM) in order to establish metastatic lesions throughout the peritoneum [3,4] Both tumorigenesis and metastasis of OvCa are influenced by proteases, a class of enzymes responsible for the catabolism of proteins [5]. MT1-MMP, in conjunction with tissue inhibitor of metalloproteinase-2 (TIMP-2), activates pro-MMP-2 [16] Both MT1-MMP and MMP-2 are modulated by β1 integrin signaling, indicating that cell-matrix contact can influence matrix remodeling [18]. Other MMPs contribute in supplementary ways to enable effective matrix penetration and metastatic anchoring of OvCa cells [19] In addition to their impact on early events in dissemination, proteases play a role in late stages of the metastatic process as well. Both catecholamine release due to chronic stress and increased plasminogen synthesis due to aging have been shown to modulate angiogenesis and thereby support OvCa tumor growth [27,28]
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