Metalloproteinases in Ovarian Cancer

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.

Keywords: extracellular matrix; matrix metalloproteinase; mesenchymal; mesothelial cells; ovarian cancer; peritoneum; proteases; proteolysis.

Figure 1

The role of TGF- β in EMT and metastasis. When TGF- β binds to its receptor, SMAD1/2/3 are released into the cytoplasm, where they bind to SMAD4. In the nucleus, the SMAD complex binds to transcription factors (TF) that upregulate the Snail family. Snail1/2 promote MMP production and downregulate E-cadherin. MMP-9 and MMP-3 degrade E-cadherin, reducing the amount of functional E-cadherin available to the cell. MMP-3 also promotes Snail family upregulation in a positive feedback loop. MT1-MMP and MMP-9 degrade the basement membrane, further promoting EMT and metastasis. Figure adapted from [33,51,52].

Figure 2

Effects of proteolysis on the VEGF pathway. Plasminogen, when cleaved by uPA into its active form plasmin, cleaves VEGF into different isoforms for multiple biological functions [97]. VEGF recruits neutrophils, which express MMP-9, which encourages VEGF production in a positive feedback loop [92,93]. MT1-MMP and MMP-2 also promote VEGF-mediated angiogenesis [83,87].

Figure 3

Relationship between stress, proteolysis, and VEGF-mediated angiogenesis. Stress induces expression of norepinephrine (NE), epinephrine (EP), and isoproterenol (Iso) [98]. NE activates β-adrenergic receptors, which activates the cyclic AMP (cAMP)- protein kinase A signaling pathway [27]. This pathway leads to an upregulation of VEGF as well as MMPs, such as MMP-2 and MMP-9 [27]. Other proteases such as MT1-MMP and uPA are upregulated by NE as well, also leading to pro-tumor effects which can be mitigated by CMT-3 [28,99]. EP and Iso have been shown to upregulate VEGF expression as well [98].

Figure 4

(a) Epithelial-to-mesenchymal transition (EMT), mediated by MMP-3, MMP-9, and MT1-MMP, promotes tumor cell detachment from the primary tumor, resulting in diffusion of cancer cells into the peritoneal cavity [44,52], where they (b) adhere to the mesothelial monolayer via binding of CA125 on the cancer cell by mesothelin on the mesothelial cell [57]. MMP-9 and MMP-2 are secreted by the cancer cell to cleave fibronectin produced by the mesothelial cell [24]. CA125 is cleaved by MT1-MMP to allow for integrin-mediated adhesion to the fibronectin fragments on the mesothelial cell and to induce mesothelial cell retraction [57]. (c) The basement membrane is degraded by MMPs and plasmin and the sub-mesothelial collagen matrix is remodeled by MT1-MMP [72,74]. (d) VEGF-mediated angiogenesis is promoted by MT1-MMP, MMP-9, and MMP-2 [83,85,86].