Roles of Metalloproteases in Metastatic Niche

Abstract

Metalloproteinases (MMPs) are a cluster of at least 23 enzymes belonging to the more wide family of endopeptidases called Metzincins, whose structure is characterized by the presence of a zinc ion at the catalytic site. Although the general view of MMPs as physiologic scissors involved in extracellular matrix (ECM) degradation and tissue remodeling is still valid, additional functions have recently emerged, including the ability to cleave non ECM molecules such as growth factors, cytokines and chemokines from their membrane-anchored proforms. These functions are utilized by tumor cells and are fundamental in the determination of tumor progression and invasion. The effect of MMPs activity in cancer progression has been traditionally associated with the acquisition by tumor cells of an invasive phenotype, an indispensable requisite for the metastatic spreading of cancer cells. In addition to the traditional view, a new role for MMPs in creating a favourable microenvironment has been proposed, so that MMPs are not only involved in cell invasion, but also in signaling pathways that control cell growth, inflammation, or angiogenesis. Finally, recent evidence suggest a role of MMPs in the so called "pre-metastatic niche" that is the hypothesis of an early distant modification of the premetastatic site by primary cancer cells. This new hypothesis is changing our traditional view about MMPs and provides important insights into the effective time window for the therapeutic use of MMP inhibitors. In this review we provide the main available data about the ability of MMPs in creating a suitable microenvironment for tumor growth in metastatic sites and we indicate the implication of these data on the potential use of MMP inhibitors in the metastatic therapy.

The CXCR4/SDF1 Axis Improves Muscle Regeneration Through MMP-10 Activity

“…However, the concomitant up-regulation of these factors could also suggest a functional interaction between them. In fact, several pieces of data support this idea: (1) MMPs and cytokines participate in the same cellular processes (eg, migration) [58][59][60]; (2) MMPs can regulate chemokine activity through direct proteolysis of chemokines; (3) and MMPs contribute to chemokine release from ECM [61][62][63]. In addition, some chemokines can affect MMP function by directly or indirectly [64,65] altering MMP activity.…”

Additive effects of EGF and IL-1β regulate tumor cell migration and invasion in gastric adenocarcinoma via activation of ERK1/2

“…Therefore, ERK1/2 signaling plays an important role in both growth factor and inflammatory factor-associated migration, and invasion in GA. To investigate the mechanism by which EGF plus IL-1β promoted the migration and invasion of GA cells, we investigated the expression of MMP-9 in GA cells. The breakdown of extracellular matrix (ECM) is an initial, critical step during cancer cell metastasis (38), and the involvement of MMPs in ECM degradation has been widely documented (38,39). MMP-9 is closely associated with cancer invasion and metastasis (30,40), as it degrades collagen in the basement membrane, allowing cancer cells to pass through the ECM and spread to the surrounding tissues.…”

Matrix Metalloproteinases: New Targets in Cancer Therapy

“…MMP-1 and MMP-3 along with heparanase and plasmin are involved in dispensing the basic fibroblast growth factor [60,61]. Degrading extracellular matrix proteoglycan, decorin, are MMP-2, -3 and -7 and release the pro-TGF 1 [62,63]. Intriguingly, MMPs like MMP-3, MMP-7, MMP-9, and MMP-12 are able to form angiostatin by degrading plasminogen and generating fragments that oppose the division of endothelial cells (ultimately leading to the inhibition of angiogenesis) and probably participate in carrying out apoptosis and EC migration and division [17].…”