Transforming growth factor‐β, matrix metalloproteinases, and urokinase‐type plasminogen activator interaction in the cancer epithelial to mesenchymal transition

Abstract

Transforming growth factor-β (TGF-β) is a pleiotropic factor that acts as a tumor suppressor in the early stages, while it exerts tumor promoting activities in advanced stages of cancer development. One of the hallmarks of cancer progression is the capacity of cancer cells to migrate and invade surrounding tissues with subsequent metastasis to different organs. Matrix metalloproteinases (MMPs) together with urokinase-type plasminogen activator (uPA) and its receptor (uPAR), whose main original function described is the proteolytic degradation of the extracellular matrix, play key cellular roles in the enhancement of cell malignancy during cancer progression. TGF-β tightly regulates the expression of several MMPs and uPA/uPAR in cancer cells, which in return can participate in TGF-β activation, thus contributing to tumor malignancy. TGF-β is one of the master factors in the induction of cancer-associated epithelial to mesenchymal transition (EMT), and recently both MMPs and uPA/uPAR have also been shown to be implicated in the cancer-associated EMT process. In this review, we analyze the main molecular mechanisms underlying MMPs and uPA/uPAR regulation by TGF-β, as well as their mutual implication in the development of EMT in cancer cells. Developmental Dynamics 247:382-395, 2018. © 2017 Wiley Periodicals, Inc.

Biphasic Role of Tgf-β Signaling during Müller Glia Reprogramming and Retinal Regeneration in Zebrafish

“…The members of the Mmp family, such as Mmp9, is involved in a variety of biological phenomena (Dziembowska and Wlodarczyk, 2012;van Kempen and Coussens, 2002), including retinal regeneration . Notably, MMP-2 and MMP-9 are known to activate extracellular matrix (ECM)-localized TGF-b1 from its latent to the active form (Santibanez et al, 2018;Yu and Stamenkovic, 2000). Tgf-b signaling, in turn, activates MMP-2 and MMP-9, creating a positive feedback loop (Kim et al, 2004).…”

A Circulating Bioreactor Reprograms Cancer Cells Toward a More Mesenchymal Niche

“…With the exception of ITGA5 , all 16 genes were upregulated in CF4. SERPINE1 is a member of uPA which plays a key role in cell–cell and cell–matrix interactions in tumor cell migration and invasion, making it a good candidate for our study. Similarly, SNAI1 and 2 are also associated with uPA system and induction of a mesenchymal and invasive phenotype .…”

Therapeutics targeting the fibrinolytic system

“…The known pro-cancer functions of plasmin are (1) to release cancer-related growth factors 53 , (2) to degrade pro-apoptotic factors 54 , and (3) to promote angiogenesis 55 either by itself or by activating pro-cancer MMPs 6 . UPAinduced fibrinolysis exhibits pro-cancer effects synergistically with transforming growth factor-β (TGF-β) and MMPs 56 . TGF-β regulates the expression of pro-MMPs and pro-uPA.…”