Epithelial-Mesenchymal Transition and Metastasis under the Control of Transforming Growth Factor β

Abstract

Metastasis of tumor cells from primary sites of malignancy to neighboring stromal tissue or distant localities entails in several instances, but not in every case, the epithelial-mesenchymal transition (EMT). EMT weakens the strong adhesion forces between differentiated epithelial cells so that carcinoma cells can achieve solitary or collective motility, which makes the EMT an intuitive mechanism for the initiation of tumor metastasis. EMT initiates after primary oncogenic events lead to secondary secretion of cytokines. The interaction between tumor-secreted cytokines and oncogenic stimuli facilitates EMT progression. A classic case of this mechanism is the cooperation between oncogenic Ras and the transforming growth factor β (TGFβ). The power of TGFβ to mediate EMT during metastasis depends on versatile signaling crosstalk and on the regulation of successive waves of expression of many other cytokines and the progressive remodeling of the extracellular matrix that facilitates motility through basement membranes. Since metastasis involves many organs in the body, whereas EMT affects carcinoma cell differentiation locally, it has frequently been debated whether EMT truly contributes to metastasis. Despite controversies, studies of circulating tumor cells, studies of acquired chemoresistance by metastatic cells, and several (but not all) metastatic animal models, support a link between EMT and metastasis, with TGFβ, often being a common denominator in this link. This article aims at discussing mechanistic cases where TGFβ signaling and EMT facilitate tumor cell dissemination.

Biophysical properties of intermediate states of EMT outperform both epithelial and mesenchymal states

“…These similarities were also consistent with a recent study on TNBCs showing that the expression of ZEB1, and not the expression of advanced mesenchymal markers, was specifically correlated with poor clinical outcome (Jang et al, 2015). Interestingly, the stimulation with TGFβ induced a distinct phenotype, with a strong contractility and clear polarization toward the extracellular matrix, even though the TGFβ pathways proceed via the induction of ZEB1 (Tsubakihara and Moustakas, 2018). We interpreted the differences between the E/M-state and M-state in our experimental models as the consequence of the activation of the RhoA pathway, which is also downstream of TGFβ (Bhowmick et al, 2001;Kardassis et al, 2009;Tavares et al, 2006) (Figure 5 and Supplementary figure S3).…”

Comparative Molecular Analysis of Cancer Behavior Cultured In Vitro, In Vivo, and Ex Vivo

“…In addition, 4T1 monolayers expressed low levels of EMT associated transcription factors Snai1, Zeb1 and Twist1. In contrast, EMT markers Krt14, Trp63, and Grhl2, which have been recently shown to correspond to an early hybrid state [25], were significantly up-regulated solely in in vivo conditions. However, late hybrid Smad3 and mesenchymal marker Mmp19 were significantly up-regulated in both 3D and in vivo conditions suggesting that tumors in vivo reside in more diverse EMT hybrid states.…”

A potential prognostic marker and therapeutic target: SPOCK1 promotes the proliferation, metastasis, and apoptosis of pancreatic ductal adenocarcinoma cells

“…Recent studies have demonstrated that the EMT is a common molecular mechanism in PDAC 14 and a vital process in cancer progression and metastasis 15,16 through which cancer cells acquire invasive properties. Our results indicated that SPOCK1 has strong tumorigenic activity in vitro and in vivo and promotes PDAC cell migration and invasion.…”