Epithelial-mesenchymal transition: a hallmark in pancreatic cancer stem cell migration, metastasis formation, and drug resistance

Abstract

Metastasis, tumor progression, and chemoresistance are the major causes of death in patients with pancreatic ductal adenocarcinoma (PDAC). Tumor dissemination is associated with the activation of an epithelial-tomesenchymal transition (EMT) process, a program by which epithelial cells lose their cell polarity and cell-tocell adhesion, and acquire migratory and invasive abilities to become mesenchymal stem cells (MSC). These MSCs are multipotent stromal cells capable of differentiating into various cell types and trigger the phenotypic transition from an epithelial to a mesenchymal state. Therefore, EMT promotes migration and survival during cancer metastasis and confers stemness features to particular subsets of cells. Furthermore, a major problem limiting our ability to treat PDAC is the existence of rare populations of pancreatic cancer stem cells (PCSCs) or cancer-initiating cells in pancreatic tumors. PCSCs may represent sub-populations of tumor cells resistant to therapy which are most crucial for driving invasive tumor growth. These cells are capable of regenerating the cellular heterogeneity associated with the primary tumor when xenografted into mice. Therefore, the presence of PCSCs has prognostic relevance and influences the therapeutic response of tumors. PCSCs express markers of cancer stem cells (CSCs) including CD24, CD133, CD44, and epithelial specific antigen as well as the drug transporter ABCG2 grow as spheroids in a defined growth medium. A major difficulty in studying tumor cell dissemination and metastasis has been the identification of markers that distinguish metastatic cancer cells from cells that are normally circulating in the bloodstream or at sites where these cells metastasize. Evidence highlights a linkage between CSC and EMT. In this review, The current understanding of the PCSCs, signaling pathways regulating these cells, PDAC heterogeneity, EMT mechanism, and links between EMT and metastasis in PCSCs

Role of FGFR2c and Its PKCε Downstream Signaling in the Control of EMT and Autophagy in Pancreatic Ductal Adenocarcinoma Cells

“…Then, in the two selected PDAC cells expressing different levels of FGFR2c, we investigated the activation of the intracellular signaling in response to FGF2, the FGF family member, which does not bind the epithelial FGFR2b, but interacts with other FGFRs, including FGFR2c. Particular attention was paid to MEK/ERK and AKT/MTOR, which are the two main signaling pathways responsible not only for cell growth deregulation and survival, but also for EMT induction [ 4 , 5 ] and for the modulation of autophagy [ 2 ] in pancreatic cancer cells. Western blot analysis showed that an enhancement of the basal phosphorylation of ERK1/2 after FGF2 stimulation was higher in PANC-1 respect to Mia PaCa-2 cells ( Figure 1 B), while that of AKT was exclusively in PANC-1 cells ( Figure 1 C).…”

“…The pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal malignancies characterized by high frequency of activating mutations in KRAS gene [ 1 , 2 ]. In this context, PI3K-AKT-MTOR and Raf-MEK-ERK signaling have been described as the main RAS downstream pathways, strongly intersecting with each other, involved in the control of several oncogenic outcomes, including cell growth dysregulation, epithelial to mesenchymal transition (EMT) induction and autophagic enhancement [ 2 , 3 , 4 , 5 ]. Since KRAS is considered an “undruggable” signaling molecule, more and more relevance has been given to the identification of new signaling molecules, possibly bypassing RAS, whose inactivation could significantly impact on the PDAC aggressive phenotype.…”

The Role of Non-Canonical Hsp70s (Hsp110/Grp170) in Cancer

“…IL-6 and TNF- α play key roles in EMT, as previously demonstrated [ 92 , 94 , 95 ]. Upon EMT activation, tumor epithelial cells lose their cell polarity and adhesion properties to gain migratory and invasive properties, becoming mesenchymal cells [ 96 , 97 ]. Interestingly, the role of EMT in various cancers, including prostate, lung, liver, pancreatic and breast cancers, has been established [ 98 , 99 ].…”

Towards an updated view on the clinical management of pancreatic adenocarcinoma: Current and future perspectives (Review)

“…Other alterations at the level of cellular expression, such as epithelial-mesenchymal transition (EMT), generate changes in the interaction of the tumor with the surrounding cells, favoring its spread and hindering the action of the diverse chemotherapeutic lines ( 35 ). The EMT alters from cell metabolism to gene expression by producing different transforming factors like SNAIL, PRRX or Twist and different types of microRNA, which are implicated in modifications of various metabolic pathways like glycolysis, promoting the Warburg effect or the tricarboxylic acid cycle causing the tumor to act as a mesenchymal invasive and chemoresistance tissue, so that even though the different antineoplastic drugs are acting, the cell can continue to proliferate and invade adjacent tissues ( 36 , 37 ).…”