Epithelial to Mesenchymal Transition: Key Regulator of Pancreatic Ductal Adenocarcinoma Progression and Chemoresistance

Palamaris, Kostas; Felekouras, Evangelos; Sakellariou, Stratigoula

doi:10.3390/cancers13215532

Cited by 40 publications

(45 citation statements)

References 200 publications

(227 reference statements)

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“…Studies have shown that ER stress plays a crucial role in activation of hepatic stellate cells [ 114 , 115 ] and that blocking the IRE1α–XBP1 pathway can significantly reduce liver fibrosis and tumor burden in several animal models for cirrhosis [ 47 ] and HCC [ 22 ]. Jia et al sought to provide a deeper investigation regarding the involvement of CAFs in epithelial–mesenchymal transition (EMT) in HCC [ 116 ], a process that is known to contribute to drug resistance in HCC and many other solid tumors [ 117 , 118 ]. Proteomic analyses identified that transglutaminase 2 (TG2) is substantially overexpressed in HCC cells that have obtained an EMT phenotype.…”

Section: Role Of the Tumor Microenvironmentmentioning

confidence: 99%

Drug Resistance and Endoplasmic Reticulum Stress in Hepatocellular Carcinoma

Khaled

Kopsida

Lennernäs

et al. 2022

Cells

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Hepatocellular carcinoma (HCC) is one of the most common and deadly cancers worldwide. It is usually diagnosed in an advanced stage and is characterized by a high intrinsic drug resistance, leading to limited chemotherapeutic efficacy and relapse after treatment. There is therefore a vast need for understanding underlying mechanisms that contribute to drug resistance and for developing therapeutic strategies that would overcome this. The rapid proliferation of tumor cells, in combination with a highly inflammatory microenvironment, causes a chronic increase of protein synthesis in different hepatic cell populations. This leads to an intensified demand of protein folding, which inevitably causes an accumulation of misfolded or unfolded proteins in the lumen of the endoplasmic reticulum (ER). This process is called ER stress and triggers the unfolded protein response (UPR) in order to restore protein synthesis or—in the case of severe or prolonged ER stress—to induce cell death. Interestingly, the three different arms of the ER stress signaling pathways have been shown to drive chemoresistance in several tumors and could therefore form a promising therapeutic target. This review provides an overview of how ER stress and activation of the UPR contributes to drug resistance in HCC.

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Section: Role Of the Tumor Microenvironmentmentioning

confidence: 99%

Drug Resistance and Endoplasmic Reticulum Stress in Hepatocellular Carcinoma

Khaled

Kopsida

Lennernäs

et al. 2022

Cells

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“…There have been some reports that several genes related to EMT in PDAC, including forkhead box protein M1 ( FOXM1 ), matrix metalloproteinase-1 ( MMP1 ), and vascular endothelial growth factor C ( VEGFC ), are targets for the treatment of PDAC. For example, the acquisition of EMT in PDAC is strongly associated with the expression of FOXM1 , which functions as a regulator of Snail and stimulates EMT [ 38 ]. A recent study reported that MMP1 promotes the metastasis of PC and that the inhibitory regulation of MMP1 with endogenous microRNA can attenuate the metastatic ability of pancreatic cancer [ 39 ].…”

Section: Discussionmentioning

confidence: 99%

Matairesinol Induces Mitochondrial Dysfunction and Exerts Synergistic Anticancer Effects with 5-Fluorouracil in Pancreatic Cancer Cells

2022

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Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive types of cancer and exhibits a devastating 5-year survival rate. The most recent procedure for the treatment of PDAC is a combination of several conventional chemotherapeutic agents, termed FOLFIRINOX, that includes irinotecan, leucovorin, oxaliplatin, and 5-fluorouracil (5-FU). However, ongoing treatment using these agents is challenging due to their severe side effects and limitations on the range of patients available for PDAC. Therefore, safer and more innovative anticancer agents must be developed. The anticarcinoma activity of matairesinol that can be extracted from seagrass has been reported in various types of cancer, including prostate, breast, cervical, and pancreatic cancer. However, the molecular mechanism of effective anticancer activity of matairesinol against pancreatic cancer remains unclear. In the present study, we confirmed the inhibition of cell proliferation and progression induced by matairesinol in representative human pancreatic cancer cell lines (MIA PaCa-2 and PANC-1). Additionally, matairesinol triggers apoptosis and causes mitochondrial impairment as evidenced by the depolarization of the mitochondrial membrane, disruption of calcium, and suppression of cell migration and related intracellular signaling pathways. Finally, matairesinol exerts a synergistic effect with 5-FU, a standard anticancer agent for PDAC. These results demonstrate the therapeutic potential of matairesinol in the treatment of PDAC.

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“…Therefore, the close contact with DS suggests that in PDAC, these cells could be more easily released into the circulation in groups or individually. 36 , 63 , 64 This is the first study to jointly assess the expression of two epithelial markers (pan-cytokeratin and EPCAM) and one mesenchymal marker (vimentin) by immunohistochemistry in PDAC and to report the association between high expression of vimentin with advanced clinical stage (III and IV). This dual interaction could explain why these types of tumors are more aggressive at advanced stages.…”

Section: Discussionmentioning

confidence: 99%

“…EMT is a reversible transdifferentiation process controlled by complex interactions between multiple signaling pathways such as TGFb, Wnt, and Notch, which converge to a network of specific transcription factors that convert cancer cells of epithelial differentiation into a more mesenchymal phenotypic state. 36 The expression of mesenchymal markers favors the development of an invasive phenotype in which the tumor cell increases its migration, 20 as shown in both in vitro 21 , 37 and in vivo 20 , 31 models. In fact, it has been shown that Tβ 4 a peptide that regulate actin polymerization is predominantly expressed at the invasion front in colorectal tumor cells undergoing EMT, which suggest a role for Tβ 4 in invasion and metastasis.…”

Section: Introductionmentioning

confidence: 99%

High expression of both desmoplastic stroma and epithelial to mesenchymal transition markers associate with shorter survival in pancreatic ductal adenocarcinoma

et al. 2022

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Desmoplastic stroma (DS) and the epithelial-to-mesenchymal transition (EMT) play a key role in pancreatic ductal adenocarcinoma (PDAC) progression. To date, however, the combined expression of DS and EMT markers, and their association with variations in survival within each clinical stage and degree of tumor differentiation is unknown. The purpose of this study was to investigate the association between expression of DS and EMT markers and survival variability in patients diagnosed with PDAC. We examined the expression levels of DS markers alpha smooth muscle actin (α-SMA), fibronectin, and vimentin, and the EMT markers epithelial cell adhesion molecule (EPCAM), pan-cytokeratin, and vimentin, by immunohistochemistry using a tissue microarray of a retrospective cohort of 25 patients with PDAC. The results were examined for association with survival by clinical stage and by degree of tumor differentiation. High DS markers expression -α-SMA, fibronectin, and vimentin- was associated with decreased survival at intermediate and advanced clinical stages (p=0.006-0.03), as well as with both poorly and moderately differentiated tumor grades (p=0.01-0.02). Interestingly, the same pattern was observed for EMT markers, i.e., EPCAM, pan-cytokeratin, and vimentin (p=0.00008-0.03). High expression of DS and EMT markers within each clinical stage and degree of tumor differentiation was associated with lower PDAC survival. Evaluation of these markers may have a prognostic impact on survival time variation in patients with PDAC.

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Epithelial to Mesenchymal Transition: Key Regulator of Pancreatic Ductal Adenocarcinoma Progression and Chemoresistance

Cited by 40 publications

References 200 publications

Drug Resistance and Endoplasmic Reticulum Stress in Hepatocellular Carcinoma

Drug Resistance and Endoplasmic Reticulum Stress in Hepatocellular Carcinoma

Matairesinol Induces Mitochondrial Dysfunction and Exerts Synergistic Anticancer Effects with 5-Fluorouracil in Pancreatic Cancer Cells

High expression of both desmoplastic stroma and epithelial to mesenchymal transition markers associate with shorter survival in pancreatic ductal adenocarcinoma

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