Epithelial-mesenchymal transition in pancreatic carcinoma

Abstract

Pancreatic carcinoma is the fourth-leading cause of cancer death and is characterized by early invasion and metastasis. The developmental program of epithelial-mesenchymal transition (EMT) is of potential importance for this rapid tumor progression. During EMT, tumor cells lose their epithelial characteristics and gain properties of mesenchymal cells, such as enhanced motility and invasive features. This review will discuss recent findings pertinent to EMT in pancreatic carcinoma. Evidence for and molecular characteristics of EMT in pancreatic carcinoma will be outlined, as well as the connection of EMT to related topics, e.g., cancer stem cells and drug resistance.

Figure 1

Characteristics of epithelial-mesenchymal transition. EMT: epithelial-mesenchymal transition, MET: mesenchymal-epithelial transition.

Figure 2

Characteristics of EMT in pancreatic adenocarcinoma (PDAC) with functional or non-functional SMAD4 protein. TGFβ binds to a type 2 TGFβ receptor (TβRII), which phosphorylates TβRI (ALK5). TβRI (ALK5) in turn phosphorylates the receptor-activated SMADs (SMAD2 and SMAD3). Left: In tumor cells with functional SMAD4, SMAD2 and SMAD3 form heterotrimeric complexes with SMAD4, translocate to the nucleus and, together with cofactors, alter gene expression. This can lead to EMT, migration, and invasion. The SMAD-induced inhibition of proliferation, which is mediated e.g., by inhibition of Myc and Id factors and activation of p15 and p21, has to be overcome in tumors. This could possibly be achieved by alterations in SMAD target genes, e.g., by alterations in co-activators and co-repressors, or by activation of other signaling pathways which favor proliferation. Right: In SMAD-deficient cells, the anti-proliferative TGFβ effect is abolished and thereby confers a growth advantage to these cells. However, SMAD-mediated EMT, migration and invasion is also halted. In that case, non-canonical TGFβ signaling (e.g., MAPK, PI3K, RhoA, PAR6) is believed to mediate migration and invasion. Also, the absence of SMAD4 leads to a disinhibition of STAT3, which mediates migration and invasion. However, whether non-canonical TGFβ signaling actually can induce EMT remains controversial; possibly, other signaling pathways (e.g., NF-κB) are necessary to replace SMAD signaling. Even in that case, the EMT in SMAD4-deficient tumor cells may not be as pronounced as in SMAD4-containing tumors.