Mesenchymal stem cells regulate epithelial–mesenchymal transition and tumor progression of pancreatic cancer cells

Abstract

Cancer-associated fibroblasts contribute to cancer progression that is caused by epithelial-mesenchymal transition (EMT). Recently, mesenchymal stem cells (MSCs) were found to be the major candidate involved in the development of tumor-promoting cancer stroma. Here we report that a-smooth muscle actin-positive myofibroblast-like cells originating from MSCs contribute to inducing EMT in side population cells of pancreatic cancer. More importantly, MSC-derived myofibroblasts function to maintain tumorinitiating stem cell-like characteristics, including augmenting expression levels of various stemness-associated genes, enhancing sphere-forming activity, promoting tumor formation in a mouse xenograft model, and showing resistance to anticancer drugs. Furthermore, both c-secretase inhibitor and siRNA directed against Jagged-1 attenuated MSC-associated E-cadherin suppression and sphere formation in pancreatic cancer side population cells. Thus, our results suggest that MSC-derived myofibroblasts play important roles in regulating EMT and tumor-initiating stem cell-like properties of pancreatic cancer cells through an intermediating Notch signal. (Cancer Sci 2013; 104: 157-164) D uring tumor progression, epithelial-mesenchymal transition (EMT) contributes considerably to the malignant characteristics of tumors such as local invasion and distant metastasis.(1,2) Epithelial-mesenchymal transition has recently been reported as the key phenomenon that tightly regulates the stem cell-like characteristics of both normal and malignant cells. (3,4) Side population (SP) technology has been widely used to isolate the stem cell-enriched fraction in a variety of tissue. Side population cells are detected by their own ability to efflux Hoechst33342 dye through an ATP-binding cassette membrane transporter. We recently found that SP cells from pancreatic cancer cells are highly responsive to transforming growth factor-b (TGF-b)-mediated EMT, invasion, and metastasis.(5) Our results suggest that SP cells are enriched with cells that undergo mesenchymal-epithelial transition (MET) after TGF-b-associated EMT. Thus, our results indicated that an EMT ⁄ MET conversion is tightly linked to malignant potential in pancreatic cancer, such as invasion ⁄ metastasis. However, the mechanisms by which the EMT ⁄ MET status is regulated within a tumor in vivo remains undetermined.The tumor microenvironment consists of various stromal cells, including tumor-associated fibroblasts, endothelial cells, pericytes, adipocytes, and immune cells.(6) Among these cell types, cancer-associated fibroblasts (CAFs) and/or myofibroblasts have been recently implicated in regulating tumor progression, invasion, and metastasis. (7,8) Cancer-associated fibroblasts and myofibroblasts secrete a number of important inflammatory mediators, including MMP-2, -3, and -9, that can alter the stromal ECM and potentiate invasion, cell motility, and metastasis.

Biological functions of lung cancer cells are suppressed in co‑culture with mesenchymal stem cells isolated from umbilical cord

“…In another study, α-smooth muscle actin-positive MSCs were co-engrafted with pancreatic cancer cells in severe combined immunodeficiency mice and the results confirmed that MSCs could promote epithelial-mesenchymal transition (20). Mechanistic analysis indicated that the 'stemness' of pancreatic cells was enhanced by Notch-associated signaling regulated by MSCs (20). Zhang et al (21) co-cultured breast cancer and prostate cancer cells with bone marrow-derived MSCs and identified that treatment with MSCs significantly enhanced angiogenesis within the tumor in nude mice.…”

“…In a study of the effects of MSCs on cholangiocarcinoma, Liu et al (19) established xenograft models by injection of HCCC-9810 cells and identified that conditioned medium from UCMSCs inhibited proliferation and induced apoptosis in a dose-and time-dependent manner. In another study, α-smooth muscle actin-positive MSCs were co-engrafted with pancreatic cancer cells in severe combined immunodeficiency mice and the results confirmed that MSCs could promote epithelial-mesenchymal transition (20). Mechanistic analysis indicated that the 'stemness' of pancreatic cells was enhanced by Notch-associated signaling regulated by MSCs (20).…”

Stem Cells in Pancreatic Cancer

“…Interestingly, not all types of MSCs have this particular ability, a recent report from Subramanian et al arguing that this is not a feature of umbilical-cord derived pluripotent cells [113]. In pancreatic cancer, like in any other type of cancer, these myofibroblast-like cells contribute to inducing EMT in side population cells, maintain tumorinitiating stem cell-like characteristics, including augmenting expression levels of various stemness-associated genes, enhancing sphere-forming activity, promoting tumor formation in a mouse xenograft model, and showing resistance to anticancer drugs [114].…”

Bone Marrow-Derived Mesenchymal Stem Cells Regulate Epithelial-Mesenchymal Transitions and Gastric Cancer Stem Cells

“…Although tumorigenesis is widely considered to be regulated by interactions between tumor cells and CAFs, the precise origin and function of CAFs are unclear. Kabashima-Niibe et al [42] focused on the role of α-smooth muscle actin (SMA)-positive myofibroblast-like cells in EMT regulation and cancer progression of pancreatic cancer cells. Their results indicated that α-SMA-positive myofibroblast-like cells are enriched in areas in which cancer cells had undergone EMT, and were frequently identified in human pancreatic cancer specimens [42] .…”