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

Ayano Kabashima-Niibe; Hajime Higuchi; Hiromasa Takaishi; Yohei Masugi; Yumi Matsuzaki; Yo Mabuchi; Shinsuke Funakoshi; Masayuki Adachi; Yasuo Hamamoto; Shigeyuki Kawachi; Koichi Aiura; Yuko Kitagawa; Michiie Sakamoto; Toshifumi Hibi

doi:10.1111/cas.12059

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

Cancer Sci. 2013 Feb;104(2):157-64. doi: 10.1111/cas.12059. Epub 2013 Jan 11.

Authors

Ayano Kabashima-Niibe¹, Hajime Higuchi, Hiromasa Takaishi, Yohei Masugi, Yumi Matsuzaki, Yo Mabuchi, Shinsuke Funakoshi, Masayuki Adachi, Yasuo Hamamoto, Shigeyuki Kawachi, Koichi Aiura, Yuko Kitagawa, Michiie Sakamoto, Toshifumi Hibi

Affiliation

¹ Division of Gastroenterology, Department of Internal Medicine, Keio University School of Medicine, Tokyo, Japan.

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 α-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 tumor-initiating 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 γ-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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Actins / genetics
Actins / metabolism
Amyloid Precursor Protein Secretases / genetics
Amyloid Precursor Protein Secretases / metabolism
Animals
Calcium-Binding Proteins / genetics
Calcium-Binding Proteins / metabolism
Cell Line, Tumor
Disease Progression
Epithelial-Mesenchymal Transition / genetics
Epithelial-Mesenchymal Transition / physiology*
Humans
Intercellular Signaling Peptides and Proteins / genetics
Intercellular Signaling Peptides and Proteins / metabolism
Jagged-1 Protein
Male
Membrane Proteins / genetics
Membrane Proteins / metabolism
Mesenchymal Stem Cells / metabolism
Mesenchymal Stem Cells / pathology*
Mice
Mice, Inbred NOD
Mice, SCID
Myofibroblasts / metabolism
Myofibroblasts / pathology
Pancreatic Neoplasms / genetics
Pancreatic Neoplasms / metabolism
Pancreatic Neoplasms / pathology*
RNA, Small Interfering / genetics
Receptors, Notch / genetics
Receptors, Notch / metabolism
Serrate-Jagged Proteins
Transforming Growth Factor beta / genetics
Transforming Growth Factor beta / metabolism

Substances

ACTA2 protein, human
Actins
Calcium-Binding Proteins
Intercellular Signaling Peptides and Proteins
JAG1 protein, human
Jag1 protein, mouse
Jagged-1 Protein
Membrane Proteins
RNA, Small Interfering
Receptors, Notch
Serrate-Jagged Proteins
Transforming Growth Factor beta
Amyloid Precursor Protein Secretases