Pancreatic stellate cells enhance stem cell-like phenotypes in pancreatic cancer cells Shin Hamada a,1 , Atsushi Masamune a,⇑,1 , Tetsuya Takikawa a,1 , Noriaki Suzuki a , Kazuhiro Kikuta a , Morihisa Hirota a , Hirofumi Hamada b , Masayoshi Kobune c , Kennichi Satoh d , Tooru Shimosegawa a a Division of Gastroenterology, Tohoku University Graduate School of Medicine, Sendai, Japan b Laboratory of Oncology, Department of Life Sciences, Tokyo University of Pharmacy and Life Sciences, Hachioji, Japan c Fourth Department of Internal Medicine, Sapporo Medical University School of Medicine, Sapporo, Japan d Division of Cancer Stem Cell, Miyagi Cancer Center Research Institute, Natori, Japan article info Article history: Received 3 April 2012 Available online 9 April 2012 Keywords: Stroma Niche Cancer stem cells Fibroblasts Desmoplastic reaction abstract The interaction between pancreatic cancer cells and pancreatic stellate cells (PSCs), a major profibrogenic cell type in the pancreas, is receiving increasing attention. There is accumulating evidence that PSCs pro- mote the progression of pancreatic cancer by increasing cancer cell proliferation and invasion as well as by protecting them from radiation- and gemcitabine-induced apoptosis. Recent studies have identified that a portion of cancer cells, called ‘‘cancer stem cells’’, within the entire cancer tissue harbor highly tumorigenic and chemo-resistant phenotypes, which lead to the recurrence after surgery or re-growth of the tumor. The mechanisms that maintain the ‘‘stemness’’ of these cells remain largely unknown. We hypothesized that PSCs might enhance the cancer stem cell-like phenotypes in pancreatic cancer cells. Indirect co-culture of pancreatic cancer cells with PSCs enhanced the spheroid-forming ability of cancer cells and induced the expression of cancer stem cell-related genes ABCG2, Nestin and LIN28. In addition, co-injection of PSCs enhanced tumorigenicity of pancreatic cancer cells in vivo. These results suggested a novel role of PSCs as a part of the cancer stem cell niche. Ó 2012 Elsevier Inc. All rights reserved. 1. Introduction Pancreatic ductal adenocarcinoma is characterized by a highly malignant phenotype such as rapid progression, early metastasis, and a limited response to chemotherapy and radiotherapy [1–3]. The abundant desmoplastic/stromal reaction is a characteristic fea- ture of the majority of pancreatic cancers [4–8]. It has been recog- nized that the cells responsible for production of the desmoplastic reaction in pancreatic cancer are pancreatic stellate cells (PSCs) [4– 10]. In normal pancreas, PSCs are quiescent and can be identified by the presence of vitamin A-containing lipid droplets in the cyto- plasm. In response to pancreatic injury or inflammation, they are transformed (‘‘activated’’) from their quiescent phenotype into myofibroblast-like cells, which express a-smooth muscle actin, ac- tively proliferate, and produce extracellular matrix components such as type I collagen [9–12]. Over a decade, there is accumulating evidence that activated PSCs play a pivotal role in the development of pancreatic fibrosis in chronic pancreatitis and pancreatic cancer [4–12]. Emerging evidence has suggested that the capability of a tumor to grow and propagate is dependent on a small subset of cells with- in a tumor, termed cancer stem cells (CSCs) [13–16]. This CSC con- cept was established as a counterpart of normal tissue stem cells, which are indispensable for the normal tissue maintenance. The current consensus definition describes a CSC as a cell within a tu- mor that is able to self-renew and to produce the heterogeneous lineages of cancer cells that comprise the tumor [13–17]. Similar to the normal tissue stem cells, the existence of CSC niche was anticipated together with the tumor-specific tissue structures [13–15]. The subpopulations with CD44 + CD24 + epithelial-specific antigen (epithelial cellular adhesion molecule) + [16] or CD133 + [17] properties in pancreatic cancer have been recognized as puta- tive CSCs, because they can both self-renew and produce differen- tiated progeny. CSCs are highly tumorigenic, metastatic, and more resistant to conventional therapies [14–17]. Previous studies have shown that PSCs play critical roles in the progression of pancreatic cancer [4–8]. PSCs increased the proliferation and migration of pancreatic cancer cells, and protected them from gemcitabine- or radiation-induced apoptosis [4–8]. In addition, PSCs increased the metastasis of pancreatic cancer cells in an orthotopic model 0006-291X/$ - see front matter Ó 2012 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.bbrc.2012.04.014 Abbreviations: CSC, cancer stem cell; EMT, epithelial-to-mesenchymal transi- tion; PSCs, pancreatic stellate cells; SV40, simian virus 40; hTERT, human telomerase reverse transcriptase. ⇑ Corresponding author. Address: Division of Gastroenterology, Tohoku Univer- sity Graduate School of Medicine, 1-1 Seiryo-machi, Aoba-ku, Sendai 980-8574, Japan. Fax: +81 22 717 7177. E-mail address: amasamune@med.tohoku.ac.jp (A. Masamune). 1 The first three authors equally contributed to this work. Biochemical and Biophysical Research Communications 421 (2012) 349–354 Contents lists available at SciVerse ScienceDirect Biochemical and Biophysical Research Communications journal homepage: www.elsevier.com/locate/ybbrc