CD146 attenuation in cancer-associated fibroblasts promotes pancreatic cancer progression
Biao Zheng
Department of Surgery and Oncology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
Search for more papers by this authorCorresponding Author
Kenoki Ohuchida
Department of Surgery and Oncology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
Advanced Medical Initiatives, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
Correspondence to: Department of Surgery and Oncology, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Fukuoka 812-8582, Japan.
Search for more papers by this authorYoshiro Chijiiwa
Department of Surgery and Oncology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
Search for more papers by this authorMing Zhao
Department of Surgery and Oncology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
Search for more papers by this authorYusuke Mizuuchi
Department of Surgery and Oncology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
Department of Anatomic Pathology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
Search for more papers by this authorLin Cui
Department of Surgery and Oncology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
Search for more papers by this authorKohei Horioka
Department of Surgery and Oncology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
Search for more papers by this authorTakao Ohtsuka
Department of Surgery and Oncology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
Search for more papers by this authorCorresponding Author
Kazuhiro Mizumoto
Department of Surgery and Oncology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
Kyushu University Hospital Cancer Center, Fukuoka, Japan
Correspondence to: Department of Surgery and Oncology, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Fukuoka 812-8582, Japan.
Search for more papers by this authorYoshinao Oda
Department of Anatomic Pathology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
Search for more papers by this authorMakoto Hashizume
Advanced Medical Initiatives, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
Search for more papers by this authorMasafumi Nakamura
Department of Surgery and Oncology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
Search for more papers by this authorMasao Tanaka
Department of Surgery and Oncology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
Search for more papers by this authorBiao Zheng
Department of Surgery and Oncology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
Search for more papers by this authorCorresponding Author
Kenoki Ohuchida
Department of Surgery and Oncology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
Advanced Medical Initiatives, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
Correspondence to: Department of Surgery and Oncology, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Fukuoka 812-8582, Japan.
Search for more papers by this authorYoshiro Chijiiwa
Department of Surgery and Oncology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
Search for more papers by this authorMing Zhao
Department of Surgery and Oncology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
Search for more papers by this authorYusuke Mizuuchi
Department of Surgery and Oncology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
Department of Anatomic Pathology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
Search for more papers by this authorLin Cui
Department of Surgery and Oncology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
Search for more papers by this authorKohei Horioka
Department of Surgery and Oncology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
Search for more papers by this authorTakao Ohtsuka
Department of Surgery and Oncology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
Search for more papers by this authorCorresponding Author
Kazuhiro Mizumoto
Department of Surgery and Oncology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
Kyushu University Hospital Cancer Center, Fukuoka, Japan
Correspondence to: Department of Surgery and Oncology, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Fukuoka 812-8582, Japan.
Search for more papers by this authorYoshinao Oda
Department of Anatomic Pathology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
Search for more papers by this authorMakoto Hashizume
Advanced Medical Initiatives, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
Search for more papers by this authorMasafumi Nakamura
Department of Surgery and Oncology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
Search for more papers by this authorMasao Tanaka
Department of Surgery and Oncology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan
Search for more papers by this authorAbstract
Cancer-associated fibroblasts (CAFs) are heterogeneous cell populations that influence tumor initiation and progression. CD146 is a cell membrane protein whose expression has been implicated in multiple human cancers. CD146 expression is also detected in pancreatic cancer stroma; however, the role it plays in this context remains unclear. This study aimed to clarify the function and significance of CD146 expression in pancreatic cancer. We performed immunohistochemical staining to investigate the prevalence of CD146 expression in stromal fibroblasts in pancreatic cancer. We also examined the influence of CD146 on CAF-mediated tumor invasion and migration and CAF activation using CD146 small interfering RNA or overexpression plasmids in primary cultures of CAFs derived from pancreatic cancer tissues. CD146 expression in CAFs was associated with high-grade pancreatic intraepithelial neoplasia and low histological grade invasive ductal carcinoma of the pancreas, while patients with low CD146 expression had a poorer prognosis. Blocking CD146 expression in CAFs significantly enhanced tumor cell migration and invasion in a co-culture system. CD146 knockdown also promoted CAF activation, possibly by inducing the production of pro-tumorigenic factors through modulation of NF-κB activity. Consistently, overexpression of CD146 in CAFs inhibited migration and invasion of co-cultured cancer cells. Finally, CD146 expression in CAFs was reduced by interaction with cancer cells. Our findings suggest that decreased CD146 expression in CAFs promotes pancreatic cancer progression. © 2015 Wiley Periodicals, Inc.
Supporting Information
Additional supporting information may be found in the online version of this article at the publisher's web-site.
| Filename | Description |
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| mc22409-sup-0001-SupFig-S1.pdf780.6 KB |
Figure S1. Immunohistochemical staining of CD146, α-SMA, and CD31 in consecutive sections of human PanIN-3 and IDC specimens. Arrows indicate blood vessels, original magnification: 200×. Figure S2. Knockdown efficiency of CD146-specific siRNAs (A) and upregulation of CD146 by transfection of expression plasmid (B) measured by qRT-PCR (n = 3) and western blot 48 h after transfection (**P < 0.01, compared with control). Figure S3. Knockdown of CD146 expression in CAF1 (A) and CAF2 (B) cells promotes invasion of GFP-SUIT-2 cancer cells subjected to direct co-culture. Representative photomicrographs are shown in the panels on the left-hand side (40× magnification). Bar charts summarize the invasive capacity of cells in each group. Bars represent mean cell counts ± SD and are normalized to the control group. (n = 3, *P < 0.05, **P < 0.01, compared with control). Figure S4. FGF2 promotes CAF-mediated pro-tumorigenic functions. (A) Migration and invasion of SUIT-2 cells co-cultured with FGF2-treated and non-treated CAFs. Representative photomicrographs are shownin the panels on the left-hand side (100× magnification). Bar charts summarize the migration and invasion of cells in each group. Bars represent mean cell counts ± SD and are normalized to the non-treated group. (B) Cell viability of CAFs exposed to FGF2. (C) CCL5 production by CAFs exposed to FGF2. (n = 3, *P < 0.05, **P < 0.01, compared with non-treated,NT: non-treated, d: day). |
| mc22409-sup-0002-SupTable-S1.pdf98.2 KB |
Table S1. Clinicopathological characteristics of patients (n = 125). Table S2. Primers used for quantitative RT-PCR. Table S3. Univariate survival analysis of conventional prognostic factors and CD146 expression in pancreatic cancer patients. |
Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.
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