Cancer-associated peritoneal mesothelial cells lead the formation of pancreatic cancer peritoneal dissemination

Abe,Toshiya; Ohuchida,Kenoki; Koikawa,Kazuhiro; Endo,Sho; Okumura,Takashi; Sada,Masafumi; Horioka,Kohei; Zheng,Biao; Moriyama,Taiki; Nakata,Kohei; Miyasaka,Yoshihiro; Manabe,Tatsuya; Ohtsuka,Takao; Nagai,Eishi; Mizumoto,Kazuhiro; Hashizume,Makoto; Nakamura,Masafumi

doi:10.3892/ijo.2016.3829

Cancer-associated peritoneal mesothelial cells lead the formation of pancreatic cancer peritoneal dissemination

Authors:
- Toshiya Abe
- Kenoki Ohuchida
- Kazuhiro Koikawa
- Sho Endo
- Takashi Okumura
- Masafumi Sada
- Kohei Horioka
- Biao Zheng
- Taiki Moriyama
- Kohei Nakata
- Yoshihiro Miyasaka
- Tatsuya Manabe
- Takao Ohtsuka
- Eishi Nagai
- Kazuhiro Mizumoto
- Makoto Hashizume
- Masafumi Nakamura
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Affiliations: Department of Surgery and Oncology, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan, Department of Advanced Medical Initiatives, Graduate School of Medical Sciences, Kyushu University, Fukuoka 812-8582, Japan
Published online on: December 30, 2016 https://doi.org/10.3892/ijo.2016.3829
Pages: 457-467

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Abstract

The interaction between the cancer cells and the peritoneal mesothelial cells (PMCs) plays an important role in the peritoneal dissemination in several types of cancer. However, the role of PMCs in the peritoneal dissemination of pancreatic cancer remains unclear. In the present study, we investigated the interaction between the pancreatic cancer cells (PCCs) and the PMCs in the formation of peritoneal dissemination in vitro and in vivo. The tumor-stromal interaction of PCCs and PMCs significantly enhanced their mobility and invasiveness and enhanced the proliferation and anoikis resistance of PCCs. In a 3D organotypic culture model of peritoneal dissemination, co-culture of PCCs and PMCs significantly increased the cells invading into the collagen gel layer compared with mono-culture of PCCs. PMCs pre-invaded into the collagen gel, remodeled collagen fibers, and increased parallel fiber orientation along the direction of cell invasion. In the tissues of peritoneal dissemination of the KPC (LSL-KrasG12D/+; LSL-Trp53R172H/+;Pdx-1-Cre) transgenic mouse, the monolayer of PMCs was preserved in tumor-free areas, whereas PMCs around the invasive front of peritoneal dissemination proliferated and invaded into the muscle layer. In vivo, intraperitoneal injection of PCCs with PMCs significantly promoted peritoneal dissemination compared with PCCs alone. The present data suggest that the cancer-associated PMCs have important promoting roles in the peritoneal dissemination of PCCs. Therapy targeting cancer-associated PMCs may improve the prognosis of patients with pancreatic cancer.

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1	Siegel R, Ma J, Zou Z and Jemal A: Cancer statistics, 2014. CA Cancer J Clin. 64:9–29. 2014. View Article : Google Scholar : PubMed/NCBI
2	Thomassen I, Lemmens VE, Nienhuijs SW, Luyer MD, Klaver YL and de Hingh IH: Incidence, prognosis, and possible treatment strategies of peritoneal carcinomatosis of pancreatic origin: A population-based study. Pancreas. 42:72–75. 2013. View Article : Google Scholar
3	Sadeghi B, Arvieux C, Glehen O, Beaujard AC, Rivoire M, Baulieux J, Fontaumard E, Brachet A, Caillot JL, Faure JL, et al: Peritoneal carcinomatosis from non-gynecologic malignancies: Results of the EVOCAPE 1 multicentric prospective study. Cancer. 88:358–363. 2000. View Article : Google Scholar : PubMed/NCBI
4	Neesse A, Michl P, Frese KK, Feig C, Cook N, Jacobetz MA, Lolkema MP, Buchholz M, Olive KP, Gress TM, et al: Stromal biology and therapy in pancreatic cancer. Gut. 60:861–868. 2011. View Article : Google Scholar
5	Tan DS, Agarwal R and Kaye SB: Mechanisms of transcoelomic metastasis in ovarian cancer. Lancet Oncol. 7:925–934. 2006. View Article : Google Scholar : PubMed/NCBI
6	Sugarbaker PH: Peritoneum as the first-line of defense in carcinomatosis. J Surg Oncol. 95:93–96. 2007. View Article : Google Scholar : PubMed/NCBI
7	Yashiro M and Hirakawa K: Cancer-stromal interactions in scirrhous gastric carcinoma. Cancer Microenviron. 3:127–135. 2010. View Article : Google Scholar
8	Akagawa S, Ohuchida K, Torata N, Hattori M, Eguchi D, Fujiwara K, Kozono S, Cui L, Ikenaga N, Ohtsuka T, et al: Peritoneal myofibroblasts at metastatic foci promote dissemination of pancreatic cancer. Int J Oncol. 45:113–120. 2014.PubMed/NCBI
9	Yáñez-Mó M, Lara-Pezzi E, Selgas R, Ramírez-Huesca M, Domínguez-Jiménez C, Jiménez-Heffernan JA, Aguilera A, Sánchez-Tomero JA, Bajo MA, Alvarez V, et al: Peritoneal dialysis and epithelial-to-mesenchymal transition of mesothelial cells. N Engl J Med. 348:403–413. 2003. View Article : Google Scholar : PubMed/NCBI
10	Tsukada T, Fushida S, Harada S, Yagi Y, Kinoshita J, Oyama K, Tajima H, Fujita H, Ninomiya I, Fujimura T, et al: The role of human peritoneal mesothelial cells in the fibrosis and progression of gastric cancer. Int J Oncol. 41:476–482. 2012.PubMed/NCBI
11	Epperly MW, Guo H, Gretton JE and Greenberger JS: Bone marrow origin of myofibroblasts in irradiation pulmonary fibrosis. Am J Respir Cell Mol Biol. 29:213–224. 2003. View Article : Google Scholar : PubMed/NCBI
12	Xu Z, Vonlaufen A, Phillips PA, Fiala-Beer E, Zhang X, Yang L, Biankin AV, Goldstein D, Pirola RC, Wilson JS, et al: Role of pancreatic stellate cells in pancreatic cancer metastasis. Am J Pathol. 177:2585–2596. 2010. View Article : Google Scholar : PubMed/NCBI
13	Mutsaers SE: The mesothelial cell. Int J Biochem Cell Biol. 36:9–16. 2004. View Article : Google Scholar
14	Sandoval P, Jiménez-Heffernan JA, Rynne-Vidal Á, Pérez-Lozano ML, Gilsanz Á, Ruiz-Carpio V, Reyes R, García-Bordas J, Stamatakis K, Dotor J, et al: Carcinoma-associated fibroblasts derive from mesothelial cells via mesothelial-to-mesenchymal transition in peritoneal metastasis. J Pathol. 231:517–531. 2013. View Article : Google Scholar : PubMed/NCBI
15	Na D, Lv ZD, Liu FN, Xu Y, Jiang CG, Sun Z, Miao ZF, Li F and Xu HM: Transforming growth factor beta1 produced in autocrine/paracrine manner affects the morphology and function of mesothelial cells and promotes peritoneal carcinomatosis. Int J Mol Med. 26:325–332. 2010.PubMed/NCBI
16	Yamaguchi H and Sakai R: Direct interaction between carcinoma cells and cancer associated fibroblasts for the regulation of cancer invasion. Cancers (Basel). 7:2054–2062. 2015. View Article : Google Scholar
17	Scherz-Shouval R, Santagata S, Mendillo ML, Sholl LM, Ben-Aharon I, Beck AH, Dias-Santagata D, Koeva M, Stemmer SM, Whitesell L, et al: The reprogramming of tumor stroma by HSF1 is a potent enabler of malignancy. Cell. 158:564–578. 2014. View Article : Google Scholar : PubMed/NCBI
18	Ksiazek K, Mikula-Pietrasik J, Korybalska K, Dworacki G, Jörres A and Witowski J: Senescent peritoneal mesothelial cells promote ovarian cancer cell adhesion: The role of oxidative stress-induced fibronectin. Am J Pathol. 174:1230–1240. 2009. View Article : Google Scholar : PubMed/NCBI
19	Mikuła-Pietrasik J, Sosińska P, Kucińska M, Murias M, Maksin K, Malińska A, Ziółkowska A, Piotrowska H, Woźniak A and Książek K: Peritoneal mesothelium promotes the progression of ovarian cancer cells in vitro and in a mice xenograft model in vivo. Cancer Lett. 355:310–315. 2014. View Article : Google Scholar
20	Satoyoshi R, Aiba N, Yanagihara K, Yashiro M and Tanaka M: Tks5 activation in mesothelial cells creates invasion front of peritoneal carcinomatosis. Oncogene. 34:3176–3187. 2015. View Article : Google Scholar
21	Sluiter N, de Cuba E, Kwakman R, Kazemier G, Meijer G and Te Velde EA: Adhesion molecules in peritoneal dissemination: Function, prognostic relevance and therapeutic options. Clin Exp Metastasis. 33:401–416. 2016. View Article : Google Scholar : PubMed/NCBI
22	Kanda M and Kodera Y: Molecular mechanisms of peritoneal dissemination in gastric cancer. World J Gastroenterol. 22:6829–6840. 2016. View Article : Google Scholar : PubMed/NCBI
23	Yung S, Li FK and Chan TM: Peritoneal mesothelial cell culture and biology. Perit Dial Int. 26:162–173. 2006.PubMed/NCBI
24	Kitayama J, Emoto S, Yamaguchi H, Ishigami H and Watanabe T: CD90⁺ mesothelial-like cells in peritoneal fluid promote peritoneal metastasis by forming a tumor permissive microenvironment. PLoS One. 9:e865162014. View Article : Google Scholar
25	Whitehead RH and Hughes LE: Tissue culture studies. Br J Cancer. 32:512–518. 1975. View Article : Google Scholar : PubMed/NCBI
26	Ohuchida K, Mizumoto K, Murakami M, Qian LW, Sato N, Nagai E, Matsumoto K, Nakamura T and Tanaka M: Radiation to stromal fibroblasts increases invasiveness of pancreatic cancer cells through tumor-stromal interactions. Cancer Res. 64:3215–3222. 2004. View Article : Google Scholar : PubMed/NCBI
27	Hingorani SR, Wang L, Multani AS, Combs C, Deramaudt TB, Hruban RH, Rustgi AK, Chang S and Tuveson DA: Trp53^R172H and Kras^G12D cooperate to promote chromosomal instability and widely metastatic pancreatic ductal adenocarcinoma in mice. Cancer Cell. 7:469–483. 2005. View Article : Google Scholar : PubMed/NCBI
28	Alkhamesi NA, Ziprin P, Pfistermuller K, Peck DH and Darzi AW: ICAM-1 mediated peritoneal carcinomatosis, a target for therapeutic intervention. Clin Exp Metastasis. 22:449–459. 2005. View Article : Google Scholar : PubMed/NCBI
29	Rezakhaniha R, Agianniotis A, Schrauwen JTC, Griffa A, Sage D, Bouten CV, van de Vosse FN, Unser M and Stergiopulos N: Experimental investigation of collagen waviness and orientation in the arterial adventitia using confocal laser scanning microscopy. Biomech Model Mechanobiol. 11:461–473. 2012. View Article : Google Scholar
30	Sada M, Ohuchida K, Horioka K, Okumura T, Moriyama T, Miyasaka Y, Ohtsuka T, Mizumoto K, Oda Y and Nakamura M: Hypoxic stellate cells of pancreatic cancer stroma regulate extracellular matrix fiber organization and cancer cell motility. Cancer Lett. 372:210–218. 2016. View Article : Google Scholar : PubMed/NCBI
31	Kasagi Y, Harada Y, Morodomi Y, Iwai T, Saito S, Yoshida K, Oki E, Saeki H, Ohgaki K, Sugiyama M, et al: Peritoneal dissemination requires an Sp1-dependent CXCR4/CXCL12 signaling axis and extracellular matrix-directed spheroid formation. Cancer Res. 76:347–357. 2016. View Article : Google Scholar : PubMed/NCBI
32	Condello S, Morgan Ca, Nagdas S, Cao L, Turek J, Hurley TD and Matei D: β-Catenin-regulated ALDH1A1 is a target in ovarian cancer spheroids. Oncogene. 34:1–12. 2014.
33	Lv Z-D, Na D, Liu F-N, Du ZM, Sun Z, Li Z, Ma XY, Wang ZN and Xu HM: Induction of gastric cancer cell adhesion through transforming growth factor-beta1-mediated peritoneal fibrosis. J Exp Clin Cancer Res. 29:1392010. View Article : Google Scholar : PubMed/NCBI
34	Kenny HA, Chiang CY, White EA, Schryver EM, Habis M, Romero IL, Ladanyi A, Penicka CV, George J, Matlin K, et al: Mesothelial cells promote early ovarian cancer metastasis through fibronectin secretion. J Clin Invest. 124:4614–4628. 2014. View Article : Google Scholar : PubMed/NCBI
35	Conklin MW, Eickhoff JC, Riching KM, Pehlke CA, Eliceiri KW, Provenzano PP, Friedl A and Keely PJ: Aligned collagen is a prognostic signature for survival in human breast carcinoma. Am J Pathol. 178:1221–1232. 2011. View Article : Google Scholar : PubMed/NCBI