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Gastric Cancer

, Volume 21, Issue 6, pp 946–955 | Cite as

Cancer–adipose tissue interaction and fluid flow synergistically modulate cell kinetics, HER2 expression, and trastuzumab efficacy in gastric cancer

  • Takashi Akutagawa
  • Shigehisa Aoki
  • Mihoko Yamamoto-Rikitake
  • Ryuichi Iwakiri
  • Kazuma Fujimoto
  • Shuji Toda
Original Article
  • 262 Downloads

Abstract

Background

Early local tumor invasion in gastric cancer results in likely encounters between cancer cells and submucosal and subserosal adipose tissue, but these interactions remain to be clarified. Microenvironmental mechanical forces, such as fluid flow, are known to modulate normal cell kinetics, but the effects of fluid flow on gastric cancer cells are poorly understood. We analyzed the cell kinetics and chemosensitivity in gastric cancer using a simple in vitro model that simultaneously replicated the cancer–adipocyte interaction and physical microenvironment.

Methods

Gastric cancer cells (MKN7 and MKN74) were seeded on rat adipose tissue fragment-embedded discs or collagen discs alone. To generate fluid flow, samples were placed on a rotatory shaker in a CO2 incubator. Proliferation, apoptosis, invasion, and motility-related molecules were analyzed by morphometry and immunostaining. Proteins were evaluated by western blot analysis. Chemosensitivity was investigated by trastuzumab treatment.

Results

Adipose tissue and fluid flow had a positive synergistic effect on the proliferative potential and invasive capacity of gastric cancer cells, and adipose tissue inhibited apoptosis in these cells. Adipose tissue upregulated ERK1/2 signaling in gastric cancer cells, but downregulated p38 signaling. Notably, adipose tissue and fluid flow promoted membranous and cytoplasmic HER2 expression and modulated chemosensitivity to trastuzumab in gastric cancer cells.

Conclusion

We have demonstrated that cancer–adipocyte interaction and physical microenvironment mutually modulate gastric cancer cell kinetics. Further elucidation of the microenvironmental regulation in gastric cancer will be very important for the development of strategies involving molecular targeted therapy.

Keywords

Cancer-associated adipocyte Fluid flow Human epidermal growth factor receptor 2 (HER2) Mitogen-activated protein kinase (MAPK) Trastuzumab 

Notes

Acknowledgements

We thank T. Sakumoto, S. Morito, M. Nishida, F. Mutoh, S. Nakahara, and I. Nanbu for excellent technical assistance. We are grateful to Mr. K. Tokaichi for refining the English of the manuscript. We also thank Alison Sherwin, PhD, from Edanz Group (http://www.edanzediting.com/ac) for editing a draft of this manuscript.

Funding

This work was supported in part by the Center for Clinical and Translational Research of Kyushu University Hospital (to S.A.), and Grants-in-Aid from the Japanese Ministry of Education, Culture, Sports, Science and Technology for Scientific Research (no. 17K09352 to S.T. and no. 16K09284 to S.A.).

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical standards

All institutional and national guidelines for the care and use of laboratory animals were followed in this study.

References

  1. 1.
    Östman A, Augsten M. Cancer-associated fibroblasts and tumor growth–bystanders turning into key players. Curr Opin Genet Dev. 2009;19(1):67–73.CrossRefGoogle Scholar
  2. 2.
    Nieman KM, Romero IL, Van Houten B, Lengyel E. Adipose tissue and adipocytes support tumorigenesis and metastasis. Biochim Biophys Acta Mol Cell Biol Lipids. 2013;1831(10):1533–41.CrossRefGoogle Scholar
  3. 3.
    Chatzizisis YS, Coskun AU, Jonas M, Edelman ER, Feldman CL, Stone PH. Role of endothelial shear stress in the natural history of coronary atherosclerosis and vascular remodeling: molecular, cellular, and vascular behavior. J Am Coll Cardiol. 2007;49(25):2379–93.CrossRefGoogle Scholar
  4. 4.
    Dewey C, Bussolari S, Gimbrone M, Davies PF. The dynamic response of vascular endothelial cells to fluid shear stress. J Biomech Eng. 1981;103(3):177–85.CrossRefGoogle Scholar
  5. 5.
    Yamamoto K, Sokabe T, Watabe T, Miyazono K, Yamashita JK, Obi S, et al. Fluid shear stress induces differentiation of Flk-1-positive embryonic stem cells into vascular endothelial cells in vitro. Am J Physiol Heart Circ Physiol. 2005;288(4):H1915–24.CrossRefGoogle Scholar
  6. 6.
    Knippenberg M, Helder MN, Zandieh Doulabi B, Semeins CM, Wuisman PI, Klein-Nulend J. Adipose tissue-derived mesenchymal stem cells acquire bone cell-like responsiveness to fluid shear stress on osteogenic stimulation. Tissue Eng. 2005;11(11–12):1780–88.CrossRefGoogle Scholar
  7. 7.
    Kumar V, Abbas AK, Aster JC. Robbins basic pathology e-book. New York: Elsevier; 2017.Google Scholar
  8. 8.
    Bang Y-J, Van Cutsem E, Feyereislova A, Chung HC, Shen L, Sawaki A, et al. Trastuzumab in combination with chemotherapy versus chemotherapy alone for treatment of HER2-positive advanced gastric or gastro-oesophageal junction cancer (ToGA): a phase 3, open-label, randomised controlled trial. Lancet. 2010;376(9742):687–97.CrossRefGoogle Scholar
  9. 9.
    Nomoto-Kojima N, Aoki S, Uchihashi K, Matsunobu A, Koike E, Ootani A, et al. Interaction between adipose tissue stromal cells and gastric cancer cells in vitro. Cell Tissue Res. 2011;344(2):287–98.CrossRefGoogle Scholar
  10. 10.
    Nakayama A, Aoki S, Uchihashi K, Nishijima-Matsunobu A, Yamamoto M, Kakihara N, et al. Interaction between esophageal squamous cell carcinoma and adipose tissue in vitro. Am J Pathol. 2016;186(5):1180–94.CrossRefGoogle Scholar
  11. 11.
    Aoki S, Udo K, Morimoto H, Ikeda S, Takezawa T, Uchihashi K, et al. Adipose tissue behavior is distinctly regulated by neighboring cells and fluid flow stress: a possible role of adipose tissue in peritoneal fibrosis. J Artif Organs. 2013;16(3):322–31.CrossRefGoogle Scholar
  12. 12.
    Aoki S, Makino J, Nagashima A, Takezawa T, Nomoto N, Uchihashi K, et al. Fluid flow stress affects peritoneal cell kinetics: possible pathogenesis of peritoneal fibrosis. Perit Dial Int. 2011;31(4):466–76.CrossRefGoogle Scholar
  13. 13.
    Gotoda T, Yanagisawa A, Sasako M, Ono H, Nakanishi Y, Shimoda T, et al. Incidence of lymph node metastasis from early gastric cancer: estimation with a large number of cases at two large centers. Gastric Cancer. 2000;3(4):219–25.CrossRefGoogle Scholar
  14. 14.
    Zhang W, Liu HT. MAPK signal pathways in the regulation of cell proliferation in mammalian cells. Cell Res. 2002;12(1):9.CrossRefGoogle Scholar
  15. 15.
    Kelesidis I, Kelesidis T, Mantzoros C. Adiponectin and cancer: a systematic review. Br J Cancer. 2006;94(9):1221.CrossRefGoogle Scholar
  16. 16.
    Housa D, Housova J, Vernerova Z, Haluzik M. Adipocytokines and cancer. Physiol Res. 2006;55(3):233.PubMedPubMedCentralGoogle Scholar
  17. 17.
    Tan J, Buache E, Chenard M-P, Dali-Youcef N, Rio M-C. Adipocyte is a non-trivial, dynamic partner of breast cancer cells. Int J Dev Biol. 2011;55(7-8-9):851–59.CrossRefGoogle Scholar
  18. 18.
    Dirat B, Bochet L, Dabek M, Daviaud D, Dauvillier S, Majed B, et al. Cancer-associated adipocytes exhibit an activated phenotype and contribute to breast cancer invasion. Cancer Res. 2011;71(7):2455–65.CrossRefGoogle Scholar
  19. 19.
    Cozzo AJ, Fuller AM, Makowski L. Contribution of adipose tissue to development of cancer. Compr Physiol. 2017;8(1):237–82.CrossRefGoogle Scholar
  20. 20.
    Burkitt DP. Epidemiology of cancer of the colon and rectum. Cancer. 1971;28(1):3–13.CrossRefGoogle Scholar
  21. 21.
    Kojima M, Wakai K, Tokudome S, Tamakoshi K, Toyoshima H, Watanabe Y, et al. Bowel movement frequency and risk of colorectal cancer in a large cohort study of Japanese men and women. Br J Cancer. 2004;90(7):1397.CrossRefGoogle Scholar
  22. 22.
    Nascimbeni R, Donato F, Ghirardi M, Mariani P, Villanacci V, Salerni B. Constipation, anthranoid laxatives, melanosis coli, and colon cancer: a risk assessment using aberrant crypt foci. Cancer Epidemiol Prev Biomark. 2002;11(8):753–7.Google Scholar
  23. 23.
    Giovannucci E, Ascherio A, Rimm EB, Colditz GA, Stampfer MJ, Willett WC. Physical activity, obesity, and risk for colon cancer and adenoma in men. Ann Intern Med. 1995;122(5):327–34.CrossRefGoogle Scholar
  24. 24.
    Anderson JC, Lacy BE. Editorial: Constipation and colorectal cancer risk: a continuing conundrum. Am J Gastroenterol. 2014;109(10):1650–2.CrossRefGoogle Scholar
  25. 25.
    Simons CC, Schouten LJ, Weijenberg MP, Goldbohm RA, van den Brandt PA. Bowel movement and constipation frequencies and the risk of colorectal cancer among men in the Netherlands Cohort Study on Diet and Cancer. Am J Epidemiol. 2010;172(12):1404–14.CrossRefGoogle Scholar
  26. 26.
    Fan R, Emery T, Zhang Y, Xia Y, Sun J, Wan J. Circulatory shear flow alters the viability and proliferation of circulating colon cancer cells. Sci Rep. 2016;6:27073.CrossRefGoogle Scholar
  27. 27.
    Ross MH, Pawlina W. Histology. Philadelphia: Lippincott Williams & Wilkins; 2006.Google Scholar
  28. 28.
    Polacheck WJ, Zervantonakis IK, Kamm RD. Tumor cell migration in complex microenvironments. Cell Mol Life Sci. 2013;70(8):1335–56.CrossRefGoogle Scholar
  29. 29.
    Candas D, Lu C-L, Fan M, Chuang FY, Sweeney C, Borowsky AD, et al. Mitochondrial MKP1 is a target for therapy-resistant HER2-positive breast cancer cells. Cancer Res. 2014;74(24):7498–509.CrossRefGoogle Scholar
  30. 30.
    Seliger B, Kiessling R. The two sides of HER2/neu: immune escape versus surveillance. Trends Mol Med. 2013;19(11):677–84.CrossRefGoogle Scholar
  31. 31.
    Bilous M, Dowsett M, Hanna W, Isola J, Lebeau A, Moreno A, et al. Current perspectives on HER2 testing: a review of national testing guidelines. Mod Pathol. 2003;16(2):173.CrossRefGoogle Scholar
  32. 32.
    Blok EJ, Kuppen PJ, Van Leeuwen JE, Sier CF. Cytoplasmic overexpression of HER2: a key factor in colorectal cancer. Clin Med Insights Oncol. 2013;7:CMO. S10811.CrossRefGoogle Scholar
  33. 33.
    Ueda S, Ogata S, Tsuda H, Kawarabayashi N, Kimura M, Sugiura Y, et al. The correlation between cytoplasmic overexpression of epidermal growth factor receptor and tumor aggressiveness: poor prognosis in patients with pancreatic ductal adenocarcinoma. Pancreas. 2004;29(1):e1–e8.CrossRefGoogle Scholar
  34. 34.
    Half E, Broaddus R, Danenberg KD, Danenberg PV, Ayers GD, Sinicrope FA. HER-2 receptor expression, localization, and activation in colorectal cancer cell lines and human tumors. Int J Cancer. 2004;108(4):540–8.CrossRefGoogle Scholar
  35. 35.
    Jindal Y, Varma K, Misra V, Kumar R, Singh A, Misra SP, et al. Cytoplasmic expression of HER2 in gastric adenocarcinoma: an unusual finding. IJMRPS. 2016;3(8):67–77.Google Scholar
  36. 36.
    Rüschoff J, Dietel M, Baretton G, Arbogast S, Walch A, Monges G, et al. HER2 diagnostics in gastric cancer—guideline validation and development of standardized immunohistochemical testing. Virchows Arch. 2010;457(3):299–307.CrossRefGoogle Scholar
  37. 37.
    Duong MN, Cleret A, Matera E-L, Chettab K, Mathé D, Valsesia-Wittmann S, et al. Adipose cells promote resistance of breast cancer cells to trastuzumab-mediated antibody-dependent cellular cytotoxicity. Breast Cancer Res. 2015;17(1):57.CrossRefGoogle Scholar
  38. 38.
    Majidinia M, Yousefi B. Breast tumor stroma: a driving force in the development of resistance to therapies. Chem Biol Drug Des. 2017;89(3):309–18.CrossRefGoogle Scholar

Copyright information

© The International Gastric Cancer Association and The Japanese Gastric Cancer Association 2018

Authors and Affiliations

  • Takashi Akutagawa
    • 1
    • 2
  • Shigehisa Aoki
    • 1
  • Mihoko Yamamoto-Rikitake
    • 1
  • Ryuichi Iwakiri
    • 2
  • Kazuma Fujimoto
    • 2
  • Shuji Toda
    • 1
  1. 1.Department of Pathology and Microbiology, Faculty of MedicineSaga UniversitySagaJapan
  2. 2.Department of Internal Medicine and Gastrointestinal Endoscopy, Faculty of MedicineSaga UniversitySagaJapan

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