Cancer–adipose tissue interaction and fluid flow synergistically modulate cell kinetics, HER2 expression, and trastuzumab efficacy in gastric cancer
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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.
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.
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.
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.
KeywordsCancer-associated adipocyte Fluid flow Human epidermal growth factor receptor 2 (HER2) Mitogen-activated protein kinase (MAPK) Trastuzumab
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.
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.
All institutional and national guidelines for the care and use of laboratory animals were followed in this study.
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