Research Papers:

Promotion of malignant phenotype after disruption of the three-dimensional structure of cultured spheroids from colorectal cancer

Jose M. Piulats, Jumpei Kondo, Hiroko Endo, Hiromasa Ono, Takeshi Hagihara, Hiroaki Okuyama, Yasuko Nishizawa, Yasuhiko Tomita, Masayuki Ohue, Kouki Okita, Hidejiro Oyama, Hidemasa Bono, Takashi Masuko and Masahiro Inoue _

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Oncotarget. 2018; 9:15968-15983. https://doi.org/10.18632/oncotarget.24641

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Jose M. Piulats1,6,*, Jumpei Kondo1,*, Hiroko Endo1, Hiromasa Ono4, Takeshi Hagihara1, Hiroaki Okuyama1, Yasuko Nishizawa2, Yasuhiko Tomita2, Masayuki Ohue3, Kouki Okita5, Hidejiro Oyama5, Hidemasa Bono4, Takashi Masuko5 and Masahiro Inoue1

1Department of Biochemistry, Osaka International Cancer Institute, Chuo-ku, Osaka, Japan

2Pathology, Osaka International Cancer Institute, Chuo-ku, Osaka, Japan

3Surgery, Osaka International Cancer Institute, Chuo-ku, Osaka, Japan

4Database Center for Life Science (DBCLS), Research Organization of Information and Systems (ROIS), Mishima, Shizuoka, Japan

5Cell Biology Laboratory, Department of Pharmaceutical Sciences, School of Pharmacy, Kinki University, Higashiƍsaka, Osaka, Japan

6Current Affiliation: Department of Medical Oncology, Institut Català d’Oncologia, Barcelona, Spain

*These authors have contributed equally to this work

Correspondence to:

Masahiro Inoue, email: [email protected]

Keywords: spheroids; stemness; WNT; differentiated adenocarcinoma; colorectal cancer

Received: August 01, 2017     Accepted: February 26, 2018     Published: March 23, 2018


Individual and small clusters of cancer cells may detach from the edges of a main tumor and invade vessels, which can act as the origin of metastasis; however, the mechanism for this phenomenon is not well understood. Using cancer tissue-originated spheroids, we studied whether disturbing the 3D architecture of cancer spheroids can provoke the reformation process and progression of malignancy. We developed a mechanical disruption method to achieve homogenous disruption of the spheroids while maintaining cell–cell contact. After the disruption, 9 spheroid lines from 9 patient samples reformed within a few hours, and 3 of the 9 lines exhibited accelerated spheroid growth. Marker expression, spheroid forming capacity, and tumorigenesis indicated that stemness increased after spheroid disruption. In addition, the spheroid forming capacity increased in 6 of 11 spheroid lines. The disruption signature determined by gene expression profiling supported the incidence of remodeling and predicted the prognosis of patients with colorectal cancer. Furthermore, WNT and HER3 signaling were increased in the reformed spheroids, and suppression of these signaling pathways attenuated the increased proliferation and stemness after the disruption. Overall, the disruption and subsequent reformation of cancer spheroids promoted malignancy-related phenotypes through the activation of the WNT and ERBB pathways.

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