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Microenvironmental elements singularity synergistically regulate the behavior and chemosensitivity of endometrioid carcinoma

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Abstract

The importance of the microenvironment is widely recognized as it regulates not only malignant cell behavior but also drug sensitivity. The cancer cell microenvironment is composed of biological, physical and chemical elements, and simultaneous reproduction of these three elements are important conditions investigated in cancer research. In the present study, we focused on the epidemiological and anatomical specificities of endometrioid carcinoma, obesity (biological), fluid flow (physical) and anticancer agents (chemical) to target the specific microenvironmental elements of endometrioid carcinoma. To elucidate the individual effects of these elements on endometrioid carcinoma and to investigate the relationships between these factors, we developed an adipose tissue fragments (ATFs)-embedded cell disc under a rotational culture method to generate carcinoma-stroma interactions and to create fluid flow. ATFs and fluid flow individually or synergistically influenced proliferative cellular behavior and the morphological changes underlying endometrioid carcinoma. ATFs and fluid flow also governed the expression of extracellular signal-regulated kinase and p38 signaling synergistically or individually, depending on the endometrioid carcinoma cell type. Adipose tissue induced chemoresistance to cis-diamminedichloro-platinum (CDDP) in endometrioid cancer, but the resistance effect was abolished by fluid flow. Thus, a simple reconstructed model was established to investigate three elements of the microenvironment of endometrioid carcinoma in vitro. This culture model unequivocally demonstrated the individual and synergistic effects of the three elements on endometrioid carcinoma. This new culture model is a promising tool for elucidating the mechanisms underlying endometrioid carcinoma and for develo** further treatment strategies.

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Data availability

The data that support the findings of this study are available from the corresponding author upon reasonable request.

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Acknowledgements

We thank S. Nishimura, M. Nishida and S. Nakahara for excellent technical assistance.

Funding

This work was partially supported by grants from JSPS KAKENHI Grant Number 19K18468 (to MN) and 21K16773 (to MH).

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Authors and Affiliations

  1. Division of Pathology, Department of Pathology and Microbiology, Faculty of Medicine, Saga University, 5-1-1 Nabeshima, Saga, Saga, 849-8501, Japan

    Sayuri Morito, Megumi Nishiyama, Takehisa Sakumoto, Mariko Hashiguchi & Shigehisa Aoki

  2. Department of Urology, Faculty of Medicine, Saga University, 5-1-1 Nabeshima, Saga, 849-8501, Japan

    Maki Kawasaki

  3. Department of Chemistry and Applied Chemistry, Faculty of Science and Engineering, Saga University, 1 Honjo, Saga, 840-8502, Japan

    Takayuki Narita

  4. Education and Research Center for Community Medicine, Faculty of Medicine, Saga University, Saga, 849-8501, Japan

    Atsushi Kawaguchi

  5. Department of Pathology, Takagi Hospital, Okawa, Fukuoka, 831-8501, Japan

    Shuji Toda

Authors
  1. Sayuri Morito
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  2. Maki Kawasaki
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  3. Megumi Nishiyama
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  4. Takehisa Sakumoto
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  6. Takayuki Narita
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  7. Atsushi Kawaguchi
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  8. Shuji Toda
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  9. Shigehisa Aoki
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Contributions

SM: Investigation, Writing—Original Draft. MK Investigation, Methodology. MN, TS, MH, TN: Investigation. AK: Statistical analysis. ST: Supervision. SA: Conceptualization, Methodology, Investigation, Writing—Reviewing and Editing, Project administration.

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Correspondence to Shigehisa Aoki.

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All procedures involving human or animal materials were performed in accordance with the ethical guidelines of Saga University.

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Morito, S., Kawasaki, M., Nishiyama, M. et al. Microenvironmental elements singularity synergistically regulate the behavior and chemosensitivity of endometrioid carcinoma. Human Cell 36, 1147–1159 (2023). https://doi.org/10.1007/s13577-023-00886-7

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