Division of Pathology, Department of Pathology and Microbiology, Faculty of Medicine, Saga University, 5-1-1 Nabeshima, Saga, Saga, 849-8501, Japan.
Department of Urology, Faculty of Medicine, Saga University, 5-1-1 Nabeshima, Saga, 849-8501, Japan.
Hum Cell. 2023 May;36(3):1147-1159. doi: 10.1007/s13577-023-00886-7. Epub 2023 Feb 28.
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 developing further treatment strategies.
微环境的重要性已得到广泛认可，因为它不仅调节恶性细胞的行为，还调节药物敏感性。癌细胞微环境由生物、物理和化学元素组成，同时复制这三种元素是癌症研究中重要的调查条件。在本研究中，我们专注于子宫内膜样癌的流行病学和解剖学特异性、肥胖（生物）、流体流动（物理）和抗癌剂（化学），以针对子宫内膜样癌的特定微环境元素。为了阐明这些元素对子宫内膜样癌的个体影响，并研究这些因素之间的关系，我们开发了一种旋转培养方法下的脂肪组织碎片（ATF）嵌入细胞盘，以产生癌-基质相互作用并产生流体流动。ATF 和流体流动单独或协同影响子宫内膜样癌细胞的增殖细胞行为和形态变化。ATF 和流体流动还根据子宫内膜样癌细胞类型协同或单独调节细胞外信号调节激酶和 p38 信号的表达。脂肪组织诱导子宫内膜样癌对顺铂（CDDP）的化疗耐药，但流体流动可消除耐药作用。因此，建立了一个简单的重建模型来体外研究子宫内膜样癌微环境的三个元素。该培养模型明确证实了这三个元素对子宫内膜样癌的个体和协同作用。这种新的培养模型是阐明子宫内膜样癌机制和开发进一步治疗策略的有前途的工具。
