Research Institute of Experimental Oncology and Biomedical Technologies, Privolzhsky Research Medical University, Nizhny Novgorod, Russia.
Faculty of Histology with Cytology and Embryology, Privolzhsky Research Medical University, Nizhny Novgorod, Russia.
Sci Rep. 2024 Nov 20;14(1):28762. doi: 10.1038/s41598-024-79948-1.
Resistance to chemotherapy remains the main challenge for cancer treatment. One of the mechanisms of tumor escape from cytotoxic agents could be the formation of cell-in-cell (CIC) structures, in which the outer cell protects the inner cell from unfavorable environment. Such structures have been found in many tumor types, however, their link to chemosensitivity is elusive. Here, we tested whether the CIC structures can promote resistance of colorectal cancer cells to chemotherapy. To identify CIC structures in cell cultures and in tumor xenografts, both transmission electron microscopy and confocal fluorescence microscopy of live and fixed cells as well as tissue slices and histopathology were used. Cytogenetic analysis was performed to detect chromosome instability associated with the drug resistance. It was found that in the five colorectal cancer cell lines intrinsic chemoresistance positively correlated with the ability of cells to spontaneously form CIC structures. Cultured cells treated with oxaliplatin and Irinotecan and tumor xenografts treated with FOLFOX or FOLFIRI regimens displayed an increased number of CICs after the treatment. The release of the inner cell from CIC structure was observed after removal of the drug. The number of CICs in the cell lines and tumors with acquired resistance to oxaliplatin was higher than in the drug-naive counterparts. The development of chemoresistance was also accompanied by the changes in the cell's ploidy. These preliminary data clearly demonstrate the associations of CIC structures with chemoresistance of colorectal cancer in cultured cells and tumor xenografts and show the prospect of further clinical validation of CICs as a potential prognostic marker for treatment efficiency.
化疗耐药仍然是癌症治疗的主要挑战。肿瘤逃避细胞毒性药物的机制之一可能是形成细胞-细胞（CIC）结构，其中外细胞保护内细胞免受不利环境的影响。这种结构已在许多肿瘤类型中被发现，但其与化疗敏感性的关系尚不清楚。在这里，我们测试了 CIC 结构是否可以促进结直肠癌细胞对化疗的耐药性。为了在细胞培养物和肿瘤异种移植物中鉴定 CIC 结构，我们使用透射电子显微镜和活细胞和固定细胞以及组织切片和组织病理学的共聚焦荧光显微镜进行了检测。进行细胞遗传学分析以检测与耐药性相关的染色体不稳定性。结果发现，在五种结直肠癌细胞系中，内在化疗耐药性与细胞自发形成 CIC 结构的能力呈正相关。用奥沙利铂和伊立替康处理的培养细胞和用 FOLFOX 或 FOLFIRI 方案处理的肿瘤异种移植物在治疗后显示出 CIC 数量增加。在去除药物后，从 CIC 结构中释放出内细胞。对奥沙利铂获得耐药性的细胞系和肿瘤中的 CIC 数量高于未经药物处理的对应物。化疗耐药的发展也伴随着细胞倍性的变化。这些初步数据清楚地表明 CIC 结构与培养细胞和肿瘤异种移植物中结直肠癌的化疗耐药性相关，并显示了进一步临床验证 CIC 作为治疗效率潜在预后标志物的前景。
