Objective In this study, we present a living biobank of patient-derived tumoroids from advanced colorectal cancer (CRC) patients and show examples of how these tumoroids can be used to simulate cancer behavior ex vivo and provide more evidence for tumoroids could be utilized as a predictive platform during chemotherapy to identify the chemotherapy response. Methods The tumor tissues of CRC patients were collected to isolate and culture tumoroids, and the histomorphology of tumoroids was evaluated. Further, tumoroids were treated with drugs of different chemotherapy schemes, and the drug sensitivity of tumoroids was evaluated by using CellTiter-GIo 3D cell viability assay, and the clinical efficacy was compared with that of patients. Results The tumoroids were still highly consistent with the original tumor histomorphology after continuous passage. The consistency between the drug sensitivity of tumoroids from different patients and the clinical efficacy of corresponding CRC patients was 91.18% (31/34). The drug inhibition rate of tumoroids was positively correlated with the progression free survival (PFS) of CRC patients (rs=0.412, P=0.016), while the area under the cell activity drug concentration curve of tumoroids was negatively correlated with the PFS of CRC patients (rs=–0.479, P=0.004). Conclusion This study established a biological sample bank of tumoroids for CRC patients, and suggested that tumoroids had the potential to be used as preclinical experimental models and predict the chemotherapy effect of CRC patients.
Objective To investigate whether miRNA (miR)-34a mediates oxaliplatin (OXA) resistance of colon cancer cells by inhibiting macroautophagy via the transforming growth factor (TGF)-β/Smad4 pathway. Methods miR-34a expression levels were detected in colon cancer tissues and colon cancer cell lines by quantitative real-time polymerase chain reaction (qRT-PCR). Computational search, functional luciferase assay, and Western blotting method were used to demonstrate the downstream target of miR-34a in colon cancer cells. Cell viability was measured with cell counting kit-8. Apoptosis and macroautophagy of colon cancer cells were analyzed by flow cytometry and transmission electron microscopy, and expressions of Beclin1 and LC3Ⅱ protein were detected by Western blotting method. Results Expression of miR-34a was significantly reduced while expressions of TGF-β and Smad4 mRNA were increased in colon cancer patients treated with OXA-based chemotherapy. OXA treatment also resulted in decreased miR-34a expression levels and increased TGF-β and Smad4 expression levels in both parental cells and the OXA-resistant colon cancer cells. Activation of macroautophagy contributed to OXA resistance in colon cancer cells. Expression levels of Smad4 and miR-34a in colon cancer patients had a significant inverse correlation and overexpressing miR-34a inhibited macroautophagy activation by directly targeting Smad4 through the TGF-β/Smad4 pathway. OXA-induced downregulation of miR-34a and increased drug resistance by activating macroautophagy in colon cancer cells. Conclusion miR-34a mediates OXA resistance of colon cancer by inhibiting autophagy via the TGF-β/Smad4 pathway.