Every cancer originates from a single cell. During expansion of the neoplastic cell population, individual cells acquire genetic and phenotypic differences from each other. Here, to investigate the nature and extent of intra-tumour diversification, we characterized organoids derived from multiple single cells from three colorectal cancers as well as from adjacent normal intestinal crypts. Colorectal cancer cells showed extensive mutational diversification and carried several times more somatic mutations than normal colorectal cells. Most mutations were acquired during the final dominant clonal expansion of the cancer and resulted from mutational processes that are absent from normal colorectal cells. Intra-tumour diversification of DNA methylation and transcriptome states also occurred; these alterations were cell-autonomous, stable, and followed the phylogenetic tree of each cancer. There were marked differences in responses to anticancer drugs between even closely related cells of the same tumour. The results indicate that colorectal cancer cells experience substantial increases in somatic mutation rate compared to normal colorectal cells, and that genetic diversification of each cancer is accompanied by pervasive, stable and inherited differences in the biological states of individual cancer cells.
Mortality in colorectal cancer is associated with the development of liver metastases. Surgical removal of these tumors is the only hope for cure, but recurrence is common. During liver surgery, ischemia/reperfusion (I/R) often occurs as a result of hemorrhage or vascular clamping. Although the adverse effects of I/R on postoperative liver function are well documented, the influence of I/R on the outgrowth of residual micrometastases is unknown. We used a highly standardized mouse model of partial hepatic I/R to study the effects of I/R on the outgrowth of preestablished colorectal micrometastases. Five days following intrasplenic injection of C26 colon carcinoma cells, the vascular structures of the left lobe were clamped for 45 minutes under hemodynamically stable conditions. Tissue glutathione, plasma liver enzymes, hepatocellular necrosis, and tumor growth were assessed over time. I/R caused oxidative stress and early liver tissue damage. The outgrowth of micrometastases in occluded liver lobes was accelerated five-to sixfold compared with nonoccluded lobes and was associated with areas of necrotic liver tissue surrounded by inflammatory cells and apoptotic hepatocytes. Accelerated tumor growth and tissue necrosis were completely prevented by occluding blood flow intermittently. In contrast, ischemic preconditioning or treatment with the antioxidants ␣-tocopherol or ascorbic acid failed to protect against late tissue necrosis and tumor growth, although early hepatocellular damage was largely prevented by these methods. In conclusion, I/R is a strong stimulus of recurrent intrahepatic tumor growth. Measures to prevent I/R-induced late tissue necrosis cross-protect against this phenomenon. (HEPATOLOGY 2005;42:165-175.)
Background
Although self‐expandable metal stent (SEMS) placement as bridge to surgery (BTS) in patients with left‐sided obstructing colonic cancer has shown promising short‐term results, it is used infrequently owing to uncertainty about its oncological safety. This population study compared long‐term oncological outcomes between emergency resection and SEMS placement as BTS.
Methods
Through a national collaborative research project, long‐term outcome data were collected for all patients who underwent resection for left‐sided obstructing colonic cancer between 2009 and 2016 in 75 Dutch hospitals. Patients were identified from the Dutch Colorectal Audit database. SEMS as BTS was compared with emergency resection in the curative setting after 1 : 2 propensity score matching.
Results
Some 222 patients who had a stent placed were matched to 444 who underwent emergency resection. The overall SEMS‐related perforation rate was 7·7 per cent (17 of 222). Three‐year locoregional recurrence rates after SEMS insertion and emergency resection were 11·4 and 13·6 per cent (P = 0·457), disease‐free survival rates were 58·8 and 52·6 per cent (P = 0·175), and overall survival rates were 74·0 and 68·3 per cent (P = 0·231), respectively. SEMS placement resulted in significantly fewer permanent stomas (23·9 versus 45·3 per cent; P < 0·001), especially in elderly patients (29·0 versus 57·9 per cent; P < 0·001). For patients in the SEMS group with or without perforation, 3‐year locoregional recurrence rates were 18 and 11·0 per cent (P = 0·432), disease‐free survival rates were 49 and 59·6 per cent (P = 0·717), and overall survival rates 61 and 75·1 per cent (P = 0·529), respectively.
Conclusion
Overall, SEMS as BTS seems an oncologically safe alternative to emergency resection with fewer permanent stomas. Nevertheless, the risk of SEMS‐related perforation, as well as permanent stoma, might influence shared decision‐making for individual patients.
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