It has long been a puzzle in cancer treatment that despite the initial appearance of apoptosis, the process could be reversed in some cancer cells and often results in more aggressive tumors and metastasis. The mechanism for this recurrence is yet unknown. Here we report that human mammary carcinoma cells induced to undergo apoptosis could recover with increased tumorigenicity in vitro and in vivo, and induced lymph node metastasis. Specifically, the reversed cells underwent epithelial-to-mesenchymal transitions in the primary tumors in situ, and mesenchymal-to-epithelial transitions in the metastatic cells. Flow cytometry confirmed an elevated percentage of cells carrying cancer stem cells (CSCs) markers (CD44+/CD24-) in the reversed breast cancer cell population, with hypomethylated CD44 promoters and hypermethylated CD24 promoters. More importantly, CSCs were generated anew from non-stem cancer cells after apoptosis reversal possibly through epigenetic modifications. The results from this study can open doors to discovering more effective cancer treatments by suppressing apoptosis reversal.

ObjectivesWe aimed to identify the risk factors and provide a nomogram for the prediction of radiotherapy-related esophageal fistula in patients with esophageal cancer (EC) using a case-control study.Patients and methodsPatients with esophageal fistula who received radiotherapy or chemoradiotherapy between 2003 and 2017 were retrospectively collected in two institutions. In the training cohort (TC), clinical, pathologic, and serum data of 136 patients (cases) who developed esophageal fistula during or after radiotherapy were enrolled and compared with 272 controls (1:2 matched with the diagnosis time of EC, sex, marriage, and race). After the univariable and multivariable logistic regression analyses, the independent risk factors were identified and incorporated into a nomogram. Then the nomogram for the risk prediction was externally validated in the validation cohort (VC; 47 cases and 94 controls) using bootstrap resampling.ResultsMultivariable analyses demonstrated that ECOG PS, BMI, T4, N2/3 and re-radiotherapy were independent factors for esophageal fistula. Then a nomogram was constructed with the C-index of 0.805 (95% CI, 0.762–0.848) for predicting the risk of developing esophageal fistula in EC patients receiving radiotherapy. Importantly, the C-index maintained 0.764 (95% CI, 0.683–0.845) after the external validation.ConclusionsWe created and externally validated the first risk nomogram of esophageal fistula associated with radiotherapy. This will aid individual risk stratification of patients with EC developing esophageal fistula.

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