Progeny from irradiated colorectal cancer cells acquire an EMT-like phenotype and activate Wnt/ß-catenin pathway.

Radiotherapy remains a major approach to adjuvant therapy for patients with advanced colorectal cancer, however, the fractionation schedules frequently allow for the repopulation of surviving tumors cells, neoplastic progression, and subsequent metastasis. The aim of the present study was to analyze the transgenerational effects induced by radiation and evaluate whether it could increase the malignant features on the progeny derived from irradiated parental colorectal cancer cells, Caco-2, HT-29, and HCT-116. The progeny of these cells displayed a differential radioresistance as seen by clonogenic and caspase activation assay and had a direct correlation with survivin expression as observed by immunoblotting. Immunofluorescence showed that the most radioresistant progenies had an aberrant morphology, disturbance of the cell-cell adhesion contacts, disorganization of the actin cytoskeleton, and vimentin filaments. Only the progeny derived from intermediary radioresistant cells, HT-29, reduced the E-cadherin expression and overexpressed ß-catenin and vimentin with increased cell migration, invasion, and metalloprotease activation as seen by immunoblotting, wound healing, invasion, and metalloprotease activity assay. We also observed that this most aggressive progeny increased the Wnt/ß-catenin-dependent TCF/LEF activity and underwent an upregulation of mesenchymal markers and downregulation of E-cadherin, as determined by qRT-PCR. Our results showed that the intermediate radioresistant cells can generate more aggressive cellular progeny with the EMT-like phenotype. The Wnt/ß-catenin pathway may constitute an important target for new adjuvant treatment schedules with radiotherapy, with the goal of reducing the migratory and invasive potential of the remaining cells after treatment.

Progênies derivadas de células de câncer colorretal que sobrevivem à radioterapia apresentamum aumento do potencial migratório e invasivo e desenvolvem um fenótipo EMT-like / [Progenies derived from colorectal cancer cells that survive radiation therapy show an increased migratory and invasive potential and develop an EMT-like phenotype]

A radioterapia constitui uma das principais terapias adjuvantes para o tratamento de câncer colorretal em pacientes com estadiamento avançado. Porém, o esquema de fracionamento dedoses pode permitir a repopulação de células tumorais sobreviventes ao tratamento e o reaparecimento do tumor, a progressão tumoral e a ocorrência de metástases tardias. Nesteestudo, foram analisados os efeitos transgeneracionais induzidos pela radioterapia na progênie derivadas de células de câncer colorretal sobreviventes ao tratamento e avaliado o quanto a radiação poderia induzir um fenótipo mais agressivo nessas progênies. Os resultados mostraram que essas células apresentam uma radiorresistência diferencial entre si, e que as células mais radiorresistentes formam progênies com aumento da expressão da proteína survivina, aquisição de uma morfologia aberrante, desorganização das junções celulares e do citoesqueleto de actina. Também foi observado que a progênie derivada de células HT-29 sobreviventes à radiação apresentam um aumento do potencial migratório invasivo, bem como um aumento da atividade de TCF-LEF, seguido do aumento da expressão demarcadores mesenquimais e redução de E-caderina...

Radiotherapy remains a major approach to adjuvant therapy for patients with advanced colorectal cancer. However, radiotherapy fractionation schedules frequently allow for the repopulation of surviving tumors cells and tumor recurrence, neoplastic progression andsubsequent metastasis. In this study, we analyzed the transgenerational effects induced by radiation on the progeny derived from irradiated parental cells of colorectal cancer andevaluated whether the radiation could increase the malignant features of radiotherapysurvivors cells. Our results showed that these cells displayed a differential radioresistance andthat the most radioresistant progeny had a direct correlation with increased survivin expression, acquisition of an aberrant morphology, disturbance of the cell-cell adhesion contacts and actin cytoskeleton disorganization. We also observed that the progeny that werederived from irradiated HT-29 cells displayed an increased migratory and invasiveness potential as well as increased Wnt/β-catenin-dependent TCF/LEF activity followed by anupregulation of mesenchymal markers and downregulation of E-cadherin...