Publicação
Effects of chemotherapy and radiotherapy in rectal cancer : significance of different cellular outcomes in tumor behavior
| Resumo: | Rectal cancers comprise 35% of all diagnosed colorectal cancers (CRC), being the third most common among gastrointestinal cancers. Despite the benefits of neoadjuvant chemoradiotherapy (CRT), 5-fluorouracil (5-FU)-based regimens plus radiotherapy (RT), 15-20% of patients suffer from relapse. Pathological staging remains the most important prognostic factor in rectal cancer and the search for new prognostic and predictive biomarkers is fundamental. DNA damaging agents and ionizing radiation used in the therapy of human cancers may induce senescence of cancer cells. Senescent cells exhibit a secretory phenotype that can affect cancer cell behavior and, eventually, clinical prognosis. In this work we hypothesize that neoadjuvant CRT-induced cellular senescence may affect rectal cancer relapse. To experimentally test our hypothesis, we cultured colon cancer cells induced into senescence by exposure to 5-FU or doxorubicin. SAS-media were enriched in IL-8, TGF-α, VEGF, cystatin C, LCN2, MIF, EMMPRIN, and uPAR, and exerts a positive effect on the proliferation of cycling colon and rectal cancer cells. SAS-medium was capable of paracrine induction of epithelial-to-mesenchymal (EMT) transition in colon and rectal cancer cell lines, of increased cell invasion in vitro, and of increased chemosensitivity to 5-FU. Moreover, we found that in rectal cancer samples from patients treated with neoadjuvant CRT tumor cell niches enriched for senescent cells bookmark regions of increased expression of EMT-related genes (slug, snail, vimentin) when compared to nearby senescent-null control regions. We provide evidences that therapy-induced senescent cancer cells influence the tumor microenvironment by promoting EMT via short range interactions. Next, to relate neoadjuvant CRT-induced cellular senescence with rectal cancer relapse, we retrospectively studied rectal cancers from 35 patients treated with neoadjuvant therapy. Data showed no correlation between the senescence markers p16INK4a and p21WAF1 and relapse, and it was not possible to validate a method for senescence detection in formalin-fixed and paraffin-embedded (FFPE) samples. Altogether, our findings showed that secretomes from senescent colon cancer cells may induce effects with opposite prognostic value. Prospective studies shall clarify whether, after neoadjuvant therapy, the presence of senescent cells add prognostic power on cancer recurrence and patient survival. |
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| Autores principais: | Costa, Joana Maria Tato Ribeiro da, 1983- |
| Assunto: | Senescência celular induzida pela terapia Cancro do reto Quimioterapia neoadjuvante Secretoma associado à senescência 5-fluorouracil Teses de doutoramento - 2015 |
| Ano: | 2015 |
| País: | Portugal |
| Tipo de documento: | tese de doutoramento |
| Tipo de acesso: | acesso aberto |
| Instituição associada: | Universidade de Lisboa |
| Idioma: | inglês |
| Origem: | Repositório da Universidade de Lisboa |
| Resumo: | Rectal cancers comprise 35% of all diagnosed colorectal cancers (CRC), being the third most common among gastrointestinal cancers. Despite the benefits of neoadjuvant chemoradiotherapy (CRT), 5-fluorouracil (5-FU)-based regimens plus radiotherapy (RT), 15-20% of patients suffer from relapse. Pathological staging remains the most important prognostic factor in rectal cancer and the search for new prognostic and predictive biomarkers is fundamental. DNA damaging agents and ionizing radiation used in the therapy of human cancers may induce senescence of cancer cells. Senescent cells exhibit a secretory phenotype that can affect cancer cell behavior and, eventually, clinical prognosis. In this work we hypothesize that neoadjuvant CRT-induced cellular senescence may affect rectal cancer relapse. To experimentally test our hypothesis, we cultured colon cancer cells induced into senescence by exposure to 5-FU or doxorubicin. SAS-media were enriched in IL-8, TGF-α, VEGF, cystatin C, LCN2, MIF, EMMPRIN, and uPAR, and exerts a positive effect on the proliferation of cycling colon and rectal cancer cells. SAS-medium was capable of paracrine induction of epithelial-to-mesenchymal (EMT) transition in colon and rectal cancer cell lines, of increased cell invasion in vitro, and of increased chemosensitivity to 5-FU. Moreover, we found that in rectal cancer samples from patients treated with neoadjuvant CRT tumor cell niches enriched for senescent cells bookmark regions of increased expression of EMT-related genes (slug, snail, vimentin) when compared to nearby senescent-null control regions. We provide evidences that therapy-induced senescent cancer cells influence the tumor microenvironment by promoting EMT via short range interactions. Next, to relate neoadjuvant CRT-induced cellular senescence with rectal cancer relapse, we retrospectively studied rectal cancers from 35 patients treated with neoadjuvant therapy. Data showed no correlation between the senescence markers p16INK4a and p21WAF1 and relapse, and it was not possible to validate a method for senescence detection in formalin-fixed and paraffin-embedded (FFPE) samples. Altogether, our findings showed that secretomes from senescent colon cancer cells may induce effects with opposite prognostic value. Prospective studies shall clarify whether, after neoadjuvant therapy, the presence of senescent cells add prognostic power on cancer recurrence and patient survival. |
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