RESUMO
Development of recurrent platinum resistant disease following chemotherapy presents a challenge in managing ovarian cancer. Using tumors derived from genetically defined mouse ovarian cancer cells, we investigated the stem cell properties of residual cells post-chemotherapy. Utilizing CD133 and Sca-1 as markers of candidate tumor initiating cells (TIC), we determined that the relative levels of CD133+ and Sca-1+ cells were unaltered following chemotherapy. CD133+ and Sca-1+ cells exhibited increased stem cell-related gene expression, were enriched in G0/G1-early S phase and exhibited increased tumor initiating capacity, giving rise to heterogeneous tumors. Our findings suggest that residual TICs may contribute to recurrent disease.
Assuntos
Antineoplásicos/farmacologia , Carboplatina/farmacologia , Células-Tronco Neoplásicas/efeitos dos fármacos , Células-Tronco Neoplásicas/metabolismo , Neoplasias Ovarianas/metabolismo , Neoplasias Ovarianas/patologia , Paclitaxel/farmacologia , Antígeno AC133 , Animais , Antígenos CD/genética , Antígenos CD/metabolismo , Antígenos Ly/genética , Antígenos Ly/metabolismo , Antineoplásicos/administração & dosagem , Carboplatina/administração & dosagem , Ciclo Celular , Linhagem Celular Tumoral , Proliferação de Células , Modelos Animais de Doenças , Feminino , Expressão Gênica , Glicoproteínas/genética , Glicoproteínas/metabolismo , Proteínas de Membrana/genética , Proteínas de Membrana/metabolismo , Camundongos , Neoplasias Ovarianas/tratamento farmacológico , Paclitaxel/administração & dosagem , Peptídeos/genética , Peptídeos/metabolismo , Carga Tumoral/efeitos dos fármacosRESUMO
BACKGROUND: Recent evidence links aberrant activation of Hedgehog (Hh) signaling with the pathogenesis of several cancers including medulloblastoma, basal cell, small cell lung, pancreatic, prostate and ovarian. This investigation was designed to determine if inhibition of this pathway could inhibit serous ovarian cancer growth. METHODOLOGY: We utilized an in vivo pre-clinical model of serous ovarian cancer to characterize the anti-tumor activity of Hh pathway inhibitors cyclopamine and a clinically applicable derivative, IPI-926. Primary human serous ovarian tumor tissue was used to generate tumor xenografts in mice that were subsequently treated with cyclopamine or IPI-926. PRINCIPAL FINDINGS: Both compounds demonstrated significant anti-tumor activity as single agents. When IPI-926 was used in combination with paclitaxel and carboplatinum (T/C), no synergistic effect was observed, though sustained treatment with IPI-926 after cessation of T/C continued to suppress tumor growth. Hh pathway activity was analyzed by RT-PCR to assess changes in Gli1 transcript levels. A single dose of IPI-926 inhibited mouse stromal Gli1 transcript levels at 24 hours with unchanged human intra-tumor Gli1 levels. Chronic IPI-926 therapy for 21 days, however, inhibited Hh signaling in both mouse stromal and human tumor cells. Expression data from the micro-dissected stroma in human serous ovarian tumors confirmed the presence of Gli1 transcript and a significant association between elevated Gli1 transcript levels and worsened survival. CONCLUSIONS/SIGNIFICANCE: IPI-926 treatment inhibits serous tumor growth suggesting the Hh signaling pathway contributes to the pathogenesis of ovarian cancer and may hold promise as a novel therapeutic target, especially in the maintenance setting.
Assuntos
Proteínas Hedgehog/metabolismo , Neoplasias Ovarianas/patologia , Transdução de Sinais , Ensaios Antitumorais Modelo de Xenoenxerto , Animais , Proliferação de Células/efeitos dos fármacos , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Proteínas Hedgehog/genética , Humanos , Quimioterapia de Manutenção , Camundongos , Neoplasias Císticas, Mucinosas e Serosas/tratamento farmacológico , Neoplasias Císticas, Mucinosas e Serosas/genética , Neoplasias Císticas, Mucinosas e Serosas/patologia , Neoplasias Ovarianas/tratamento farmacológico , Neoplasias Ovarianas/genética , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Transdução de Sinais/efeitos dos fármacos , Células Estromais/efeitos dos fármacos , Células Estromais/metabolismo , Células Estromais/patologia , Análise de Sobrevida , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Alcaloides de Veratrum/farmacologia , Alcaloides de Veratrum/uso terapêutico , Proteína GLI1 em Dedos de ZincoRESUMO
Pancreatic adenocarcinoma is an aggressive cancer with a greater than 95% mortality rate and short survival after diagnosis. Chemotherapeutic resistance hinders successful treatment. This resistance is often associated with mutations in codon 12 of the K-Ras gene (K-Ras 12), which is present in over 90% of all pancreatic adenocarcinomas. Codon 12 mutations maintain Ras in a constitutively active state leading to continuous cellular proliferation. Our study determined if TRAIL resistance in pancreatic adenocarcinomas with K-Ras 12 mutations could be overcome by first sensitizing the cells with Benzyl isothiocyanate (BITC). BITC is a component of cruciferous vegetables and a cell cycle inhibitor. BxPC3, MiaPaCa2 and Panc-1 human pancreatic adenocarcinoma cell lines were examined for TRAIL resistance. Our studies show BITC induced TRAIL sensitization by dual activation of both the extrinsic and intrinsic apoptotic pathways.