RESUMO
Increasing evidence supports the idea that cancer cell plasticity promotes metastasis and tumor recurrence, resulting in patient mortality. While it is clear that the tumor microenvironment (TME) contributes to cancer cell plasticity, the specific TME factors most actively controlling plasticity remain largely unknown. Here, we performed a screen to identify TME cytokines and growth factors that promote epithelial-mesenchymal plasticity, and acquisition of cancer stem cell (CSC) properties. Of 28 TME cytokines and growth factors tested, we identified Oncostatin M (OSM) as the most potent inducer of mesenchymal/CSC properties. OSM-induced plasticity was Signal Transducer and Activator of Transcription 3 (STAT3)-dependent, and also required a novel intersection with transforming growth factor-ß (TGF-ß)/SMAD signaling. OSM/STAT3 activation promoted SMAD3 nuclear accumulation, DNA binding and induced SMAD3-dependent transcriptional activity. Suppression of TGF-ß receptor activity or ablation of SMAD3 or SMAD4, but not SMAD2, strongly suppressed OSM/STAT3-mediated plasticity. Moreover, removal of OSM or inhibition of STAT3 or SMAD3 resulted in a marked reversion to a non-invasive, epithelial phenotype. We propose that targeted blockade of the STAT3/SMAD3 axis in tumor cells may represent a novel therapeutic approach to prevent the plasticity required for metastatic progression and tumor recurrence.
Assuntos
Plasticidade Celular/genética , Neoplasias/patologia , Oncostatina M/fisiologia , Fator de Transcrição STAT3/metabolismo , Proteína Smad3/metabolismo , Linhagem Celular Tumoral , Plasticidade Celular/efeitos dos fármacos , Células Cultivadas , Progressão da Doença , Transição Epitelial-Mesenquimal/genética , Humanos , Metástase Neoplásica , Neoplasias/genética , Oncostatina M/genética , Oncostatina M/farmacologia , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genéticaRESUMO
Despite the progress made in targeted anticancer therapies in recent years, challenges remain. The identification of new potential targets will ensure that the arsenal of cancer therapies continues to expand. FAM83B was recently discovered in a forward genetic screen for novel oncogenes that drive human mammary epithelial cell (HMEC) transformation. We report here that elevated FAM83B expression increases Phospholipase D (PLD) activity, and that suppression of PLD1 activity prevents FAM83B-mediated transformation. The increased PLD activity is engaged by hyperactivation of epidermal growth factor receptor (EGFR), which is regulated by an interaction involving FAM83B and EGFR. Preventing the FAM83B/EGFR interaction by site-directed mutation of lysine 230 of FAM83B suppressed PLD activity and MAPK signaling. Furthermore, ablation of FAM83B expression from breast cancer cells inhibited EGFR phosphorylation and suppressed cell proliferation. We propose that understanding the mechanism of FAM83B-mediated transformation will provide a foundation for future therapies aimed at targeting its function as an intermediary in EGFR, MAPK and mTOR activation.
Assuntos
Receptores ErbB/metabolismo , Proteínas de Neoplasias/metabolismo , Oncogenes/genética , Fosfolipase D/metabolismo , Neoplasias da Mama/enzimologia , Neoplasias da Mama/genética , Neoplasias da Mama/metabolismo , Processos de Crescimento Celular/fisiologia , Linhagem Celular , Transformação Celular Neoplásica/genética , Transformação Celular Neoplásica/metabolismo , Ativação Enzimática , Células Epiteliais/metabolismo , Receptores ErbB/genética , Feminino , Humanos , Proteínas Quinases Ativadas por Mitógeno/genética , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Proteínas de Neoplasias/genética , Fosfolipase D/genética , Fosforilação , Transdução de SinaisAssuntos
Traumatismos Abdominais/diagnóstico por imagem , Traumatismos Torácicos/diagnóstico por imagem , Tomografia Computadorizada por Raios X , Ferimentos não Penetrantes/diagnóstico por imagem , Adolescente , Adulto , Idoso , Feminino , Hemoperitônio/diagnóstico por imagem , Humanos , Masculino , Pessoa de Meia-Idade , Irrigação TerapêuticaAssuntos
Colecistectomia , Adolescente , Adulto , Idoso , Antibacterianos/uso terapêutico , Criança , Pré-Escolar , Colecistectomia/mortalidade , Colecistite/cirurgia , Colelitíase/cirurgia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Complicações Pós-Operatórias , Pré-Medicação , Infecção da Ferida Cirúrgica/prevenção & controleRESUMO
Determining adequacy of mechanical ventilation is as important during CPR as in a more stable situation (such as, a patient on a ventilator in an ICU). Yet, such assessment during CPR usually only means listening for breath sounds, checking chest excursion, and blood gases. Exhaled tidal volume (VT) was measured on 45 intubated adult patients during resuscitation using a Wright's spirometer attached to a T-valve above the endotracheal tube. Ten patients had aspiration prior to intubation; 15 received advanced cardiac life support in the field, including esophageal airway insertion. CPR was performed in all cases with a mechanical compression device (Thumper). The pressure ventilator on this device was calibrated (peak inspiratory pressure, VT vs compliance) using a Dixie Test Lung, allowing indirect assessment of pulmonary compliance during CPR. Our findings suggest that lung compliance is markedly reduced within a short time after cardiac arrest. Fifty-five % of patients in this series could not be adequately oxygenated (PaO2 less than 50 torr) despite an FIO2 of 0.8 and adequate ventilation. Due to the reduced cardiac output during CPR causing venoarterial shunting, it is speculated that pulmonary edema is the most plausible explanation for this observation.
