Assuntos
Neoplasias Cardíacas/secundário , Leiomiossarcoma/secundário , Neoplasias Hepáticas/cirurgia , Veia Cava Inferior/cirurgia , Idoso , Feminino , Átrios do Coração , Neoplasias Cardíacas/cirurgia , Humanos , Leiomiossarcoma/cirurgia , Neoplasias Hepáticas/secundário , Imagem Multimodal , Neoplasias de Tecido Vascular/cirurgia , Trombose Venosa/etiologiaRESUMO
Epidermal growth factor receptor (EGFR) signaling has a critical role in oncogenic Kras-driven pancreatic carcinogenesis. However, the downstream targets of this signaling network are largely unknown. We developed a novel model system utilizing murine primary pancreatic ductal epithelial cells (PDECs), genetically engineered to allow time-specific expression of oncogenic Kras(G12D) from the endogenous promoter. We show that primary PDECs are susceptible to Kras(G12D)-driven transformation and form pancreatic ductal adenocarcinomas in vivo after Cdkn2a inactivation. In addition, we demonstrate that activation of Kras(G12D) induces an EGFR signaling loop to drive proliferation. Interestingly, pharmacological inhibition of EGFR fails to decrease Kras(G12D)-activated ERK or PI3K signaling. Instead our data provide novel evidence that EGFR signaling is needed to activate the oncogenic and pro-proliferative transcription factor c-MYC. EGFR and c-MYC have been shown to be essential for pancreatic carcinogenesis. Importantly, our data link both pathways and thereby explain the crucial role of EGFR for Kras(G12D)-driven carcinogenesis in the pancreas.
Assuntos
Células Epiteliais/metabolismo , Receptores ErbB/metabolismo , Ductos Pancreáticos/metabolismo , Proteínas Proto-Oncogênicas c-myc/metabolismo , Proteínas Proto-Oncogênicas p21(ras)/metabolismo , Animais , Carcinoma Ductal Pancreático/genética , Carcinoma Ductal Pancreático/metabolismo , Carcinoma Ductal Pancreático/patologia , Linhagem Celular Tumoral , Proliferação de Células/genética , Transformação Celular Neoplásica/genética , Transformação Celular Neoplásica/metabolismo , Células Cultivadas , Células Epiteliais/transplante , Receptores ErbB/genética , Perfilação da Expressão Gênica/métodos , Immunoblotting , Camundongos Endogâmicos NOD , Camundongos Knockout , Camundongos SCID , Camundongos Transgênicos , Mutação , Ductos Pancreáticos/citologia , Neoplasias Pancreáticas/genética , Neoplasias Pancreáticas/metabolismo , Neoplasias Pancreáticas/patologia , Proteínas Proto-Oncogênicas c-myc/genética , Proteínas Proto-Oncogênicas p21(ras)/genética , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Transdução de Sinais/genéticaRESUMO
This study was performed to assess the role of additional myocardial perfusion imaging during high dose dobutamine/atropine stress magnetic resonance (DSMR-wall motion) for the evaluation of patients with intermediate (50-70%) coronary artery stenosis. Routine DSMR-wall motion was combined with perfusion imaging (DSMR-perfusion) in 174 consecutive patients with chest pain syndromes who were scheduled for a clinically indicated coronary angiography. When defining CAD as the presence of a ≥ 50% stenosis, the addition of perfusion imaging improved sensitivity (90 vs. 79%, P < 0.001) with a non-significant reduction in specificity (85 vs. 90%, P = 0.13) and an improvement in overall diagnostic accuracy (88 vs. 84%, P = 0.008). Adding perfusion imaging improved sensitivity in patients with intermediate stenosis (87 vs. 72%, P = 0.03), but not in patients with severe (≥70%) stenosis (93 vs. 84%, P = 0.06). In patients with severe stenosis specificity of DSMR-perfusion versus DSMR-wall motion decreased (61 vs 70%, P = 0.001) resulting in a lower overall accuracy (71 vs 74%, P = 0.03). Using a cutoff of ≥50% for the definition of CAD, sensitivity of DSMR-perfusion compared to DSMR-wall motion was significantly higher in patients with single vessel (88 vs. 77%, P = 0.03) and multi vessel disease (93 vs. 79%, P = 0.03), whereas no significant differences were found using a cutoff of ≥70% stenosis for the definition of CAD. The addition of perfusion imaging during DSMR-wall motion improved the sensitivity in patients with intermediate coronary artery stenosis. Overall diagnostic accuracy increased only when defining CAD as ≥50% stenosis. In patients with ≥70% stenosis DSMR-wall motion alone had higher accuracy due to more false-positive cases with DSMR-perfusion.