RESUMO
Pancreatic cancer has the lowest survival rate out of all types of cancer. Pancreatic cancer patients are often diagnosed at advanced stages, hence an urgent need for a better therapeutic development of this devastating disease. Receptor for hyaluronan-mediated motility (RHAMM), not expressed in adult normal pancreas, has been suggested as a prognostic factor and a potential therapeutic target for pancreatic ductal adenocarcinoma (PDAC) and pancreatic neuroendocrine tumor (PNET). In this study, we initially sought to determine whether genetic deletion of RHAMM would slow down pancreatic cancer progression using Rhamm-/- mice. However, we found that Rhamm-/- mice expressed a truncated HMMRΔexon8-16 protein at higher abundance levels than wild-type RHAMM. While HMMRΔexon8-16 did not enable malignant progression of pancreatic intraepithelial neoplasia in p48-Cre; LSL-KRASG12D mice, it accelerated the formation of invasive PDAC and shortened the survival of p48-Cre; LSL-KRASG12D mice with heterozygous p53 knockout. KrasG12D PDAC mice with homozygous p53 knockout mice died around 10 weeks, and the effect of HMMRΔexon8-16 was not apparent in these short lifespan mice. In addition, HMMRΔexon8-16 shortened the survival of PNET-bearing RIP-Tag mice, which had inactivated p53. In our analysis of TCGA dataset, pancreatic cancer patients with mutant TP53 or loss of one copy of TP53 had higher RHAMM expression, which, combined, predicted worse outcomes. Taken together, by collaborating with dysfunctional p53, high levels of HMMRΔexon8-16 , which lacks the centrosome targeting domain and degrons for interaction with the Anaphase-Promoting Complex (APC), accelerated pancreatic cancer progression.
Assuntos
Proteínas da Matriz Extracelular/genética , Receptores de Hialuronatos/genética , Neoplasias Pancreáticas/genética , Proteína Supressora de Tumor p53/genética , Animais , Progressão da Doença , Feminino , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Ductos Pancreáticos/patologia , Neoplasias Pancreáticas/patologiaRESUMO
Pancreatic neuroendocrine tumors (PNETs) are the second most common primary pancreatic neoplasms after pancreatic ductal adenocarcinoma. PNETs present with widely various clinical manifestation and unfavorable survival rate. The recent advances in next generation sequencing have significantly increased our understanding of the molecular landscape of PNETs and help guide the development of targeted therapies. This review intends to outline a holistic picture of the tumors by discussing current understanding of clinical presentations, up-to-date treatment strategies, novel mouse models, and molecular biology of PNETs. Furthermore, we will provide insight into the future development of more effective targeted therapies that are necessary to manage PNETs.