ABSTRACT
BACKGROUND: Activation of embryonic signaling pathways quiescent in the adult pancreas is a feature of pancreatic cancer (PC). These discoveries have led to the development of novel inhibitors of pathways such as Notch and Hedgehog signaling that are currently in early phase clinical trials in the treatment of several cancer types. Retinoid signaling is also essential for pancreatic development, and retinoid therapy is used successfully in other malignancies such as leukemia, but little is known concerning retinoid signaling in PC. METHODOLOGY/PRINCIPAL FINDINGS: We investigated the role of retinoid signaling in vitro and in vivo in normal pancreas, pancreatic injury, regeneration and cancer. Retinoid signaling is active in occasional cells in the adult pancreas but is markedly augmented throughout the parenchyma during injury and regeneration. Both chemically induced and genetically engineered mouse models of PC exhibit a lack of retinoid signaling activity compared to normal pancreas. As a consequence, we investigated Cellular Retinoid Binding Protein 1 (CRBP1), a key regulator of retinoid signaling known to play a role in breast cancer development, as a potential therapeutic target. Loss, or significant downregulation of CRBP1 was present in 70% of human PC, and was evident in the very earliest precursor lesions (PanIN-1A). However, in vitro gain and loss of function studies and CRBP1 knockout mice suggested that loss of CRBP1 expression alone was not sufficient to induce carcinogenesis or to alter PC sensitivity to retinoid based therapies. CONCLUSIONS/SIGNIFICANCE: In conclusion, retinoid signalling appears to play a role in pancreatic regeneration and carcinogenesis, but unlike breast cancer, it is not mediated directly by CRBP1.
Subject(s)
Pancreas/pathology , Pancreas/physiopathology , Pancreatic Neoplasms/metabolism , Pancreatic Neoplasms/pathology , Regeneration , Retinoids/metabolism , Signal Transduction , 9,10-Dimethyl-1,2-benzanthracene , Aging/pathology , Animals , Cell Line, Tumor , DNA Methylation/genetics , Disease Models, Animal , Gene Expression Regulation, Neoplastic , Humans , Mice , Pancreatic Neoplasms/genetics , Pancreatic Neoplasms/physiopathology , RNA, Messenger/genetics , RNA, Messenger/metabolism , Regeneration/genetics , Response Elements/genetics , Retinol-Binding Proteins/genetics , Retinol-Binding Proteins/metabolism , Signal Transduction/genetics , Staining and LabelingABSTRACT
The microtubule-depolymerizing drug, vincristine, is effective in the treatment of acute lymphoblastic leukemia (ALL). Although vincristine resistance mechanisms have been extensively characterized in cell lines, their clinical relevance is poorly understood. The aim of the current study was to define clinically relevant mechanisms of vincristine resistance in a panel of childhood ALL xenografts established in immune-deficient (nonobese diabetic/severe combined immunodeficient) mice. We also studied two independent xenograft sublines that were selected by in vivo vincristine exposure. In vitro vincristine sensitivity determined by a stromal coculture, murine bone marrow stromal cell line (MS-5), assay, but not methyl-thiazolyl-tetrazolium metabolic activity assay, significantly correlated (P = 0.05) with the length of the patients' first remission. Investigations into mechanisms of resistance revealed no association with steady-state vincristine accumulation or increased activity and/or expression of ATP-binding cassette transporters, although increased intracellular levels of polymerized tubulin significantly correlated with resistance (r = 0.85; P = 0.0019). Two xenograft sublines selected by in vivo vincristine exposure exhibited a 2-fold increase in polymerized tubulin levels compared with the parental subline (P < 0.05), reflecting their in vivo vincristine resistance. In this study, a vincristine-resistant xenograft with high levels of polymerized tubulin was relatively sensitive to the microtubule-polymerizing drug paclitaxel. These results indicate that the balance between polymerized and nonpolymerized tubulin may be an important determinant of response to Vinca alkaloid-based chemotherapy regimens in childhood ALL.
