CRIPTO and its signaling partner GRP78 drive the metastatic phenotype in human osteotropic prostate cancer

CRIPTO (CR-1, TDGF1) is a cell surface/secreted oncoprotein actively involved in development and cancer. Here, we report that high expression of CRIPTO correlates with poor survival in stratified risk groups of prostate cancer (PCa) patients. CRIPTO and its signaling partner glucose-regulated protein 78 (GRP78) are highly expressed in PCa metastases and display higher levels in the metastatic ALDHhigh sub-population of PC-3M-Pro4Luc2 PCa cells compared with non-metastatic ALDHlow. Coculture of the osteotropic PC-3M-Pro4Luc2 PCa cells with differentiated primary human osteoblasts induced CRIPTO and GRP78 expression in cancer cells and increases the size of the ALDHhigh sub-population. Additionally, CRIPTO or GRP78 knockdown decreases proliferation, migration, clonogenicity and the size of the metastasis-initiating ALDHhigh sub-population. CRIPTO knockdown reduces the invasion of PC-3M-Pro4Luc2 cells in zebrafish and inhibits bone metastasis in a preclinical mouse model. These results highlight a functional role for CRIPTO and GRP78 in PCa metastasis and suggest that targeting CRIPTO/GRP78 signaling may have significant therapeutic potential.Oncogene advance online publication, 10 April 2017; doi:10.1038/onc.2017.87

Novel treatments for hemophilia through rebalancing of the coagulation cascade

Hemophilia A and B are inherited hemorrhagic disorders that result from alterations in the coagulation cascade. Aside from spontaneous bleeding, the main complication of hemophilia is hemarthrosis. Progress over the last three decades, specifically prophylaxis using recombinant factor, has prevented hemarthrosis and lengthened patient life expectancies. However, many treatments require frequent dosing up to three times a week, and alloantibodies (inhibitors) against replacement factor continues to be an issue. These problems call for novel treatments for patients with hemophilia. Although there has been progress in extended half‐life factors and mimetics of factor VIII, an alternative treatment methodology is to rebalance the activities of pro‐ and anticoagulant factors through inhibition of the natural anticoagulants: antithrombin, tissue factor pathway inhibitor, protein C, and protein S. This review will explore the efficacy of targeting these inhibitory pathways from preclinical development through clinical trials, and delve into concerns of thrombotic risk.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/167079/1/pbc28934.pdfhttp://deepblue.lib.umich.edu/bitstream/2027.42/167079/2/pbc28934_am.pd