Tyrosine 23 Phosphorylation-Dependent Cell-Surface Localization of Annexin A2 Is Required for Invasion and Metastases of Pancreatic Cancer

The aggressiveness of pancreatic ductal adenocarcinoma (PDA) is characterized by its high metastatic potential and lack of effective therapies, which is the result of a lack of understanding of the mechanisms involved in promoting PDA metastases. We identified Annexin A2 (ANXA2), a member of the Annexin family of calcium-dependent phospholipid binding proteins, as a new molecule that promotes PDA invasion and metastases. We found ANXA2 to be a PDA-associated antigen recognized by post-treatment sera of patients who demonstrated prolonged survival following treatment with a PDA-specific vaccine. Cell surface ANXA2 increases with PDA development and progression. Knockdown of ANXA2 expression by RNA interference or blocking with anti-ANXA2 antibodies inhibits in vitro invasion of PDA cells. In addition, post-vaccination patient sera inhibits in vitro invasion of PDA cells, suggesting that therapeutic anti-ANXA2 antibodies are induced by the vaccine. Furthermore, cell-surface localization of ANXA2 is tyrosine 23 phosphorylation-dependent; and tyrosine 23 phosphorylation is required for PDA invasion. We demonstrated that tyrosine 23 phosphorylation resulting in surface expression of ANXA2 is required for TGFβ-induced, Rho-mediated epithelial-mesenchymal transition (EMT), linking the cellular function of ANXA2 which was previously shown to be associated with small GTPase-regulated cytoskeletal rearrangements, to the EMT process in PDA. Finally, using mouse PDA models, we showed that shRNA knock-down of ANXA2, a mutation at tyrosine 23, or anti-ANXA2 antibodies, inhibit PDA metastases and prolong mouse survival. Thus, ANXA2 is part of a novel molecular pathway underlying PDA metastases and a new target for development of PDA therapeutics

Combination therapies for cancer: challenges and opportunities

Abstract Background Gastrointestinal cancers represent a major challenge to public health. Pancreatic cancer is the most lethal cancer among all gastrointestinal cancers. Most patients cannot meet the criteria of resection at diagnosis, indicating these patients will have dismal prognosis. Main text Neoadjuvant chemotherapy helps some patients regain the opportunity of radical resection. An optimal regimen of chemotherapy is one that maximizes the anti-tumor efficacy while maintaining a relatively manageable safety profile. The development of surgical procedures further improves the outcomes of these patients. Conclusions Combination therapies in a multidisciplinary manner that involves modified chemotherapy regimen, radical resection, and intestine auto-transplantation may provide the currently best possible care to patients with locally advanced pancreatic cancer

Portal Venous Stenting in Locally Advanced Pancreatic Cancer to Decrease Risk of Thrombosis Before Irreversible Electroporation: A Case Report and Review of the Literature

Background: For patients with locally advanced pancreatic cancer, irreversible electroporation (IRE) is a fairly novel treatment tool that has shown promise in improving survival. However, many patients being considered for IRE have tumors adjacent to and/or encasing portal vasculature, increasing risk of postoperative portal vein thrombosis and associated complications. This report describes a successful new approach of portal venous stenting preoperatively to decrease this risk. Case Presentation: A 64-year-old female with locally advanced pancreatic cancer, initially deemed too high risk for IRE therapy because of portal vein–superior mesenteric vein confluence encasement and compression, was offered and underwent venous stenting to decrease the chance of postoperative thrombosis and related complications. Stenting improved portal venous flow, decreased collateralization, and allowed for successful IRE. At 61 days post-IRE, there was no significant tumor growth and the stent remained patent. Conclusion: Preoperative portomesenteric stenting could expand the population eligible for IRE therapy, allowing for this treatment in patients without other options. To the authors' knowledge, this is the first reported case of portal venous stenting for this purpose