title: Targeting Pancreatic Cancer Metastasis by Inhibition of Vav1, a Driver of Tumor Cell Invasion.
abstract: Pancreatic cancer, one of the most lethal forms of human cancer, is largely resistant to many conventional chemotherapeutic agents. Although many therapeutic approaches focus on tumor growth, metastasis is a primary factor contributing to lethality. Therefore, novel therapies to target metastatic invasion could prevent tumor spread and recurrence resulting from local and distant metastasis. The protein Vav1 is aberrantly expressed in more than half of pancreatic cancers. Its expression promotes activation of Rac and Cdc42 and leads to enhanced invasion and migration, as well as increased tumor cell survival and proliferation, suggesting that Vav1 could be a potent therapeutic target for pancreatic cancer. The purine analogue azathioprine, well known for its function as an anti-inflammatory compound, was recently shown to function by inhibiting Vav1 signaling in immune cells. We therefore hypothesized that azathioprine could also inhibit Vav1 in pancreatic tumor cells to reduce its proinvasive functions. Indeed, we have found that treatment of cultured pancreatic tumor cells with azathioprine inhibited Vav1-dependent invasive cell migration and matrix degradation, through inhibition of Rac and Cdc42 signaling. Furthermore, azathioprine treatment decreased metastasis in both xenograft and genetic mouse models of pancreatic cancer. Strikingly, metastasis was dramatically reduced in Vav1-expressing tumors arising from p48(Cre/+), Kras(G12D/+), p53(F/+) mice. These inhibitory effects were mediated through Vav1, as Vav1-negative cell lines and tumors were largely resistant to azathioprine treatment. These findings demonstrate that azathioprine and related compounds could be potent antimetastatic agents for Vav1-positive pancreatic tumors.
authors.affiliation: Center for Basic Research in Digestive Diseases, Division of Gastroenterology & Hepatology, Mayo Clinic, Rochester, Minnesota. Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, Minnesota.
authors.forename: Gina L
authors.initials: GL
authors.lastname: Razidlo
authors.affiliation: Center for Basic Research in Digestive Diseases, Division of Gastroenterology & Hepatology, Mayo Clinic, Rochester, Minnesota.
authors.forename: Christopher
authors.initials: C
authors.lastname: Magnine
authors.affiliation: Center for Basic Research in Digestive Diseases, Division of Gastroenterology & Hepatology, Mayo Clinic, Rochester, Minnesota.
authors.forename: Arthur C
authors.initials: AC
authors.lastname: Sletten
authors.affiliation: Mayo Graduate School, Mayo Clinic, Rochester, Minnesota.
authors.forename: Rachel M
authors.initials: RM
authors.lastname: Hurley
authors.affiliation: Schulze Center for Novel Therapeutics, Mayo Clinic, Rochester, Minnesota.
authors.forename: Luciana L
authors.initials: LL
authors.lastname: Almada
authors.affiliation: Schulze Center for Novel Therapeutics, Mayo Clinic, Rochester, Minnesota.
authors.forename: Martin E
authors.initials: ME
authors.lastname: Fernandez-Zapico
authors.affiliation: Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, Minnesota.
authors.forename: Baoan
authors.initials: B
authors.lastname: Ji
authors.affiliation: Center for Basic Research in Digestive Diseases, Division of Gastroenterology & Hepatology, Mayo Clinic, Rochester, Minnesota. Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, Minnesota. mcniven.mark@mayo.edu.
authors.forename: Mark A
authors.initials: MA
authors.lastname: McNiven
mesh_terms: D000230:Adenocarcinoma / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology*; D000818:Animals; D000970:Antineoplastic Agents / Q000627:therapeutic use*; D001379:Azathioprine / Q000627:therapeutic use*; D005260:Female; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D008822:Mice, Transgenic; D058990:Molecular Targeted Therapy / Q000379:methods; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D010190:Pancreatic Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology*; D051567:Proto-Oncogene Proteins c-vav / Q000037:antagonists & inhibitors* / Q000235:genetics; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D051567:Proto-Oncogene Proteins c-vav; C496619:Vav1 protein, mouse; D001379:Azathioprine