title: Murine pancreatic adenocarcinoma dampens SHIP-1 expression and alters MDSC homeostasis and function.
abstract: BACKGROUND
  Pancreatic cancer is one of the most aggressive cancers, with tumor-induced myeloid-derived suppressor cells (MDSC) contributing to its pathogenesis and ineffective therapies. In response to cytokine/chemokine receptor activation, src homology 2 domain-containing inositol 5'-phosphatase-1 (SHIP-1) influences phosphatidylinositol-3-kinase (PI3K) signaling events, which regulate immunohomeostasis. We hypothesize that factors from murine pancreatic cancer cells cause the down-regulation of SHIP-1 expression, which may potentially contribute to MDSC expansion, and the suppression of CD8(+) T cell immune responses. Therefore, we sought to determine the role of SHIP-1 in solid tumor progression, such as murine pancreatic cancer.
  
  
  RESULTS
  Immunocompetent C57BL/6 mice were inoculated with either murine Panc02 cells (tumor-bearing [TB] mice) or Phosphate Buffer Saline (PBS) (control mice). Cytometric Bead Array (CBA) analysis of supernatants of cultured Panc02 detected pro-inflammatory cytokines such as IL-6, IL-10 and MCP-1. TB mice showed a significant increase in serum levels of pro-inflammatory factors IL-6 and MCP-1 measured by CBA. qRT-PCR and Western blot analyses revealed the in vivo down-regulation of SHIP-1 expression in splenocytes from TB mice. Western blot analyses also detected reduced SHIP-1 activity, increased AKT-1 and BAD hyper-phosphorylation and up-regulation of BCL-2 expression in splenocytes from TB mice. In vitro, qRT-PCR and Western blot analyses detected reduced SHIP-1 mRNA and protein expression in control splenocytes co-cultured with Panc02 cells. Flow cytometry results showed significant expansion of MDSC in peripheral blood and splenocytes from TB mice. AutoMACS sorted TB MDSC exhibited hyper-phosphorylation of AKT-1 and over-expression of BCL-2 detected by western blot analysis. TB MDSC significantly suppressed antigen-specific CD8(+) T cell immune responses in vitro.
  
  
  CONCLUSIONS
  SHIP-1 may regulate immune development that impacts MDSC expansion and function, contributing to pancreatic tumor progression. Thus, SHIP-1 can be a potential therapeutic target to help restore immunohomeostasis and improve therapeutic responses in patients with pancreatic cancer.
authors: Immunology Program, H. Lee Moffitt Comprehensive Cancer Center and Research Institute, Tampa, Florida, United States of America.
authors: Shari
authors: S
authors: Pilon-Thomas
authors: Nadine
authors: N
authors: Nelson
authors: Nasreen
authors: N
authors: Vohra
authors: Maya
authors: M
authors: Jerald
authors: Laura
authors: L
authors: Pendleton
authors: Karoly
authors: K
authors: Szekeres
authors: Tomar
authors: T
authors: Ghansah
mesh_terms: D000230:Adenocarcinoma / Q000150:complications / Q000201:enzymology* / Q000235:genetics / Q000473:pathology*; D000818:Animals; D045744:Cell Line, Tumor; D002470:Cell Survival; D018920:Coculture Techniques; D015536:Down-Regulation; D000939:Epitopes / Q000276:immunology; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006706:Homeostasis; D018836:Inflammation Mediators / Q000378:metabolism; D000072181:Inositol Polyphosphate 5-Phosphatases; D051379:Mice; D008810:Mice, Inbred C57BL; D022423:Myeloid Cells / Q000378:metabolism / Q000473:pathology*; D010190:Pancreatic Neoplasms / Q000150:complications / Q000201:enzymology* / Q000235:genetics / Q000473:pathology*; D000072183:Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases; D010744:Phosphoric Monoester Hydrolases / Q000235:genetics / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D013154:Spleen / Q000201:enzymology / Q000473:pathology; D013163:Splenomegaly / Q000150:complications / Q000473:pathology; D013601:T-Lymphocytes / Q000276:immunology
chemical_list: D000939:Epitopes; D018836:Inflammation Mediators; D019253:Proto-Oncogene Proteins c-bcl-2; D051057:Proto-Oncogene Proteins c-akt; D010744:Phosphoric Monoester Hydrolases; D000072181:Inositol Polyphosphate 5-Phosphatases; C000606433:Inpp5d protein, mouse; D000072183:Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases