Article ; Online: Murine pancreatic adenocarcinoma dampens SHIP-1 expression and alters MDSC homeostasis and function.
PloS one
2011 Volume 6, Issue 11, Page(s) e27729
Abstract: ... We hypothesize that factors from murine pancreatic cancer cells cause the down-regulation of SHIP-1 expression ... Therefore, we sought to determine the role of SHIP-1 in solid tumor progression, such as murine pancreatic ... in splenocytes from TB mice. In vitro, qRT-PCR and Western blot analyses detected reduced SHIP-1 mRNA and protein ...
| 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. Methodology and principal findings: 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. Conclusion/significance: 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. |
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| MeSH term(s) | Adenocarcinoma/complications ; Adenocarcinoma/enzymology ; Adenocarcinoma/genetics ; Adenocarcinoma/pathology ; Animals ; Cell Line, Tumor ; Cell Survival ; Coculture Techniques ; Down-Regulation ; Epitopes/immunology ; Female ; Gene Expression Regulation, Neoplastic ; Homeostasis ; Inflammation Mediators/metabolism ; Inositol Polyphosphate 5-Phosphatases ; Mice ; Mice, Inbred C57BL ; Myeloid Cells/metabolism ; Myeloid Cells/pathology ; Pancreatic Neoplasms/complications ; Pancreatic Neoplasms/enzymology ; Pancreatic Neoplasms/genetics ; Pancreatic Neoplasms/pathology ; Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases ; Phosphoric Monoester Hydrolases/genetics ; Phosphoric Monoester Hydrolases/metabolism ; Proto-Oncogene Proteins c-akt/metabolism ; Proto-Oncogene Proteins c-bcl-2/metabolism ; Spleen/enzymology ; Spleen/pathology ; Splenomegaly/complications ; Splenomegaly/pathology ; T-Lymphocytes/immunology |
| Chemical Substances | Epitopes ; Inflammation Mediators ; Proto-Oncogene Proteins c-bcl-2 ; Proto-Oncogene Proteins c-akt (EC 2.7.11.1) ; Phosphoric Monoester Hydrolases (EC 3.1.3.2) ; Inositol Polyphosphate 5-Phosphatases (EC 3.1.3.56) ; Inpp5d protein, mouse (EC 3.1.3.86) ; Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases (EC 3.1.3.86) |
| Language | English |
| Publishing date | 2011-11-22 |
| Publishing country | United States |
| Document type | Journal Article ; Research Support, Non-U.S. Gov't |
| ISSN | 1932-6203 |
| ISSN (online) | 1932-6203 |
| DOI | 10.1371/journal.pone.0027729 |
| Database | MEDical Literature Analysis and Retrieval System OnLINE |
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