Murine Pancreatic Adenocarcinoma Dampens SHIP-1 Expression and Alters MDSC Homeostasis and Function

Autor: Tomar Ghansah, Laura C. Pendleton, Karoly Szekeres, Shari Pilon-Thomas, Maya Jerald, Nasreen A. Vohra, Nadine Nelson
Rok vydání: 2011
Předmět:
Mouse
T-Lymphocytes
medicine.medical_treatment
lcsh:Medicine
Epitopes
Mice
Pancreatic tumor
Molecular Cell Biology
Basic Cancer Research
Homeostasis
Myeloid Cells
Lymphoid Organs
lcsh:Science
Apoptotic Signaling Cascade
Multidisciplinary
medicine.diagnostic_test
T Cells
Inositol Polyphosphate 5-Phosphatases
Animal Models
Signaling Cascades
Gene Expression Regulation
Neoplastic
Cytokine
medicine.anatomical_structure
Proto-Oncogene Proteins c-bcl-2
Oncology
Phosphatidylinositol-3
4
5-Trisphosphate 5-Phosphatases
Cytokines
Medicine
Female
Immunotherapy
Inflammation Mediators
Research Article
Signal Transduction
Tumor Immunology
Cell Survival
Immune Cells
T cell
Immunology
Down-Regulation
Adenocarcinoma
Biology
Immune Suppression
Flow cytometry
Immunomodulation
Pancreatic Cancer
Model Organisms
Immune system
Western blot
Cell Line
Tumor
Pancreatic cancer
Gastrointestinal Tumors
Akt Signaling Cascade
medicine
Animals
Inflammation
lcsh:R
Immunity
Immunoregulation
Cancers and Neoplasms
Immunologic Subspecialties
medicine.disease
Molecular biology
Coculture Techniques
Phosphoric Monoester Hydrolases
Mice
Inbred C57BL
Pancreatic Neoplasms
Phospholipid Signaling Cascade
Immune System
Splenomegaly
lcsh:Q
Proto-Oncogene Proteins c-akt
Spleen
CD8
Zdroj: PLoS ONE
PLoS ONE, Vol 6, Iss 11, p e27729 (2011)
ISSN: 1932-6203
DOI: 10.1371/journal.pone.0027729
Popis: 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.
Databáze: OpenAIRE
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