The antitumor potential of Interleukin-27 in prostate cancer.

Abstract

Prostate cancer (PCa) is of increasing significance worldwide as a consequence of the population ageing. Fragile elderly patients may particularly benefit from noninvasive and well tolerable immunotherapeutic approaches. Preclinical studies have revealed that the immune-regulatory cytokine IL-27 may exert anti-tumor activities in a variety of tumor types without discernable toxicity. We, thus, investigated whether IL-27 may function as anti-tumor agent in human (h) PCa and analyzed the rationale for its clinical application. In vitro, IL-27 treatment significantly inhibited proliferation and reduced the angiogenic potential of hPCa cells by down-regulating the pro-angiogenesis-related genes fms-related tyrosine kinase (FLT)1, prostaglandin G/H synthase 1/cyclooxygenase-1 (PTGS1/COX-1) and fibroblast growth factor receptor (FGFR)3. In addition, IL-27 up-regulated the anti-angiogenesis-related genes such as CXCL10 and TIMP metallopeptidase inhibitor 3 (TIMP3). In vivo, IL-27 reduced proliferation and vascularization in association with ischemic necrosis of tumors developed after PC3 or DU145 cell injection in athymic nude mice. In patients' prostate tissues, IL-27R was expressed by normal epithelia and low grade PCa and lost by high tumor grade and stages. Nevertheless, IL-27R was expressed by CD11c(+), CD4(+) and CD8(+) leukocytes infiltrating the tumor and draining lymph nodes. These data lead to the conclusion that i) IL-27's anti-PCa potential may be fully exploited in patients with well-differentiated, localized IL-27R positive PCa, since in this case it may act on both cancerous epithelia and the tumor microenvironment; ii) PCa patients bearing high grade and stage tumor that lack IL-27R may benefit, however, from IL-27's immune-stimulatory properties.

• Authors: Emma Di Carlo, Carlo Sorrentino, Alessia Zorzoli, Serena Di Meo, Maria Grazia Tupone, Emanuela Ognio, Gabriella Mincione, Irma Airoldi
• Journal: Oncotarget (Oncotarget) Vol. 5 Issue 21 Pg. 10332-41 (Nov 15 2014) ISSN: 1949-2553 [Electronic] United States
• PMID: 24681516 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Antineoplastic Agents
• Chemokine CXCL10
• IL27RA protein, human
• Interleukin-27
• Receptors, Interleukin
• Tissue Inhibitor of Metalloproteinase-3
• Cyclooxygenase 1
• FLT1 protein, human
• Receptor, Fibroblast Growth Factor, Type 3
• Vascular Endothelial Growth Factor Receptor-1

Topics

• Aged
• Aged, 80 and over
• Animals
• Antineoplastic Agents (administration & dosage)
• Carcinoma (immunology, therapy)
• Cell Growth Processes (drug effects)
• Cell Line, Tumor
• Chemokine CXCL10 (genetics, metabolism)
• Cyclooxygenase 1 (genetics, metabolism)
• Gene Expression Regulation, Neoplastic (drug effects)
• Humans
• Immunotherapy (methods)
• Interleukin-27 (administration & dosage)
• Lymphocytes, Tumor-Infiltrating (metabolism)
• Male
• Mice
• Mice, Nude
• Middle Aged
• Prostatic Neoplasms (immunology, therapy)
• Receptor, Fibroblast Growth Factor, Type 3 (genetics, metabolism)
• Receptors, Interleukin (metabolism)
• Tissue Inhibitor of Metalloproteinase-3 (genetics, metabolism)
• Vascular Endothelial Growth Factor Receptor-1 (genetics, metabolism)
• Xenograft Model Antitumor Assays