title: 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.affiliation: Department of Medicine and Sciences of Aging, Section of Anatomic Pathology and Molecular Medicine, "G. d'Annunzio" University, Chieti, Italy. Ce.S.I. Aging Research Center, "G. d'Annunzio" University Foundation, Chieti, Italy.
authors.forename: Emma
authors.initials: E
authors.lastname: Di Carlo
authors.affiliation: Department of Medicine and Sciences of Aging, Section of Anatomic Pathology and Molecular Medicine, "G. d'Annunzio" University, Chieti, Italy. Ce.S.I. Aging Research Center, "G. d'Annunzio" University Foundation, Chieti, Italy.
authors.forename: Carlo
authors.initials: C
authors.lastname: Sorrentino
authors.affiliation: Laboratory of Oncology, Istituto Giannina Gaslini, Genova, Italy.
authors.forename: Alessia
authors.initials: A
authors.lastname: Zorzoli
authors.affiliation: Department of Medicine and Sciences of Aging, Section of Anatomic Pathology and Molecular Medicine, "G. d'Annunzio" University, Chieti, Italy. Ce.S.I. Aging Research Center, "G. d'Annunzio" University Foundation, Chieti, Italy.
authors.forename: Serena
authors.initials: S
authors.lastname: Di Meo
authors.affiliation: Department of Medicine and Sciences of Aging, Section of Anatomic Pathology and Molecular Medicine, "G. d'Annunzio" University, Chieti, Italy. Ce.S.I. Aging Research Center, "G. d'Annunzio" University Foundation, Chieti, Italy.
authors.forename: Maria Grazia
authors.initials: MG
authors.lastname: Tupone
authors.affiliation: Animal Facility, IRCCS AOU San Martino-IST Istituto Nazionale per la Ricerca sul Cancro, Genova, Italy.
authors.forename: Emanuela
authors.initials: E
authors.lastname: Ognio
authors.affiliation: Ce.S.I. Aging Research Center, "G. d'Annunzio" University Foundation, Chieti, Italy. Department of Experimental and Clinical Sciences, "G. d'Annunzio" University, Chieti, Italy.
authors.forename: Gabriella
authors.initials: G
authors.lastname: Mincione
authors.affiliation: Laboratory of Oncology, Istituto Giannina Gaslini, Genova, Italy.
authors.forename: Irma
authors.initials: I
authors.lastname: Airoldi
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage*; D002277:Carcinoma / Q000276:immunology / Q000628:therapy*; D048708:Cell Growth Processes / Q000187:drug effects; D045744:Cell Line, Tumor; D054357:Chemokine CXCL10 / Q000235:genetics / Q000378:metabolism; D051545:Cyclooxygenase 1 / Q000235:genetics / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D007167:Immunotherapy / Q000379:methods*; D064094:Interleukin-27 / Q000008:administration & dosage*; D016246:Lymphocytes, Tumor-Infiltrating / Q000378:metabolism; D008297:Male; D051379:Mice; D008819:Mice, Nude; D008875:Middle Aged; D011471:Prostatic Neoplasms / Q000276:immunology / Q000628:therapy*; D051498:Receptor, Fibroblast Growth Factor, Type 3 / Q000235:genetics / Q000378:metabolism; D018123:Receptors, Interleukin / Q000378:metabolism; D019717:Tissue Inhibitor of Metalloproteinase-3 / Q000235:genetics / Q000378:metabolism; D040281:Vascular Endothelial Growth Factor Receptor-1 / Q000235:genetics / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: D000970:Antineoplastic Agents; D054357:Chemokine CXCL10; C112441:IL27RA protein, human; D064094:Interleukin-27; D018123:Receptors, Interleukin; D019717:Tissue Inhibitor of Metalloproteinase-3; D051545:Cyclooxygenase 1; C501162:FLT1 protein, human; D051498:Receptor, Fibroblast Growth Factor, Type 3; D040281:Vascular Endothelial Growth Factor Receptor-1