title: Interleukin-1β promotes skeletal colonization and progression of metastatic prostate cancer cells with neuroendocrine features.
abstract: Despite the progress made in the early detection and treatment of prostate adenocarcinoma, the metastatic lesions from this tumor are incurable. We used genome-wide expression analysis of human prostate cancer cells with different metastatic behavior in animal models to reveal that bone-tropic phenotypes upregulate three genes encoding for the cytokine interleukin-1β (IL-1β), the chemokine CXCL6 (GCP-2), and the protease inhibitor elafin (PI3). The Oncomine database revealed that these three genes are significantly upregulated in human prostate cancer versus normal tissue and correlate with Gleason scores ≥7. This correlation was further validated for IL-1β by immunodetection in prostate tissue arrays. Our study also shows that the exogenous overexpression of IL-1β in nonmetastatic cancer cells promotes their growth into large skeletal lesions in mice, whereas its knockdown significantly impairs the bone progression of highly metastatic cells. In addition, IL-1β secreted by metastatic cells induced the overexpression of COX-2 (PTGS2) in human bone mesenchymal cells treated with conditioned media from bone metastatic prostate cancer cells. Finally, we inspected human tissue specimens from skeletal metastases and detected prostate cancer cells positive for both IL-1β and synaptophysin while concurrently lacking prostate-specific antigen (PSA, KLK3) expression. Collectively, these findings indicate that IL-1β supports the skeletal colonization and metastatic progression of prostate cancer cells with an acquired neuroendocrine phenotype.
authors.affiliation: Department of Pharmacology and Physiology, Pathology and Laboratory Medicine, Drexel University College of Medicine; and Kimmel Cancer Center, Philadelphia, PA 19102, USA.
authors.forename: Qingxin
authors.initials: Q
authors.lastname: Liu
authors.forename: Mike R
authors.initials: MR
authors.lastname: Russell
authors.forename: Kristina
authors.initials: K
authors.lastname: Shahriari
authors.forename: Danielle L
authors.initials: DL
authors.lastname: Jernigan
authors.forename: Mercedes I
authors.initials: MI
authors.lastname: Lioni
authors.forename: Fernando U
authors.initials: FU
authors.lastname: Garcia
authors.forename: Alessandro
authors.initials: A
authors.lastname: Fatatis
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D000818:Animals; D001859:Bone Neoplasms / Q000235:genetics / Q000378:metabolism / Q000556:secondary*; D018278:Carcinoma, Neuroendocrine / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D045744:Cell Line, Tumor; D018450:Disease Progression; D015972:Gene Expression Regulation, Neoplastic; D064593:Heterografts; D006801:Humans; D016867:Immunocompromised Host; D053583:Interleukin-1beta / Q000096:biosynthesis* / Q000235:genetics; D008297:Male; D051379:Mice; D041681:NIH 3T3 Cells; D055099:Neuroendocrine Cells / Q000378:metabolism / Q000473:pathology; D011471:Prostatic Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D020796:Receptor, Platelet-Derived Growth Factor alpha / Q000235:genetics / Q000378:metabolism; D016708:Synaptophysin / Q000096:biosynthesis; D015854:Up-Regulation
chemical_list: D053583:Interleukin-1beta; C569014:SYP protein, human; D016708:Synaptophysin; D020796:Receptor, Platelet-Derived Growth Factor alpha