title: Macrophage inhibitory cytokine-1 (MIC-1/GDF15) gene deletion promotes cancer growth in TRAMP prostate cancer prone mice.
abstract: The divergent TGF-β superfamily member, macrophage inhibitory cytokine-1 (MIC-1/GDF15), is overexpressed by most cancers, including prostate cancer (PCa). Whilst its circulating levels are linked to cancer outcome, the role MIC-1/GDF15 plays in cancer development and progression is incompletely understood. To investigate its effect on PCa development and spread, we have used TRAMP prostate cancer prone mice bearing a germline deletion of MIC-1/GDF15 (TRAMPMIC-/-). On average TRAMPMIC-/- mice died about 5 weeks earlier and had larger prostatic tumors compared with TRAMP mice that were wild type for MIC-1/GDF15 (TRAMPMIC+/+). Additionally, at the time of death or ethical end point, even when adjusted for lifespan, there were no significant differences in the number of mice with metastases between the TRAMPMIC+/+ and TRAMPMIC-/- groups. However, consistent with our previous data, more than twice as many TRAMP mice overexpressing MIC-1/GDF15 (TRAMPfmsmic-1) had metastases than TRAMPMIC+/+ mice (p<0.0001). We conclude that germ line gene deletion of MIC-1/GDF15 leads to increased local tumor growth resulting in decreased survival consistent with an overall protective role for MIC-1/GDF15 in early primary tumor development. However, in advancing disease, as we have previously noted, MIC-1/GDF15 overexpression may promote local invasion and metastatic spread.
authors.affiliation: St. Vincent's Centre for Applied Medical Research, St. Vincent's Hospital and University of New South Wales, Sydney, NSW 2010, Australia.
authors.forename: Yasmin
authors.initials: Y
authors.lastname: Husaini
authors.affiliation: St. Vincent's Centre for Applied Medical Research, St. Vincent's Hospital and University of New South Wales, Sydney, NSW 2010, Australia.
authors.forename: Glen P
authors.initials: GP
authors.lastname: Lockwood
authors.affiliation: St. Vincent's Centre for Applied Medical Research, St. Vincent's Hospital and University of New South Wales, Sydney, NSW 2010, Australia.
authors.forename: Trung V
authors.initials: TV
authors.lastname: Nguyen
authors.affiliation: St. Vincent's Centre for Applied Medical Research, St. Vincent's Hospital and University of New South Wales, Sydney, NSW 2010, Australia.
authors.forename: Vicky Wang-Wei
authors.initials: VW
authors.lastname: Tsai
authors.affiliation: St. Vincent's Centre for Applied Medical Research, St. Vincent's Hospital and University of New South Wales, Sydney, NSW 2010, Australia.
authors.forename: Mohammad G
authors.initials: MG
authors.lastname: Mohammad
authors.affiliation: Australian Prostate Cancer Research Centre-Queensland, Institute of Health and Biomedical Innovation, Queensland University of Technology, Translational Research Institute, Brisbane, QLD 4102, Australia.
authors.forename: Pamela J
authors.initials: PJ
authors.lastname: Russell
authors.affiliation: St. Vincent's Centre for Applied Medical Research, St. Vincent's Hospital and University of New South Wales, Sydney, NSW 2010, Australia.
authors.forename: David A
authors.initials: DA
authors.lastname: Brown
authors.affiliation: St. Vincent's Centre for Applied Medical Research, St. Vincent's Hospital and University of New South Wales, Sydney, NSW 2010, Australia.
authors.forename: Samuel N
authors.initials: SN
authors.lastname: Breit
mesh_terms: D000818:Animals; D017353:Gene Deletion; D055436:Growth Differentiation Factor 15 / Q000172:deficiency* / Q000235:genetics / Q000378:metabolism*; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D011471:Prostatic Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology*
chemical_list: D055436:Growth Differentiation Factor 15