title: Macrophage inhibitory cytokine-1 (MIC-1/GDF15) slows cancer development but increases metastases in TRAMP prostate cancer prone mice.
abstract: Macrophage inhibitory cytokine-1 (MIC-1/GDF15), a divergent member of the TGF-β superfamily, is over-expressed by many common cancers including those of the prostate (PCa) and its expression is linked to cancer outcome. We have evaluated the effect of MIC-1/GDF15 overexpression on PCa development and spread in the TRAMP transgenic model of spontaneous prostate cancer. TRAMP mice were crossed with MIC-1/GDF15 overexpressing mice (MIC-1(fms)) to produce syngeneic TRAMP(fmsmic-1) mice. Survival rate, prostate tumor size, histopathological grades and extent of distant organ metastases were compared. Metastasis of TC1-T5, an androgen independent TRAMP cell line that lacks MIC-1/GDF15 expression, was compared by injecting intravenously into MIC-1(fms) and syngeneic C57BL/6 mice. Whilst TRAMP(fmsmic-1) survived on average 7.4 weeks longer, had significantly smaller genitourinary (GU) tumors and lower PCa histopathological grades than TRAMP mice, more of these mice developed distant organ metastases. Additionally, a higher number of TC1-T5 lung tumor colonies were observed in MIC-1(fms) mice than syngeneic WT C57BL/6 mice. Our studies strongly suggest that MIC-1/GDF15 has complex actions on tumor behavior: it limits local tumor growth but may with advancing disease, promote metastases. As MIC-1/GDF15 is induced by all cancer treatments and metastasis is the major cause of cancer treatment failure and cancer deaths, these results, if applicable to humans, may have a direct impact on patient care.
authors.affiliation: St Vincent's Centre for Applied Medical Research, St Vincent's Hospital and University of New South Wales, Sydney, New South Wales, Australia.
authors.forename: Yasmin
authors.initials: Y
authors.lastname: Husaini
authors.forename: Min Ru
authors.initials: MR
authors.lastname: Qiu
authors.forename: Glen P
authors.initials: GP
authors.lastname: Lockwood
authors.forename: Xu Wei
authors.initials: XW
authors.lastname: Luo
authors.forename: Ping
authors.initials: P
authors.lastname: Shang
authors.forename: Tamara
authors.initials: T
authors.lastname: Kuffner
authors.forename: Vicky Wang-Wei
authors.initials: VW
authors.lastname: Tsai
authors.forename: Lele
authors.initials: L
authors.lastname: Jiang
authors.forename: Pamela J
authors.initials: PJ
authors.lastname: Russell
authors.forename: David A
authors.initials: DA
authors.lastname: Brown
authors.forename: Samuel N
authors.initials: SN
authors.lastname: Breit
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D004198:Disease Susceptibility; D005260:Female; D055436:Growth Differentiation Factor 15 / Q000235:genetics / Q000378:metabolism*; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D060787:Neoplasm Grading; D009362:Neoplasm Metastasis; D011471:Prostatic Neoplasms / Q000235:genetics / Q000473:pathology*; D053219:Receptors, Tumor Necrosis Factor, Member 25 / Q000235:genetics*; D016019:Survival Analysis
chemical_list: C526141:Gdf15 protein, mouse; D055436:Growth Differentiation Factor 15; D053219:Receptors, Tumor Necrosis Factor, Member 25; C506034:Tnfrsf25 protein, mouse