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-1fms) to produce syngeneic TRAMPfmsmic-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-1fms and syngeneic C57BL/6 mice. Whilst TRAMPfmsmic-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-1fms 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.

Diet-induced macrophage inhibitory cytokine 1 promotes prostate cancer progression

“…Furthermore, LNCaP and C42 cell viability was significantly increased in the medium containing HFD mouse serum, and this effect was diminished by treatment with MAB957, indicating that extracellular MIC1 may be a growth enhancer in some types of PCa cells. Recent studies have shown that MIC1-overexpressing TRAMP mice exhibited significantly increased metastasis to the liver, kidney, lung, and rectum compared with normal TRAMP mice (Husaini et al 2012). In addition, intracellular and extracellular MIC1 levels were significantly higher in the metastatic PCa cells (Senapati et al 2010).…”

Circulating Levels of GDF15, MMP7 and miR-200c as a Poor Prognostic Signature in Gastric Cancer

“…This gives rise to the generation, and consequent release, of [64] and perhaps GDF15. In fact, it was recently demonstrated that the overexpression of GDF15 is able to restrict the development of prostate cancer, but promotes metastasis in mouse tumor models [65]. As seeds for metastasis, CTC released by primary tumors may also account for the production and induction of several cytokines and proteins.…”

Local and Systemic Protumorigenic Effects of Cancer-Associated Fibroblast-Derived GDF15

“…Overexpression of this factor reduces the tumorigenic potential of some cancer cells, but enhances the protumorigenic activity of other cancer cells (21,(26)(27)(28)(29)(30). Importantly, recent studies identified GDF15 as a prometastatic factor in different prostate cancer models (31,32). Together, these findings suggest that GDF15 action is highly dependent on the cellular and microenvironmental context and on experimental conditions (6,11).…”