NAG-1/GDF-15: No Evidence for an Inhibitory Role in Colon Cancer?

Abstract

We read with interest the recent article by Baek et al1Baek S.J. Okazaki R. Lee S.H. Martinez J. Kim J.S. Yamaguchi K. Mishina Y. Martin D.W. Shoieb A. McEntee M.F. Eling T.E. Nonsteroidal anti-inflammatory drug-activated gene-1 over expression in transgenic mice suppresses intestinal neoplasia.Gastroenterology. 2006; 131: 1553-1560Abstract Full Text Full Text PDF PubMed Scopus (138) Google Scholar examining potential suppression of intestinal neoplasia in mice by overexpression of the human protein nonsteroidal anti-inflammatory drug-activated gene (NAG-1). NAG-1 is a transforming growth factor-β family member officially named growth differentiation factor-15 (GDF-15),2Hsiao E. Koniaris L.G. Zimmers T.A. Sebalt S.A. Hyun T. Lee S.-J. Growth differentiation factor-15 a new TGF-β family member regulated following liver and bile duct injury.Mol Cell Bio. 2000; 20: 3742-3751Crossref PubMed Scopus (225) Google Scholar but also termed MIC-1, PDF, PLAB, and PTGFB. Baek et al describe a reduction in AOM-induced aberrant crypt foci and colon tumors in NAG-1/GDF-15 transgenic mice versus nontransgenic littermates, along with reduced small intestine tumor number and tumor burden in ApcMin mice bearing the human NAG-1/GDF-15 transgene. They conclude that NAG-1/GDF-15 acts as a tumor suppressor to inhibit both chemically and genetically induced neoplasms in the intestinal tract. We believe the data shown do not support such a contention. Tumor suppressors classically act by inhibiting cell proliferation or promoting cell death. Baek et al do not measure cell proliferation or apoptosis, either globally in the transgenic gut or locally in neoplastic foci or tumors. Moreover, they do not describe intestinal morphometry, morphology, length, or diameter. NAG-1/GDF-15 transgenic mice overall were substantially smaller (∼20% reduction in body weight) than nontransgenic controls; therefore, one might speculate that gut length, diameter, and total cell number were correspondingly reduced in NAG-1/GDF-15 transgenic mice at baseline. Consistent with a baseline difference in cell number, Figure 3C reveals that the mucosal layer in the NAG-1/GDF-15 transgenic shown was 20% thinner than the nontransgenic control. If both the intestinal length and mucosal cell layer are reduced by 20%, then the surface area of the transgenic intestines would be reduced by ∼35%. This is almost precisely the reduction in tumor load in ApcMin mice (which appears to be 35% in the graph, although reported as 60% in the text). This interpretation suggests that the transgenic NAG-1/GDF-15 mice had a phenotype consistent with a global reduction in size as described but overall, the rate of tumor initiation and growth was the same in NAG-1/GDF-15 transgenic and nontransgenic mice. We submit, therefore, that based on the data presented, an alternative interpretation is that NAG-1/GDF-15 does not have a direct regulatory role in gastrointestinal carcinogenesis. Nonsteroidal Anti-Inflammatory Drug-Activated Gene-1 Over Expression in Transgenic Mice Suppresses Intestinal NeoplasiaGastroenterologyVol. 131Issue 5PreviewBackground & Aims: The nonsteroidal anti-inflammatory drug-activated gene (NAG-1) was identified as a proapoptotic, antitumorigenic protein in vitro, induced by many antitumorigenic and chemopreventive drugs including cyclooxygenase inhibitors. However, its antitumorigenic activity has not been elucidated in vivo. Methods: Transgenic mice were generated that ubiquitously overexpress human NAG-1 under the control of a chicken β-actin promoter (CAG). The NAG-1 transgenic mice (NAG-Tg+) were characterized, and then the antitumorigenic activity was evaluated with 2 colorectal carcinogenesis models: chemical induction with azoxymethane and genetic induction using the ApcMin+ mutation. Full-Text PDF ReplyGastroenterologyVol. 132Issue 3PreviewAs recently published in Gastroenterology,1 we reported the reduction in AOM induced aberrant cryptic foci and colon tumors as well as the reduction in intestinal polyps in ApcMin/+ mice expressing the human NAG-1/GDF-15, as compared with littermate controls. We propose that NAG-1/GDF-15 may act as a tumor suppressor based on these data and other data we have reviewed.2 For example, the expression of this protein is up-regulated by 2 tumor suppressor pathways, p53 and GSK-3β. In a Letter to the Editor, Drs Zimmers, Gutierrez, and Koniaris have questioned this conclusion. Full-Text PDF