Effect of in vivo loss of GDF-15 on hepatocellular carcinogenesis.
BACKGROUND
Growth/differentiation factor-15(GDF-15) is a divergent TGF-beta family member that is expressed following liver injury and carcinogen exposure. GDF-15 expression is highly associated with gastrointestinal cancer stage, size, and metastasis and has been implicated in inhibition of tumor growth and increased tumor invasiveness. The current study sought to determine the effect of GDF-15 ablation on the development of hepatocellular carcinoma (HCC) in vivo.


METHODS
Male mice genetically deleted for the gene encoding GDF-15 (Gdf15 (-/-) mice) and wild-type controls were exposed to the hepatocarcinogen diethylnitrosamine (DEN). Mice were killed at 6 months of age and their livers dissected and processed for histology. Tumor number and size relative to total liver area examined were determined.


RESULTS
At 6 months of age, tumors were identified in 16 of 20 (80%) Gdf15 (-/-) mice and 16 of 19 wild-type mice (84%). No significant difference in tumor-occupied area was observed in Gdf15 (-/-) mice versus wild-type mice. In addition, no difference in invasiveness was observed in HCC arising in Gdf15 (-/-) as compared to wild-type mice. In wild type mice strong immunohistochemical staining for GDF-15 was noted on small HCC foci, whereas a loss of GDF-15 expression was found in a number of advanced HCC tumors.


CONCLUSIONS
Although highly expressed in association with multiple gastrointestinal cancers, and lost in some advanced HCC, genetic ablation of GDF-15 has no apparent effect on HCC tumor formation rate, growth rate or invasiveness in diethylnitrosamine-induced HCC in vivo.
Zimmers
Teresa A
TA
DeWitt Daughtry Family Department of Surgery and Sylvester Comprehensive Cancer Center, University of Miami Miller School of Medicine, Miami, FL, USA.
Jin
Xiaoling
X
Gutierrez
Juan C
JC
Acosta
Cary
C
McKillop
Iain H
IH
Pierce
Robert H
RH
Koniaris
Leonidas G
LG
D000477:Alkylating Agents / Q000633:toxicity; D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology; D016207:Cytokines / Q000235:genetics / Q000378:metabolism*; D004052:Diethylnitrosamine / Q000633:toxicity; D055436:Growth Differentiation Factor 15; D007150:Immunohistochemistry; D008113:Liver Neoplasms / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology; D008114:Liver Neoplasms, Experimental / Q000139:chemically induced / Q000378:metabolism* / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008817:Mice, Mutant Strains; D009361:Neoplasm Invasiveness / Q000235:genetics / Q000473:pathology
D000477:Alkylating Agents; D016207:Cytokines; C526141:Gdf15 protein, mouse; D055436:Growth Differentiation Factor 15; D004052:Diethylnitrosamine