Abstract
Hepatocellular carcinoma (HCC) occurs more frequently and aggressively in men than women, but the mechanistic basis of this gender disparity is obscure. Chronic inflammation is a major etiologic factor in HCC, so we investigated the role of cortisol in gender discrepancy in a zebrafish model of HCC. Inducible expression of oncogenic KrasV12 in hepatocytes of transgenic zebrafish resulted in accelerated liver tumor progression in males. These tumors were more heavily infiltrated with tumor-associated neutrophils (TAN) and tumor-associated macrophages (TAM) versus females, and they both showed protumor gene expression and promoted tumor progression. Interestingly, the adrenal hormone cortisol was predominantly produced in males to induce Tgfb1 expression, which functioned as an attractant for TAN and TAM. Inhibition of cortisol signaling in males, or increase of cortisol level in females, decreased or increased the numbers of TAN and TAM, respectively, accompanied by corresponding changes in protumor molecular expression. Higher levels of cortisol, TGFB1, and TAN/TAM infiltration in males were also confirmed in human pre-HCC and HCC samples, features that positively correlated in human patients. These results identify increased cortisol production and TAN/TAM infiltration as primary factors in the gender disparity of HCC development in both fish and human. Cancer Res; 77(6); 1395-407. ©2017 AACR.
Highlights
Hepatocellular carcinoma (HCC) is a gender-biased disease, as men are 3 to 5 times more likely to develop HCC than women [1, 2]
To examine whether krasV12-induced zebrafish HCC is similar in a male biased manner, 3-month-old male and female krasþ zebrafish were exposed to doxycycline for 7 days, and their state of tumor progression was examined
In male krasV12-expressing livers, oncogenic hepatocytes were densely arranged with prominent nucleolus; the typical 2-cell plate of hepatocytes observed in wildtype (WT) siblings were completely abrogated, denoting an early carcinoma status
Summary
Hepatocellular carcinoma (HCC) is a gender-biased disease, as men are 3 to 5 times more likely to develop HCC than women [1, 2]. Men generally have more aggressive HCC than women, and female patients HCC tend to survive about 2 times longer than male patients with HCC [3]. This gender bias has been attributed to the fact that men are more predisposed to known risk factors of HCC, such as high alcohol consumption and unhealthy diet [4]. The gender disparity appears to be hormone-dependent. The gender disparity in HCC seems to be mediated by immune cells
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