Partial hepatectomy is a promoter of hepatocarcinogenesis in C57BL/6J male mice but not in C3H/HeJ male mice

We have shown previously that the difference between C57BL/6J and C3H/HeJ male mice in their susceptibilities to chemically-induced liver tumors results predominantly from an allelic difference at the Hepatocarcinogen sensitivity (Hcs) locus. This locus modulates the rate of growth of preneoplastic liver lesions and may also play a role in the turnover of normal hepatocytes in the adult liver. To define further the growth regulatory pathway of which the Hcs gene is a component, we asked whether the expression of the Hcs gene would modulate the response of preneoplastic liver lesions to the physiologic growth stimulus generated by a two-thirds hepatectomy. Twelve-day-old male and female C57BL/6J and C3H/HeJ mice were injected with 0.5 mumols N-ethyl-N-nitrosourea/g body weight. At six weeks of age half the animals received a two-thirds hepatectomy. Groups of animals were killed between 14 and 44 weeks of age for analysis of glucose-6-phosphatase (G6Pase)-deficient foci and hepatic tumors. The partial hepatectomy induced a regenerative response that caused both the G6Pase-deficient foci and the surrounding, histochemically normal hepatocytes to undergo several rapid rounds of division. As a result, the G6Pase-deficient foci were larger in the hepatectomized animals than in the sham operated controls. The foci in the non-hepatectomized C57BL/6J male mice grew more slowly than in the C3H/HeJ male mice [volume doubling time (Td) = 2.9 +/- 0.1 weeks and 2.0 +/- 0.6 weeks, respectively]. Following partial hepatectomy, the G6Pase-deficient foci in the C57BL/6J male mice maintained a significantly higher growth rate (Td = 2.2 +/- 0.3 weeks) than the foci in the sham operated C57BL/6J male mice. The partial hepatectomy did not have any long term effect on the growth rate of the G6Pase-deficient foci in the C3H/HeJ male mice nor in female mice of either strain. At 32 weeks of age, the mean liver tumor multiplicity for hepatectomized C57BL/6J male mice was approximately 5.3-fold greater than that for sham operated animals. In contrast, a two-thirds hepatectomy resulted in a 60% reduction in the number of liver tumors in C3H/HeJ male mice relative to sham operated mice. These data demonstrate that partial hepatectomy can act as a promoter of hepatocarcinogenesis in C57BL/6J male mice but not C3H/HeJ male mice. We propose that the Hcs gene and partial hepatectomy may promote hepatocarcinogenesis through the same pathway of growth regulation.