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Partial hepatectomy is a promoter of hepatocarcinogenesis in C57BL/6J male mice but not in C3H/HeJ male mice
1Department of Anatomy and Cell Biology Box 439, Medical Center, University of Virgima, Charlottesville, Virgima 22908
2McArdle Laboratory for Cancer Research, University of Wisconsin Madison. WI 53706, USA
3To whom reprint requests should be addressed
We have shown previously that the difference between C57BL/6J and C3W/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 preneoplastk liver lesions to the physiobgic 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 µmol 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 glucose4phosphatase (G6Pase)-deflcient 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 C3H/HeJ male mice grew more slowly than in the C3W/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 opwated C57BL/6J male mice. The partial hepatectorny did not have any long term effect on the growth rate of the G6Pase-deficient foci in the C37BL/6J 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 -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 tiver tumors in C3H/HeJ male mice relative to sham operated mice. These data demonstrate that partial hepatectomy can act as a promoter of hepate carcinogenesis 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.
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