Insulin‐independent promotion of chemically induced hepatocellular tumor development in genetically diabetic mice

Cancer Science - Tập 101 Số 1 - Trang 65-72 - 2010
Kohtaro Yamasaki1, Yoshihiro Hayashi1, Sumika Okamoto1, Makoto Osanai1, Gang‐Hong Lee2
1Department of Pathology, Kochi University School of Medicine, Nankoku, Kochi, Japan.
2Kōchi University

Tóm tắt

Diabetes mellitus has been proposed as an epidemiological risk factor for human liver cancer development. One reasonable possibility is that this is attributable to hyperinsulinemia compensatory for obesity‐related insulin resistance. However, diabetes mellitus is a complex disease with multiple abnormal conditions essentially caused by hyperglycemia. Therefore, it is not evident whether hyperinsulinemia is prerequisite for the elevated cancer risk. To gain a clue to answer this question, we characterized chemically induced hepatocarcinogenesis in diabetic model mice genetically deficient for insulin. Akita inbred mice originating from the C57BL/6 strain carry a heterozygous germline mutation of the insulin II gene and suffer from inherited insulin deficiency and diabetes in an autosomal dominant manner. They were mated with normal C3H/HeJ mice with high sensitivity to liver carcinogenesis and the resultant F1 littermates, which were either normal or insulin deficient, were exposed to diethylnitrosamine and induced hepatocellular tumors were evaluated for number, size, proliferative activity, and apoptosis. Unexpectedly, both mean and total volumes of hepatocellular tumors in the insulin‐deficient animals were more than twofold larger than those in the normal controls, with no significant difference in tumor number. The tumors in insulin‐deficient mice showed a significantly lower frequency of apoptosis but no alteration in cell proliferation. In conclusion, our results indicate that insulin‐independent liver tumor promotion occurred in diabetic mice. Clearly, insulin‐independent mechanisms for the human case also deserve consideration. (Cancer Sci 2009)

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Tài liệu tham khảo

10.1053/j.gastro.2004.09.016

10.1053/j.gastro.2004.09.017

Lawson DH, 1986, Diabetes mellitus and primary hepatocellular carcinoma, Q J Med, 61, 945

10.1053/j.gastro.2003.10.065

10.1016/j.cgh.2005.12.007

10.1089/152091501300209633

10.1001/archinte.166.17.1871

10.1097/01.cej.0000228404.37858.40

10.1158/1055-9965.EPI-08-1131

10.1358/mf.2006.28.3.985230

10.1080/13813450801969715

10.1093/aje/kwg100

10.1001/jama.293.2.194

Dombrowski F, 1997, Hepatocellular neoplasms induced by low‐number pancreatic islet transplants in streptozotocin diabetic rats, Am J Pathol, 150, 1071

10.1158/0008-5472.CAN-05-2787

10.1093/carcin/2.8.799

10.1093/carcin/5.10.1235

10.1038/221068a0

10.2337/diab.46.5.887

10.1172/JCI4431

10.1093/carcin/10.12.2227

Lee G‐H, 1991, Strain specific sensitivity to diethylnitrosamine‐induced carcinogenesis is maintained in hepatocytes of C3H/HeN ↔ C57BL/6N chimeric mice, Cancer Res, 51, 3257

Poole TM, 1995, Hormonal and genetic interactions in murine hepatocarcinogenesis, Prog Clin Biol Res, 391, 187

Lee G‐H, 1998, Mechanism of the paradoxical, inhibitory effect of phenobarbital on hepatocarcinogenesis initiated in infant B6C3F1 mice with diethylnitrosamine, Cancer Res, 58, 1665

10.1093/carcin/8.2.231

Lee G‐H, 1997, Correlation between Bcl‐2 expression and histopathology in diethylnitrosamine‐induced mouse hepatocellular tumors, Am J Pathol, 151, 957

10.1007/s004180050321

10.1006/excr.1996.0240

10.1007/978-3-642-71617-1_2

10.1093/oxfordjournals.jbchem.a021719

Atsumi T, 2002, High expression of inducible 6‐phosphofructo‐2‐kinase/fructose‐2,6‐bisphosphatase (iPFK‐2; PFKFB3) in human cancers, Cancer Res, 62, 5881

10.1038/nrc1387

10.1016/j.beem.2008.08.004

10.1038/sj.bjc.6603051

10.1002/jcp.20472

Pavelić K, 1979, Growth and treatment of Ehrlich tumor in mice with alloxan‐induced diabetes, Cancer Res, 39, 1807

10.1093/carcin/21.2.161

10.1016/j.febslet.2006.04.093

10.1210/me.2003-0357

10.1073/pnas.93.5.2198

10.1016/0006-291X(87)91503-8

10.1159/000163577

10.1016/S0168-8278(00)80369-4

10.1158/0008-5472.CAN-06-4237

10.1073/pnas.0308671100

10.1158/0008-5472.CAN-05-4102

10.1158/0008-5472.CAN-05-4679

Schiel R, 2005, Risk of malignancies in patients with insulin‐treated diabetes mellitus: results of a population‐based trial with 10‐year follow‐up (JEVIN), Eur J Med Res, 10, 339

10.1016/j.jdiacomp.2007.11.004

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Cancer Science

Tập 101 Số 1

65-72

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