Kiguchi, Kaoru

Kiguchi, Kaoru M.D., Ph.D.

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Research Interests

EGF receptor, ErbB family, tumor promotion, multistage skin carcinogenesis, biliary tract cancers

Current Research

Receptor tyrosine kinases (RTKs) play a fundamental role in growth control, and alteration in regulation of RTKs may result in uncontrolled growth and oncogenic transformation. In the transgenic mice we generated, in which ErbB2 is overexpressed in the basal layer of biliary tract epithelium, gallbladder adenocarcinomas develop in 100% of the animals by 3 months of age. In addition, tumors develop in other parts of the biliary tree (e.g., cholangiocarcinoma). These adenocarcinomas arise via a stepwise process involving hyperplasia, adenoma formation, and then adenocarcinoma formation. In the United States, about 7500 new cases of biliary tract cancer (BTC) are diagnosed per year, and about 5000 of those cases are diagnosed as gallbladder cancer. Gallbladder carcinoma is an aggressive and frequently lethal cancer. Unfortunately, poor detection methods and screening have resulted in sustained high mortality rates. Our laboratory generated a novel mouse model of biliary tract cancer, in which rat erbB2 is overexpressed in the basal layer of multiple epithelia, including the biliary tract epithelium, under the control of the bovine keratin 5 (BK5) promoter. Adenocarcinoma develop rapidly in the gallbladder and cystic duct of these transgenic mice at an incidence of ~ 90% by two months of age. The gallbladder carcinoma that develop in the BK5.erbB2 mice are sufficiently similar to human gallbladder carcinoma that develop via the adenoma-carcinoma sequence to support the relevance of this animal model as a tool for studying BTC development and its treatment (Kiguchi K, et al. 2001). We have found that a number of critical signaling pathways involved in cell proliferation and survival are altered in the gallbladder of the BK5.erbB2 transgenic mice. In addition to the activation of the erbB2/EGFR and COX-2 pathways, increases in phosphorylation of Akt, MAPK and mTOR are observed in the gallbladder of transgenic mice (Kiguchi K and DiGiovanni J, 2008). During our recent studies tyrosine kinase inhibitors (TKI), including Gefitinib and GW2974 showed a potent therapeutic efficacy against gallbladder cancer in BK5.erbB2 mice (Kiguchi K, et al. 2005).

We also studied the effects of a COX-2 inhibitor, CS-706, on the development of gallbladder carcinomas using the BK5.erbB2 mouse model. Ultrasound image analysis as well as histological evaluation revealed a significant therapeutic effect of CS-706 on the gallbladder tumors either as reversion to a milder phenotype or inhibition of tumor progression. The antitumor effect was associated with inhibition of PGE2 synthesis. CS-706-based treatment also downregulated the activation of erbB2 and EGFR, resulting in decreased levels of phosphorylated Akt and COX-2 in gallbladder cancers of BK5.erbB2 mice. Based on our results, targeting COX-2 could provide a potentially new and effective therapy alone or in combination with other therapeutic agents for patients with BTC (Kiguchi K, et al. 2007).

Recently, analysis of human gallbladder tumors by immunohistochemistry revealed an increase in the level of phosphorylation of both Akt and mTOR indicating that the mechanism through which mTOR is activated in these tumors warrants further investigation. Furthermore, we have found that treatment of BK5.erbB2 mice with rapamycin, a well-known inhibitor of mTOR, was anti-tumorigenic in vivo and resulted in a decrease of phosphorylation of p70S6K, a downstream target of mTOR (Wu Q, et al. 2007).

In our current studies, we are determining the mechanisms that lead to activation of mTOR in the gallbladder tumors that develop in the BK5.erbB2 mice as well as in human gallbladder tumors. In addition, we will examine the therapeutic efficacy of selective small molecule inhibitors, including rapamycin, of these pathways either alone or in combination with each other on gallbladder cancer in BK5.erbB2 mice. In addition, we will examine the therapeutic efficacy of these inhibitors to human gallbladder cancer cell lines in vitro as well as in an in vivo orthotopic model of human gallbladder cancer.

Supported by 5 R01 CA102575-02, Pharmacia LS 2002-00006809 MM01, NIEHS Center Grant ES 07784, CA 16672, CA 099562, and the Al Njoo Fund.

Selected Publications

  1. Kiguchi K and DiGiovanni J. Molecular Epidemiology of Gallbladder and Cholangiocarcinoma: Role of Growth Factor Pathways & Signal Transduction. In: Biliary Tract and Gallbladder Neoplasms textbook, In press, 2008
  2. Kiguchi K, Ruffino L, Kawamoto T, Franco E, Kurakata S, Fujiwara K, Hanai M, Rumi M, Digiovanni J. Therapeutic effect of CS-706, a specific cyclooxygenase-2 inhibitor, on gallbladder carcinoma in BK5.ErbB-2 mice, Mol Cancer Ther, 6 (6), 1709-17, 2007
  3. Wu Q, Kiguchi K, Kawamoto T, Ajiki T, Traag J, Carbajal S, Ruffino L, Thames H, Wistuba I, Thomas M, Vasquez KM, DiGiovanni J. Therapeutic effect of rapamycin on gallbladder cancer in a transgenic mouse model, Cancer Res, 67 (8), 3794-800, 2007
  4. Kiguchi K, Ruffino L, Kawamoto T, Ajiki T, Digiovanni J. Chemopreventive and therapeutic efficacy of orally active tyrosine kinase inhibitors in a transgenic mouse model of gallbladder carcinoma, Clin Cancer Res, 11 (15), 5572-80, 2005
  5. Sano S, Chan KS, Kira M, Kataoka K, Takagi S, Tarutani M, Itami S, Kiguchi K, Yokoi M, Sugasawa K, Mori T, Hanaoka F, Takeda J, Digiovanni J. Signal transducer and activator of transcription 3 is a key regulator of keratinocyte survival and proliferation following UV irradiation, Cancer Res, 65 (13), 5720-9, 2005
  6. Kiguchi K, Carbajal S, Chan K, Beltran L, Ruffino L, Shen J, Matsumoto T, Yoshimi N, DiGiovanni J. Constitutive expression of ErbB-2 in gallbladder epithelium results in development of adenocarcinoma, Cancer Res, 61 (19), 6971-6, 2001
  7. DiGiovanni J, Bol DK, Wilker E, Beltran L, Carbajal S, Moats S, Ramirez A, Jorcano J, Kiguchi K. Constitutive expression of insulin-like growth factor-1 in epidermal basal cells of transgenic mice leads to spontaneous tumor promotion, Cancer Res, 60 (6), 1561-70, 2000
  8. DiGiovanni J, Kiguchi K, Frijhoff A, Wilker E, Bol DK, Beltran L, Moats S, Ramirez A, Jorcano J, Conti C. Deregulated expression of insulin-like growth factor 1 in prostate epithelium leads to neoplasia in transgenic mice, Proc Natl Acad Sci U S A, 97 (7), 3455-60, 2000
  9. Kiguchi K, Bol D, Carbajal S, Beltran L, Moats S, Chan K, Jorcano J, DiGiovanni J. Constitutive expression of erbB2 in epidermis of transgenic mice results in epidermal hyperproliferation and spontaneous skin tumor development, Oncogene, 19 (37), 4243-54, 2000

Contact Information


Mailing Address: P.O. Box 389, Smithville, Texas 78957
Physical Address: 1808 Park Road 1C, Smithville, Texas 78957
Phone: (512) 237-9425