Trosko, James E.

About

After receiving a Ph.D. in radiation genetics, Dr. Trosko did a postdoctoral fellowship at Oak Ridge National Laboratory (1963-66) under Drs. Ernest Chu, Sheldon Wolf and Richard B. Setlow in DNA damage/repair and in vitro mutagenesis. He published the first paper showing that normal human cells could repair their UV-damaged DNA [1]. He went to Michigan State University (1966) to work on the xeroderma pigmentosum (which he & Dr. James E. Cleaver first showed that cells from these patients did not repair their UV-damaged DNA [2]), Cockaynes [3] and Blooms [4] syndromes (human genetic, sun-sensitive syndromes, predisposed to either cancer or premature aging) and to work on anti-cancer drug, cisplatin, with the late Dr. Barnett Rosenberg [5]. Later, after receiving a NCI-Career Development award, he went to work at the McArdle Laboratory for Cancer Research-University of Wisconsin on chemical carcinogenesis under the late Dr.Van R. Potter, where he discovered that the tumor promoter, TPA, was not genotoxic but inhibited gap junctional intercellular communication GJIC) [6]. After returning to MSU,  Trosko’s  lab developed 4 new in vitro assays to detect non-genotoxic chemicals that had teratogenic, tumor promoting, immuno-modulatory, neuro-, cardiovascular -and reproductive- toxic effects [7-10]. He was featured on the cover of Cancer Research as one of the investigators who linked gap junctions to the carcinogenesis process.

He coined the term, “epigenetic toxicology” [11], after showing that most of the toxic chemicals in the environment (TCDD, PBB, PCB, DDT, Dieldrin, Adrin, toxaphene, pthalates, PFOA, etc.) were (a) not genotoxic and (b) could inhibit GJIC, reversibly at non-cytotoxic concentrations.[12] Also, his lab discovered that oncogenes, such as src, ras, raf, neu,[13] could stably inhibit GJIC, while tumor suppressor genes [14], as well as multiple cancer chemo-preventive agents ( green tea components, caffeic acid ethyl ester, genistein, beta-sitosterol, resveratrol, retinoids, carotinoids, kaempherol, etc.) [15-20], and even some chemotherapeutic agents ( Lovastatin ,SAHA) [21, 22], could either prevent the inhibition of GJIC by tumor promoters or increase GJIC in tumor cells, deficient in GJIC.

All this was done based on assuming the “stem cell theory of cancer”. That led his lab to search for the few stem cells that must exist in normal tissues of cancer-generating organs. Together with Dr. Chia- Cheng Chang, they discovered, in 1986, a human adult stem cell from the kidney [23]. It was based on assuming stem cells had no functional gap junctions. Later, they discovered human breast epithelial stem cells [24, 25, 26], and other adult stem cells (pancreas, mesenchyme, liver) [27]. This led Dr. Trosko to hypothesize that the adult stem cell was the target for breast (and other cancers) and he successfully demonstrated this in his paper showing the adult human breast stem cell could be immortalized and subsequently neoplastically transformed [ 28].

In 1990-92, Dr. Trosko was Chief of Research at the Radiation Effects Research Foundation (RERF) in Hiroshima, Japan. After returning to MSU, he demonstrated that Oct4A was a biomarker for human adult stem cells and that the human adult breast stem cell was the target cell for breast neoplastic transformation and the probable origin of the human breast “cancer stem cell”.[28] He spent a sabbatical studying human prostate stem cells and the Mediterranean diet at ARNAS-Civic Cancer Institute, Palermo, Sicily [29 ] and 6 months at Seoul National University in the Human Adult Stem Cell Laboratory , where he is continuing his studies on characterizing adult human stem cells for their potential uses in drug discovery & toxicity assessment. [30]

He plans to characterize the human “cancer stem cell” for possible specific cancer targeted chemopreventive and chemotherapy [15-22, 30] in order not to harm normal adult stem cells. Moreover, he has been the pioneer in providing a new concept to provide a mechanistic explanation of the “Barker Hypothesis”, namely that events early in embryonic/fetal/neonatal development can alter the risk to chronic diseases, such as cancer , to the individual later in life , simply by altering the quantity of adult stem cells in utero [31,32]. He has been recognized as a model teacher [ one specific example is his first graduate student’s achievement, Dr. Stephen Warren, discover of the cloned Fragile X gene] and a internationally-recognized basic science cancer researcher , in the fact that  Dr. Trosko has given over 700 lectures around the world .and research mentor by awards such as the MSU-Teacher Scholar; MSU Distinguished Professor; NCI- Career Development Awardee; Sigma Xi Senior Research Scholar; Japan Society for the Promotion of Science; Korean Ministry of Science & Technology’s “Brain Pool” Awardee; and Seoul National University “World Class University Invited Professorship”.

 

REFERENCES;

1. Regan, J., J.E. Trosko, and W.L. Carrier: "Evidence for excision of ultra?
    violet-induced pyrimidine dimers from DNA of human cells in vitro". Biophysical J.
    8:319-325, 1968.
2. Cleaver, J.E. and J.E. Trosko: "Absence of excision of ultraviolet-induced cyclobutane
    dimers in Xeroderma pigmentosum". Photochem. Photobiol. 11:547-550, 1970.
3. Schmickel, R.D., E.H.Y. Chu, J.E. Trosko and C.C. Chang: "Cockayne
    syndrome: A cellular sensitivity to ultraviolet light". Pediatrics 60:135-139,
    1977.
4. Warren, S., R.A. Schultz, C.C. Chang, M.H. Wade and J.E. Trosko: "Elevated
     spontaneous mutation rate in Bloom syndrome fibroblasts". Proc. Natl. Acad.
     Science USA 78:3133?3137, 1981.
5. Rosenberg, B., L. VanCamp, J.E. Trosko and V. Mansour: "New class of
    potent anti-tumor agents". Nature 222:385-386, 1969.
6. Yotti, L.P., J.E. Trosko and C.C. Chang:  "Elimination of metabolic
    cooperation in Chinese hamster cells by a tumor promoter". Science
    206:1089-1091, 1979.
7. Trosko, J.E., L.P. Yotti, S.T. Warren and C.C. Chang: "In vitro detection of
     potential tumor promoters". In: Short-Term Tests for Prescreening of
     Potential Carcinogens, (L. Santi and S. Parodi, eds.), Instituto Scientifico
     per lo studio e la Cura dei Tumori, Genoa, 1979, pp. 45-53.
 8. Wade, M.H., J.E. Trosko and M. Schindler: A fluorescence photobleaching
      assay of gap junction mediated cell-cell communication in human cells. 
      Science 232:525-528, 1986.
9.  El-Fouly, M.H., J.E. Trosko and C.C. Chang: "Scrape-loading and dye
    transfer: A rapid and simple technique to study gap junctional intercellular
    communication”. Exp. Cell Res. 168:422-430, 1987
10. Kavanagh, T., G.M. Martin, M. El-Fouly, J.E. Trosko, C.C. Chang and P.S.
      Rabinovitch: "Flow cytometery and scrape-loading/dye transfer as a rapid
      quantitative measure of intercellular communication in vitro". Cancer Res.
     47:6046-6051, 1987.
11. Trosko, J.E., C.C. Chang, B.V. Madhukar and S.Y. Oh: "Modulators of gap
      junction function: The scientific basis of epigenetic toxicology”. In Vitro
      Toxicology 3:9-26, 1990.
12. Trosko, J.E. and C.C. Chang: "Nongenotoxic mechanisms in
      carcinogenesis: Role of inhibited intercellular communication". In: 
      Banbury Report 31: New Directions in the Qualitative and Quantitative
      Aspects of Carcinogen Risk Assessment, R. Hart and F.D. Hoerger, eds.,
      Cold Spring Harbor Press, Cold Spring Harbor, NY, pp. 139-170, 1989.
13. Trosko, J.E. and R.J. Ruch: “Cell-cell communication in carcinogenesis”. 
       Frontiers in Bioscience 3:208-236, 1998.
14. de Feijter-Rupp, H. L., T. Hayashi, G.H. Kalimi, P. Edwards, J.L. Redpath,
       C.C. Chang, E.J. Stanbridge and J.E. Trosko: “Restored gap junctional
       communication in non-tumorigenic Hela-normal human fibroblast hybrids”. 
       Carcinogenesis 19:747-754, 1998.
15. Trosko, J.E. and Ruch, R. J. “Gap junctions as targets for cancer
      chemoprevention and chemotherapy”, Current Drug Targets, 3: 465-482,
      2002.
16. Na, H.-K., M.R. Wilson, K.-S. Kang, C.C. Chang, D. Grunberger and J.E. Trosko: 
       “Restoration of gap junctional intercellular communication by caffeic acid phenethyl
       ester (CAPE) in a ras-transformed rat liver epithelial cell line”. Cancer Letters 157:
       31-38, 2000.
17. Sai, K., J. Kanno, R. Hasegawa, J.E. Trosko and T. Inoue: “Prevention of the down-
      regulation of gap junctional intercellular communication by green tea in the liver of
      mice fed pentachlorophenol”. Carcinogenesis 21: 1671-1676, 2000.
18. Nakamura, Y.,Yoshikawa, N., Hiroki,I., Sato, K., Ohtsuki,K., Chang, C.C.,   
      Upham, B.L., and Trosko. J.E. “b-Sitosterol, From Psyllium Seed Husk (Plantago  
      ovata Forsk), Restores Gap Junctional Intercellular Communication in Ha-ras
      Transfected Rat Liver Cells. Nutrition and Cancer, 5: 218-225, 2005.
19.  Sai, K., J. Kanno, R. Hasegawa, J.E. Trosko and T. Inoue: “Prevention of
       the down-regulation of gap junctional intercellular communication by green
       tea in the liver of mice fed pentachlorophenol”. Carcinogenesis 21: 1671-
       1676, 2000.
20. Upham,B.L., Guzvic, M., Scott, J., Carbone, J.M., Blaha, L., Coe, C., Li,
       L.L., Rummel, A.L. and J.E. Trosko, “Inhibition of gap junctional
       intercellular communication and activation of mitogen-activation protein
       kinase by tumor-promoting organic peroxides and protection by
       resveratrol”. Nutrition Cancer 57: 38-47, 2007.
21.  Ruch, R.J., B.V. Madhukar, J.E. Trosko and J.E. Klaunig: "Reversal of ras-
       induced inhibition of gap junctional intercellular communication,
       transformation, and tumorigenesis by lovastatin”. Mol. Carcinog. 7:50-59,
       1993.
22.  Ogawa, T., Hayashi, T., Tokunou, M., Nakachi, K., Trosko, J.E., Chang,
        C.C., and Yorioka, N., “Suberoylanilide hydroxamic acid enhances gap
        junctional intercellular communication via acetylation of histone
        containing connexin43 gene locus”. Cancer Res. 65: 9771-9778, 2005.
23.  Chang, C.C., J.E. Trosko, M.H. El-Fouly, R.E. Gibson-D'Ambrosio and S.M.
        D'Ambrosio:  "Contact insensitivity of a subpopulation of normal human
        fetal kidney epithelial cells and of human carcinoma cell lines". Cancer
        Res. 47:1634-1645, 1987.
24.  Kang, K.-S. M. Ikue, A. Cruz, Y.J. Jeon, J.E. Trosko and C.C. Chang: 
        “Expression of estrogen receptors in a normal human breast epithelial cell
         type with luminal and stem cell characteristics and its neoplastic
         transformed cell lines”. Carcinogenesis 18:251-257, 1997.
 25.  Sun, W., K.S. Kang, I. Morita, J.E. Trosko and C.C. Chang: “High
         susceptibility of a human breast epithelial cell type with stem cell
         characteristics to telomerase activation and immortalization”. Cancer Res.
         59: 6118-6123, 1999.
26.  Chang, C.C., W. Sun, A. Cruz, M. Saitoh, M.-H. Tai and J.E. Trosko: “A
       human breast epithelial cell type with stem cell characteristics as target
       cells for carcinogenesis”. Radiation Res. 155: 201-207, 2001.
 27. Trosko, J.E., C.C. Chang, M.R. Wilson, B.L. Upham, T. Hayashi and M.
        Wade:  “Gap junction and the regulation of cellular functions of stem cells
        during development and differentiation”. Methods 20: 245-264, 2000.
 28.   Tai, M.H., Chang, C.C., kiupel, M., Webster, J.D., Olson, L.K. and Trosko,
         J.E., “Oct-4 expression in adult human stem cells: evidence in support
          of the stem cell theory of carcinogenesis. Carcinogenesis 26: 495-502,
          2005.
 29.  Cocciadiferro,L., Miceli,V., Kang,K.-S., Polito, L.M., Trosko, J.E., Carruba, G.
        Profiling cancer stem cells in androgen-responsive and refractory human prostate
         tumor cell lines. Ann.N.Y. Acad Sci. 1155: 257-262, 2009.
 30.  Trosko, J. E. & Kang, K-S. The Use of Human Stem Cells for Drug Discovery,  
        Toxicity Assessment and Therapeutic Safety Concerns”. Toxicol. Sci., In press.
 31. Trosko, J.E. “Role of diet and nutrition on the alteration of the quality and
       quantity of  stem cells in human aging and the diseases of aging”. Curr
        Pharm Des. 14: 2707-  2718,2008.
 32.  Trosko, J.E. & Suzuki, K. Adult stem cells, the Barker Hypothesis , epigenetic
        events and low level radiation effects. In:  Radiatiation Health Risk
        Sciences.   M.Nakashima, N. Takamura, K. Tsukasaki, Y. Nagayama, S.
         Yamashita, eds., Springer Publisher, Tokyo, pp.216-226,  2009.