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Carcinogenesis and Chemotherapy—Cancer's Continuing Core Challenges: Third Charles Heidelberger Symposium1

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Carcinogenesis and Chemotherapy—Cancer's Continuing Core Challenges: Third Charles Heidelberger Symposium1 (CANCER RESEARCH 50. 7405-7409. November 15. 1990) Meeting Report Carcinogenesis and Chemotherapy—Cancer's Continuing Core Challenges: Third Charles Heidelberger Symposium1 Dr. Charles Heidelberger (1920-1983) devoted his entire delberger was able to attend the symposium and to share working life to cancer research and made outstanding contri memories of Charlie with us. butions in the areas of cancer chemotherapy and chemical carcinogenesis. According to his words (1), these parallel threads of research are "cancer's continuing core challenges." Keynote Lecture Dr. Heidelberger was a pioneer in the development of antime- The program of 38 scientific presentations was commenced tabolic drugs for the treatment of cancer. He introduced a with a keynote lecture given by Dr. T. Sugimura (National fluorine atom into uracil to produce 5-FU,2 a standard com Cancer Center, Tokyo, Japan) on "multiple genetic alterations during carcinogenesis." Dr. Sugimura summarized the multiple ponent of long standing, used in several protocols for the treatment of human solid cancers. His contributions to chemi genetic alterations observed in human cancers, which include cal carcinogenesis include the synthesis of radioactive polycyclic point mutations, rearrangements, sequence deletions, gene am aromatic hydrocarbons in the 1940s, the binding of polycyclic plification, and integration of viral genomes. Through these alterations, activation of oncogenes and inactivation of antion- aromatic hydrocarbons to cellular macromolecules in the 1950s cogenes occur, resulting in the acquisition of malignant phe- and 1960s, and the development of mammalian cell transfor mation in vitro in the C3H/10T'/2 cell line in the 1960s and notypes. Multiple genetic alterations are commonly found in many cancers, but the patterns of alterations vary depending 1970s. on origins and histological types of the cancers, with some The symposium held at the International Conference Hall, specificities being observed. Kyoto, Japan, from December 10 to 13, 1989, was the third commemorating Charles Heidelberger's contributions to cancer research. It followed on the success of two previous symposia Session 1: Cell Differentiation organized by his former postdoctoral fellows. The first, on the Dr. Y. Nagai (University of Tokyo, Tokyo, Japan) reported role of chemicals and radiation in the etiology of cancer, was on the significance of "B-pathway" gangliosides in the regula organized by Dr. E. Huberman (Argonne National Laboratory', tion of neural cell growth and differentiation. Among B-path Argonne, IL) and was held from August 26 to 29, 1984, in way gangliosides (GD.„GD2,Gmb, GTn,, and Gyu,), GDj and Oakbrook, IL (2). The second, on transformation and differ G0ib are found to increase in association with the proliferation entiation in vitro, was organized by Dr. J. S. Bertram (Cancer of neuronal cells at the embryonic stage and also with active Research Center of Hawaii, University of Hawaii, Honolulu, gliosis. Exogenous Gylb enhances neurite outgrowth of human HI) from February 9 to 12, 1988, in Honolulu, HI (3). The neuroblastoma cell lines. His observation provides evidence purpose of the third symposium, held in Kyoto, was to discuss that GD.Iand GQib of B-pathway gangliosides are of particular in depth the two areas of research initiated and developed by- importance in relation to cell growth and differentiation in Charles Heidelberger, i.e., carcinogenesis and chemotherapy. neural tissue and possibly to its malignancy. The organizing committee' invited speakers from among Dr. Dr. P. A. Jones (University of Southern California, Los Heidelberger's former postdoctoral fellows, colleagues, and Angeles, CA) reported on the relationship between the meth- those who are extending the research he initiated. The sympo ylation and expression of the MyoDl muscle determination gene in C3H/10T'/: cells. The MyoDl gene is more methylated sium was open for a limited number (about 150) of participants. in C3H/10T'/2 cells than in myogenic derivatives. In addition, We were honored by the presence of Her Royal Highness Chulabhorn of Thailand and fortunate that Mrs. Patricia Hei- transformation results in a marked stimulation of the methyl- ation of the determination gene. The abilities of chemical Received 7/2/90; accepted 8/8/90. carcinogens to perturb DNA methylation patterns may there 'This symposium was held in Kyoto. December 10-13, 1989 at the Kyoto fore be important in silencing genes known to elicit the differ International Conference Hall, Kyoto, Japan. The Osaka Foundation for Pro motion of Fundamental Medical Research and Taiho Pharmaceutical Co., Ltd.. entiation of cells. supported its organization locally while travel of United States participants was Dr. E. Huberman (Argonne National Laboratory, Argonne, sponsored by the following organizations: Bristol-Myers Co.. Pharmaceutical Research and Development Division: The Proctor & Gamble Co.. Miami Valley IL) has been studying early biochemical events that cause Laboratories: The Upjohn Co.. Pharmaceutical Research and Development Di alterations in gene expression leading to terminal differentia vision; Sterling Drug. Inc., a subsidiary of Eastman Kodak: The National Institute tion of human promyelocytic leukemia cells, HL-60. He found of Environmental Health Sciences; The Department of Energy, Office of Health and Environmental Research; Argonne National Laboratory/The University of that a number of early events, such as subcellular translocation Chicago; and The University of Texas M. D. Anderson Science Park. and activation of PKC, phosphorylation of proteins, and mod 2The abbreviations used are: 5-FU. 5-fluorouracil; TPA. 12-O-tetradecanoyl- phorbol-13-acetate; PKC. protein kinase C: XP. xeroderma pigmentosum; G- ulation of topoisomerase II activity, may be early steps in the CSF, granulocyte colony-stimulating factor; cDNA, complementary DNA. signal transduction preceding the induction of cell differentia 3Members of the organizing committee were: Toshio Kuroki (University of tion and tumor promotion by phorbol esters. Tokyo, Tokyo, Japan), (the late) Setsuro Fuji! and Tetsuhiko Shirasaka (The Osaka Foundation for Promotion of Fundamental Medical Research, Osaka, Dr. T. Nakamura (Kyusyu University, Fukuoka, Japan) pre Japan). Toshikazu Oki (Bristol-Myers Research Institute, Ltd., Tokyo. Japan), sented data on molecular cloning of hepatocyte growth factor Shigeru Tsukagoshi (Cancer Chemotherapy Center, Japanese Foundation for and its relevance in liver regeneration. This growth factor is a Cancer Research, Tokyo. Japan), Thomas J. Slaga. (M. D. Anderson Cancer Center. Science Park, Smithville, TX), and Eliezer Huberman (Argonne National heterodimer composed of an «-chain(A/r 69,000) and a ß-chain Laboratory, Argonne. IL). (M, 34,000). Both «-and 0-chains are contained in a single 7405 Downloaded from cancerres.aacrjournals.org on September 25, 2021. © 1990 American Association for Cancer Research. MEETING REPORT open reading frame coding a protein with 728 amino acids, ylation in tumor promotion which can be regulated by the from which the mature heterodimer structure is derived by balance of protein kinases and protein phosphatases. proteolytic cleavage. Its mRNA was detected in nonparenchy- Dr. T. Kuroki (University of Tokyo, Tokyo, Japan) described mal cells of injured liver, suggesting paracrine action of hepa- his work on the purification and characterization of target tocyte growth factor. proteins of PKC in tumor promotion systems in vivo and in cell Cadherin-mediated cell adhesion in normal and transformed culture. In mouse skin in vivo and keratinocytes in culture, M, cells was reported by Dr. M. Takeichi (Kyoto University, Kyoto, 34,000 and M, 40,000 proteins (p34 and p40) are phosphory- Japan). Cadherins, a family of transmembrane glycoproteins lated by PKC at the serine residue. p40 was identified as creatine responsible for Ca2+-dependent intercellular adhesion, were phosphokinase B. It was found, also, that papillomas and discovered and cloned by Takeichi and his colleagues. The carcinomas of mouse skin overexpress "secondary" response amino-terminal 113-amino acid region of the extracellular do genes which are induced 4 h or more after TPA treatment (e.g., main of the molecule is important in determining the specific metallothionein, osteopontin, and urokinase), while the early ities. The intracellular domain is anchored to the cytoskeleton. responding nuclear oncogenes in these tumors remain at low The finding that tumor cell lines with greater metastatic activity levels similar to those in normal skin. express smaller amounts of cadherin suggests possible involve Dr. G. T. Bowden (University of Arizona, Tucson, AZ) ment of cadherins in metastasis. reported on differential gene expression in multistage carcino genesis. Using differential and subtractive hybridization of cDNA libraries he was able to identify five cellular genes that Session 2: Tumor Promotion/Gene Expression are overexpressed at different stages of mouse skin carcinogen TPA, an example of phorbol ester tumor promoters, activates esis. One of these genes, called transin or stromelysin encodes PKC and is known to induce expression of the nuclear onco- a secreted, metalloproteinase which may degrade proteins of genes c-fos and c-jun, the products of which cooperate in the the basement membrane and may play a functional role in transcription of many TPA-inducible genes. It is therefore malignant tumor cell invasion. A similar gene, matrix
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