Innovative approaches to the prevention, diagnosis, and therapy of cancer: fourth joint conference of the American Association for Cancer Research (AACR) and the Japan Cancer Association (JCA).

The fourth joint conference of the AACR and Japan Cancer Association entitled “Innovative Approaches to the Prevention, Diagnosis, and Therapy of Cancer,” held February 16–21, 1998, at the Maui Marriott Resort, Maui, Hawaii, was attended by over 350 scientists from Japan and the United States. In addition, representatives from approximately 19 other countries were present. The goals of the joint conferences have been and continue to be informing scientists from both the United States and Japan on various facets of recent cancer research and stimulating potential collaborations between investigators, aimed at the ultimate solution of the cancer problem. Opening remarks were made by the co-organizers of the conference, Kaoru Abe (National Cancer Center, Tokyo, Japan) and Edward Bresnick (University of Massachusetts Medical Center, Worcester, MA). This introduction was followed by two keynote lectures. In his talk, “Cancer Control through Genetics,” Frederick Li (Dana-Farber Cancer Institute, Boston, MA) addressed the importance of studying populations at high risk for development of cancer, which could provide leads that could be pursued in humans with sporadic incidence of this disease. These types of studies have led to mutational analyses, for example, of the retinoblastoma (Rb), p53, BRCA1 and BRCA2, APC, and the DNA mismatch repair genes. He pointed out the sequential occurrence of second and third cancers in individuals who exhibit Rb and p53 mutations and, therefore, the importance of early diagnosis. The relevance to cancer research of the germ-line p53 mutations in the disease that was named after this investigator, the Li-Fraumeni syndrome, was clearly emphasized. The studies cited by Dr. Li reinforced the key role of early diagnosis through mutational analysis in any cancer prevention program. The second keynote lecture, by Tadamitsu Kishimoto (Osaka University Medical School, Osaka, Japan), entitled “Cytokines in Cancer: From the Gene to the Clinic,” summarized the recent progress in cytokine research that has led to clinical application in diverse fields. He illustrated the present understanding of cytokine-induced signaling pathways, with particular reference to his discovery of interleukin 6, a protein that evokes a response through a novel regulatory molecule, SSI-1. SSI-1 acts as a negative feedback inhibitor of the Janusactivated kinase-signal transducers and activators of transcription regulatory pathway. Functions of other cytokines, such as cardiotrophin-1, a member of the interleukin 6 family, were discussed. The importance of transgenic and knockout mouse experiments in defining the physiological function of this cytokine was emphasized. This lecture clearly demonstrated the outstanding success of research on cytokines in developing an information base that will contribute to future cancer treatment protocols. Session 1 of the conference, “Growth Factors, Cytokines, and Signal Transduction,” was cochaired by Kumao Toyoshima (Osaka Medical Center for Cancer and Cardiovascular Diseases, Osaka, Japan) and Harold Moses (Vanderbilt Cancer Center, Nashville, TN). In the first talk in this session, Frank McCormick (University of California, San Francisco, CA) discussed the clever use in cancer therapy of a unique adenoviral vector, which only replicates in cells that contain a mutated p53 and, subsequently, results in their lysis. The efficacy of this vector was initially established in the nude mouse bearing human tumor xenografts. Confirmation of the approach, i.e., effective cancer therapy, was afforded in humans by injection of the vector directly into head and neck cancers. This therapy is currently under investigation in a Phase II clinical trial. Dr. McCormick indicated additional applications of this gene therapy approach in ovarian cancer; prior animal work had shown the localization of the viral vector in peripheral tumors after i.p. administration. Both Jeffrey Wrana (Hospital for Sick Children, Toronto, Ontario, Canada) and Harold Moses discussed various phases of TGF-b signaling. This cytokine occurs as a superfamily, the members of which must dimerize, in general, to demonstrate biological activity. In addition, Dr. Wrana clearly pointed out the necessity for specific receptors in transducing the signal and for the involvement of Smad proteins as effectors. The latter have been conserved throughout evolution, which is indicative of their importance as signal transducers in normal development. Dr. Moses presented the many biological effects of TGF-b, including chemotaxis, formation of connective tissue, modulation of the immune response, and inhibition of cell proliferation in certain tissues. He also discussed the complexity of interactions between TGF-a and TGF-b in mammary tumorigenesis. Finally, he presented data on the involvement of a number of the Rho family of G proteins in the negative regulation of TGF-b-mediated transcriptional activation, which may be accomplished through an effect upon ubiquitin-facilitated proteolysis. Masabumi Shibuya (University of Tokyo, Tokyo, Japan) summarized the role of the VEGF/VEGF receptor system in tumor angiogenesis. He also reviewed the role of tumor-derived VEGF in the formation of ascites and in tumor cell growth. He indicated that GFX but not wortmannin inhibited VEGF-induced mitogen-activated protein kinase and DNA synthesis; these were unique aspects of the VEGF receptors in the tyrosine kinase-type receptors. Tadatsugu Taniguchi (University of Tokyo, Tokyo, Japan) presented studies leading to the identification of novel transcription factors, IRF-1 and IRF-2, which bind to the virus-inducible enhancer-like elements of the human IFN-b gene. By use of knockout technology, IRF-1 was shown to be responsible for the Th1-type immune response. He also discussed the role of IRF-1 in the regulation of oncogenesis and demonstrated that this transcription factor acted as a tumor suppressor in concert with p53. Session 2, “Cell Cycle Control and Transcriptional Activation,”