METASTASIS PROGRAM AREA REPORT
September 1977 to October 1978

Program Coordinators: Dr. Haruo Sato
Dr. Philip G. Stansly


Summary Report
The past year has seen an increased interest in metastasis research. A beginning has been made in the joint effort to study metastasis under the U.S.-Japan Cooperative Cancer Research Pro-gram, and interest among investigators has gained momentum. Investigations must be accomplished to understand the location of tumor cells, transport lodgment of micrometastatic cells, vascularization of cells and tissue, and the formation of metastatic foci.

MEETINGS, SEMINARS, AND CONFERENCES
A workshop on "Experimental Approaches to the Therapy of Micrometastasis" was held in Nara, Japan, from October 26 to 28, 1978. The extremely informative and stimulating discussions included such topics as: immunologic host factors; properties of metastatic cells, including cell membrane, and the differences in the enzymes in normal and tumor cells; the effect of glucose on potentiating drugs, delivery of antitumor drugs to tumor cells; and studies of models. The metastatic process is very important in several types of cancer (such as lung cancer) and until the mechanisms of metastasis can be well understood and properly treated, it was generally concluded at this meeting that cancer cannot be conquered. Brief reports were presented on the possible role of protease inhibitors in the therapy of micrometastasis. The mechanism of action and joint study on the use of a model system to study the role of protease inhibitors were also discussed.

EXCHANGE OF SCIENTISTS
Dr. Saburo Sone, from Dr. Eiro Tsubura's laboratory at Tokushima University, will join Dr. Fidler as a Research Fellow to collaborate on studies of the hympohcyie-macrophage system for the therapy of micrometastasis.

Five-Year Summary Report
The first five years of collaboration between Japan and the United States produced significant achievements through the scientific interaction of Japanese and American investigators. A summary of the activities during this five-year period is highlighted below.

MEETINGS, SEMINARS, AND CONFERENCES
At the invitation of the U.S. coordinator, a small contingent of American and Japanese scientists met in Bethesda, Maryland, on March 7, 1975, to plan future activities for the Metastasis Program Area. This meeting resulted initially in the participation of several Japanese investigators in a workshop/symposium on "Fundamental Aspects of Metastasis" at Roswell Park Memorial Institute in July 1975. The proceedings of this symposium were published in 1976 (Fundamental Aspects of Metastasis, edited by L, Weiss, Elsevier Publishing Company, New York).
In May 1976, eight Japanese and ten American scientists participated in the "Workshop on Metastasis" sponsored by the U.S.-Japan Cooperative Cancer Research Program and held in Kona, Hawaii. The results of this workshop were published in GANN Monograph on Cancer Research (No. 20): Cancer Metastasis, Approaches to the Mechanism, Prevention and Treatment (edited by P.G. Stansly and H. Sato, University Park Press, Baltimore, 1977).
The Memorial Sloan-Kettering Cancer Institute and the National Cancer Institute (NCI) later collaborated in a conference and workshop on metastasis held in New York in November 1976. The U.S.-Japan Cooperative Cancer Research Program was included in this effort and the Japanese investigators were supported with funds provided by the NCI. This conference was subsequently also published in Progress in Cancer Research and Therapy, Volume 5, "Cancer Invasion and Metastasis: Biologic Mechanisms and Therapy" (edited by S.B. Day, W.P. Laird, P.G. Stansly, S. Garrattini, and M:.G. Lewis, Raven Press, New York, 1977).

Exchange of Scientists
Three Japanese scientists spent varying amounts of time in collaborative research in U.S. laboratories under the auspices of the U.S.-Japan Program as follows:
• During February and March 1975, Dr. Maroh Suzuki, Tohoku University, collaborated with Dr. Benjamin Zweifach at the University of California at San Diego.
• Dr. Toshio Takahashi, Akita University, visited with Dr. Bernard Fisher, University of Pittsburgh. November 1975 through January 1976.
• Dr. Noritaka Kimura. Kyushu University, collaborated with Dr. Joseph Leighton, Medical College of Pennsylvania, for seven months, from September 1976 to March 1977.
Two American investigators, Dr. Isaiah J. Fidler, Frederick Cancer Research Center, and Dr. George Poste, Roswell Park Memorial Institute, spent two weeks lecturing at eight Japanese medical research centers from May 29 to June 15, 1977. This activity was sponsored by the exchange scientists program of the U.S.-Japan Cooperative Cancer Research Program.
GENERAL COMMENTS
There is no doubt that the U.S.-Japan Cooperative Cancer Research Program serves a useful function in encouraging scientific interaction between our two countries. Japanese and American investigators, who otherwise might not have en-countered each other, have grown to appreciate each others skills and perceptions and, as a result, are in a better position to collaborate in areas of mutual interest, an activity which is now taking place.
Despite the limited progress in understanding and controlling the metastatic process, it is hoped that this area of the U.S. -Japan Program will maintain visibility. It is a most important aspect of clinical cancer research and needs special stimulation and support precisely because it is a poorly understood process and a frustrating area of research. It can easily fall into a state of neglect as investigators become discouraged and seek greener pastures.
Dr. Isaiah J. Fidler, of the Frederick Cancer Research Center, was recommended to represent American interest and to help sustain the momentum in metastasis research that has already been achieved in the U.S.-Japan Cooperative Cancer Research Program.



WORKSHOP ON EXPERIMENTAL APPROACHES TO THE THERAPY OF MICROMETASTASES
Nara, Japan
October 26 to 28, 1978

AGENDA
Coordinators:
Dr. Philip G. Stansly, National Cancer Institute, Bethesda
Dr. Haruo Sato, Tohoku University, Sendai

Thursday, October 26
9:00 a.m. Welcoming Remarks H. Sato
9: 10 a.m. Plan of Workshop P. Stansly
Chairman: P. Stansly
9:20 a.m. Introduction to Biology of Metastasis-Individuality in Malignant Tumor H. Sato
9:50 a.m. Discussion
10:00 a.m. COFFEE
Session 1: Models for Experimental Metastasis
Chairmen: M. Kripke and S. Tsukagoshi
11:00 a.m. Experimental Models for the Study of Metastasis G. Poste
11:20 a.m. Discussion
11:30 a.m. U.V. Carcinogenesis M. Kripke
11:50 a.m. Discussion
Session 2: Host Factors in Metastasis
Chairmen: L. Peters and K. Tanaka
2:00 p.m. Host Factors in Inhibition of Metastasis in Lewis Lung Tumor E. Tsubura
2:20 p.m. Discussion
2:30 p.m. Immunologic Factors in UV Carcinogenesis M. Kripke
2:50 p.m. Discussion
3:00 p.m. COFFEE
Session 3: Tumor Factors in Metastasis
Chairmen: H. Sato and J. Killion
3:30 p.m. Fate of Tumor Cells Arrested In the Lung of Nude Mice K. Tanaka
3:50 p.m. Discussion
4:00 p.m. Heterogeneity of Metastatic Tumor Cells I. Fidler
4:20 p.m. Discussion
4:30 p.m. Characteristic Blood Circulation in Tumor Tissue M. Suzuki
4:50 p.m. Discussion
5:00 p.m. Some Biologic Characteristics of Clinical Lymph Node Metastasis E. Sugarbaker
5:20 p.m. Discussion

Friday, October 27
Session 3: Therapy by Manipulation of the Host
Immunotherapy
Chairmen: I. Fidler and H. Kobayashi
9:00 a.m. Prevention of Metastasis with Cell Wall Skeletons of BCG and Nocardia rubra T. Ogura
9:20 a.m. Discussion
9:30 a.m. Immunogenic Properties of Tumor Cell Vaccines J. Killion
9:50 a.m. Discussion
10:00 a.m. COFFEE
10:30 a.m. Enhanced Metastasis of Rat Tumor Cells after Cryosurgery H. Kobayashi
10:50 a.m. Discussion
11:00 a.m. Effect of Progressive Tumor Growth and Tumor Extracts on Macrophage Proliferation and Metastasis in a Murine Model E. Sugarbaker
11:20 a.m. Discussion
Hyperthermia
Chairmen: T. Baba and L. Peters
1:30 p.m. The Influence of Hyperthermia on Tumor Metastasis L. Peters
1:50 p.m. Discussion
2:00 p.m. Selective Intratumoral Potentiation of Anticancer Drug Effect by Glucose Treatment of the Host; Two Experimental Evidences T. Baba
2:20 p.m. Discussion
3:00 p.m. COFFEE
Session 4: Regression of Micrometastasis
Chairmen: L. Liotta and T. Matsushima
3:30 p.m. Regression of Tumor Metastasis by Viral Xenogenization H. Kobayashi
3:50 p.m. Discussion
4:00 p.m. Monitoring the Death Rate of Artificial Murine Pulmonary Micrometastasis L. Liotta
4:20 p.m. Discussion
Session 5: Chemotherapy of Micrometastasis
Chairmen: H. Watanabe and E. Sugarbaker
4:30 p.m. Suppression of Metastasis by Protease Inhibitors of Microbial Origin T. Matsushima
4:50 p.m. Discussion
5:00 p.m. Experimental and Clinical Studies of the Treatment with Local Application of Solid-form Anti-cancer Agent (Bleomycin) as an Adjuvant Lymph Node Dissection H. Watanabe
5:20 p.m. Discussion
5:30 p.m. Mechanism of Enhancement of Tumor Transplantability by Irradiation and Cytotoxic Drugs L. Peters
5:50 p.m. Discussion

Saturday, October 28
Session 6: Delivery of Drugs
Chairmen: C. Poste and T. Takahashi
9:30 a.m. Delivery of Antitumor Drugs to Experimental Lymph Node Metastasis S. Tsukagoshi
9:50 a.m. Discussion
10:00 a.m. New Approaches to Drug Delivery in Cancer Chemotherapy C. Poste
10:20 a.m. Discussion
10:30 a.m. COFFEE
11:00 a.m. Enhancement of Chemotherapeutic Effect on Lymph Node Metastasis by Anticancer Agents in Fat Emulsion T. Takahashi
11:20 a.m. Discussion
1:30 p.m. Participants Separate into Groups to Work out Details of Collaborative Protocols
2:00 p.m. Working Groups Report to Participants
2:30 p.m. Consideration of Future Efforts of U.S. -Japan Pro-gram on Micrometastasis Dr. Stansly, Dr. Sato, and Conferees
3:00 p.m. Adjourn


PARTICIPANTS

UNITED STATES

Isaiah J. Fidler, D.V.M., Ph.D.
Head, Biology of Metastasis
Frederick Cancer Research Center
Frederick, Maryland, U.S.A.

Jerald J. Killion, Ph.D.
Assistant Professor of Physiology
Oral Roberts University
Tulsa, Oklahoma, U.S.A.

Margaret L. Kripke. Ph.D.
Head, Immunobiology of Physical and Chemical Carcinogenesis
Frederick Cancer Research Center
Frederick, Maryland, U.S.A.

Lance A. Liotta, M.D., Ph.D.
Pathologist, Laboratory of Pathology
National Cancer Institute
Bethesda, Maryland, U.S.A.

Lester Peters, M.D.
Associate Radiotherapist
M.D. Anderson Hospital and Tumor Institute
Houston, Texas, U.S.A.

Ceorge H. Poste, D.V.M., Ph.D.
Professor, Experimental Pathology
Roswell Park Memorial Institute
Buffalo, New York, U.S.A.

Philip C. Stansly, Ph.D.
Coordinator for Metastasis
U.S. - Japan CCRP
Program Director for Viral Oncology
National Cancer Institute
Bethesda, Maryland, U.S.A.

Everett V. Sugarbaker, M.D.
Associate Professor of Surgery
University of Miami
Miami, Florida, U.S.A.

JAPAN

Tsuneo Baba
Professor, Experimental Pathology
Kyushu University, Fukuoka, Japan

Hiroshi Kobayashi
Professor, Cancer Immunology
Hokkaido University, Sapporo, Japan

Taijiro Matsushima
Assistant Professor, Cancer Biology
University of Tokyo, Tokyo, Japan

Takeshi Ogura
Research Associate, Internal Medicine
Osaka University, Osaka, Japan

Haruo Sato. M.D.
Coordinator for Metastasis
U.S. - Japan CCRP
Professor, Pathology
Tohoku University, Sendai, Japan

Maroh Suzuki
Assistant Professor
Experimental Pathology
Tohoku University, Sendai, Japan

Toshio Takahashi, M.D.
Professor, Surgery
Akita University Medical Center, Japan

Kenzo Tanaka
Professor, Pathology
Kyushu University, Fukuoka, Japan

Eiro Tsubura
Professor, Internal Medicine
Tokushima University, Tokushima, Japan

Shigeru Tsukagoshi
Head, Experimental Chemotherapy
Cancer Institute, Tokyo, Japan

Hiroshi Watanabe
Section Head, Surgery
National Cancer Center, Tokyo, Japan



JOINT PUBLICATIONS

1. Comparative Epidemiology of Cancer in the U.S. and Japan: Morbidity. Edited by T. Hirayama. Japan Society for the Promotion of Science, Tokyo, Japan, May 1978 (107 pages).
2. Comparative Epidemiology of Cancer in the U.S. and Japan; Mortality. Edited by T. Hirayama. Japan Society for the Promotion of Science, Tokyo, Japan, January 1977.
3. "Comparison of the Effects of Various Cyclotron-Produced Fast Neutrons on the Reproductive Capacity of Cultured Human Kidney (T-1) Cells." P. Todd, J.P. Geraci, P.S. Furcinitti, R.M. Rossi, F. Mikage, R.B. Theus, and C.B. Schroy. International Journal of Radiation Oncology Biology Physics 4: 1015-1022, 1978.
4. "Cytology Automation and Computer." I. Nishiya and I. Sawamura. Obstetrics and Gynecology 44(11): 11, 1977 (In Japanese).
5. "Early Changes Caused by N-butyl-N-(4-hydroxbutyl) Nitrosamine in Bladder Epithelium of Different Animal Species." G. Murasaki, M. Hananouchi. Y. Shinohara, M. Hirose. S.M. Cohen, Y. Yoshioka, and M. Tatematsu. Proceedings of the Japan Cancer Association 36:203, 1977.
6. "Effect of Azathiopurine and OK-432 on Urinary Bladder Carcinogenesis in Rats.' S.M. Cohen. S. Fukushima, H. Tsuda. G. Murasaki. and N Ito. GANN, Japanese Journal of Cancer Research 69:773. 1978.
7. "Experimental Study on Neovascularization in Benign and Malignant Rat Urinary Bladder Epithelial Proliferations Observed by Scanning Electron Microscopy and Auto-radiography. " M. Tatematsu, S. M. Cohen, Y. Shinohara, K. Nakanishi. T. Yoshimura, and N. Ito. Proceedings of the Japan Cancer Association 36:59, 1977.
8. GANN Monograph on Cancer Research. Number 20, "Cancer Metastasis: Approaches to Mechanism, Prevention, and Treatment." Edited by P.G. Stansly and H. Sato. University of Tokyo Press, Tokyo, Japan, August 1977.
9. "Histopathological Studies of Preneoplastic and Neoplastic Changes in Rat Urinary Bladders Induced by N-butyl-N- (4-hydrox-butyl)-Nitrosamine." S. Fukushima, G. Murasaki, M. Shibata, S.M. Cohen, M. Tatematsu, M. Mizutani, and N. Ito. Proceedings of the Japan Cancer Association 36:59, 1977.
10. Immunobiology and Immunotherapy of Cancer. Edited by W.D. Terry and Y. Yamamura. Elsevier, New York (to be published in 1979).
11. "Measurement of Cellular DNA Mass by Flow Microfluorometry Using a Biological Internal Standard." E. Tannenbaum, M. Cassidy, O. Alabaster, C.J. Herman, and l. Nishiya. Recent Progress in Medicine (Igaku no Ayumi). In press (In Japanese).
12. "Neovascularization During Urinary Bladder Carcinogenesis Induced by N-[4-(5-nitro--2-furyl)-2-thiazohyllformamide (FANFT). Proceedings of the Japan Cancer Association 36:240, 1977.
13. "Neovascularization in Benign and Malignant Urinary Bladder Epithelial Proliferative Lesions of the Rat Observed In Situ by Scanning Electron Microscopy and Auto-radiography. " M. Tatematsu, S. M. Cohen, S. Fukushima, T. Shirai, Y. Shinohara, and N. Ito. Cancer Research 38: 1792-1800, 1978.
14. Polycyclic Hydrocarbons and Cancer. Vol-ume 1, "Environment, Chemistry, and Metabolism." Edlted by H:. Gelboin, P. Ts'o, and C. Nagata. New York: Aca-demlc Press, 1978.
15. Polycyclic Hydrocarbons and Cancer. Volume 2, "Molecular and Cell Biology." Edited by H. Gelboin and P. Ts'o. New York: Academic Press (to be published in 1979).
16. "Present Status of Automated Cyiology in the United States of America." T. Sugishita. Clinical Cynecology and Obstetrics (Rin-shyo Fujinka Sanka) 31(7) : 1-13, 1977 (In Japanese).
17. "Proceedings from the U.S.-Japan Confer-ence on Biostatistics in the Study of Human Cancer." Series of 25 articles in Environmental Health Perspectives (to be published in August 1979).
18. Progress in Cancer Research and Therapy. Volume 1, "Control Mechanisms in Cancer." Edited by W.C. Criss, T. Ono, and J.R. Sabine. New York: Raven Press, 1976.
19. Progress in Cancer Research and Therapy. Volume 10, "Hormones, Receptors, and Breast Cancer." Edited by W.L. McGuire. New York: Raven Press, 1978.
20. "Progress Report: U.S.-Japan Cooperative Cancer Research Program." Y. Ikawa. Journal of the Japan Society for the Pro-motion of Science 30(9):672-681, 1977 (In Japanese).
21. "Promoting Effect of DL-tryptophan and Saccharin in Urinary Bladder Carcinogenesis in the Rat." S.M. Cohen, M. Arai, and G.H. Friedell. Proceedings of the American Association of Cancer Research 19:4 1978.
22. "Quantitative Analysis of Flow Microfluorometry Data for Screening Gynecologic Samples." M. Habbersett, M. Shapiro, B. Bunnag, I. Nishiya, and C.J. Herman. Journal of Histochemistry and Cytochemistry 27 (1) : 536-544, June 1979.
23. "Radiobiological Intercomparisons of Fast Neutron Beams Used for Therapy in Japan and the United States." E.J. Hall, H.R. Withers, J.P. Geraci, R.E. Meyn. J. Rasey, P. Todd, and G.E. Sheline. Inter-national Journal of Radiation Oncology Biology Physics 5:227-233, 1979.
24. "Rapid Induction of Preneoplastic Lesions in Rats with Chemical Carcinogens." N. Ito, M. Takahasi, S.M. Cohen, T. Shirari, M. Tatematsu, Y. Miyata, and Y. Shinohara. Proceedings of the Japan Cancer Association 36:21, 1977.
25. "Recent Aspects in Automated Cytology." I Nishiya et al. Practice of Obstetrics and Gynecoogy (Sanfujinka no Zissai) 27(2):533-542, 1978 (In Japanese).
26. Recent Results in Cancer Research. Volume 63, "Anti-Tumor Antibiotics." S.K. Carter. Berlin, Heidelberg, an d New York : Springer-Verlag, 1978 (303 pages).
27. Recent Results in Cancer Research, Volume 65. Edited by S.K. Carter, H. Umezawa, J. Douros, and Y. Sakurai. Berlin, Heidel-berg, and New York: Springer-Verlag (to be published in 1979).
28. "Reversible Papillary Hyperplasia in Rat Uri-nary Bladder Induced by Means of Serosal Freezing." T. Shirari, S.M. Cohen, S. Fukushima, and N. Ito. Proceedings of the Japan Cancer Association 36:241, 1977.
29. "Reversible Papillary Hyperplasia of the Rat Urinary Bladder." M. Tatematsu, S.M. Cohen, S. Fukushima, M. Hananouchi, and N. Ito. American Journal of Pathology 91:33-48, 1978.
30. U.S.-Japan Cooperative Cancer Research Program, First Report 1974-1975. Japan Society for the Promotion of Science. Tokyo, Japan, May 1976.
31. U.S.-Japan Cooperative Cancer Research Program' Progress Report 1 976-1977. National Cancer Institute, Bethesda. Maryland, June 3, 1978.
32. "U.S.-Japan Cooperative Cancer Research Program." G.R. Newell and H. Sugano. Journal of the National Cancer Institute (JNCI) 58(2), February 1977.
33. "U.S. Japan Cooperative Cancer Research Program-Conference on Breast Cancer and Diet." Edited by T. Hirayama, Preventive Medicine 7(2):159-229, June 1978,
34. "Vascular Changes During Rat Urinary Bladder Carcinogenesis Induced by BBN," M. Tatematsu, S.M, Cohen, G. Murasaki. N. Ito, and S, Fukushima, Transactions of the Society of Pathology of Japan 66, 1977.
35. "Vascular Changes in Neoplasia and Hyperplasia of the Urinary Bladder." N, Ito. M. Tatematsu, T, Shirai. S.M, Cohen. H, Arai, and S. Fukushima. Proceedings of the American Association of Cancer Research 18:39, 1977.