Isaiah J. Fidler, DVM, PhD of MD Anderson Hospital
The spread of tumor cells from a primary neoplasm to distant organs and the production of metastases is the most devastating aspect of cancer. Metastasis involves the release of cells from the primary tumor, dissemination to distant sites, and lodging and growth in different organs. The outcome of the process has been shown to depend on host factors and tumor cell properties. The balance of these interactions varies among different tumors, but ultimately determines tumor behavior. Although our understanding of the pathogenesis of metastasis has increased considerably, comparable improvement in the treatment of metastasis disease produced by solid tumors in man has been minimal. Despite major advances in general patient care, in surgical techniques, and in adjuvant therapies, most deaths from cancer are caused by the growth of metastases that are resistant to therapy. In the majority of patients, by the time of diagnosis of primary malignant neoplasms (excluding skin cancers), metastasis may well have occurred. The biggest obstacle to the treatment of metastasis is the fact that cancers are not composed of cells with uniform properties. Rather, by the time of diagnosis, most cancers contain multiple cell populations exhibiting a wide range of biological heterogeneity in such characteristics as cell surface properties, growth rate; susceptibility to destruction by host immune response; sensitivity to various cytotoxic drugs; and the ability to invade and spread.
For all these reasons, it is clear that, short of the prevention of cancer, the major goal of clinical oncologists remains the prevention of eradication of cancer metastasis. Major advancements in the treatment of metastasis will be forthcoming only when the basic mechanisms responsible for tumor diversification, progression and spread are better understood. The purpose of the 1986 William Guy Forbeck Foundation “Think Tank” was to bring together prominent basic and clinical scientists who have made significant contributions to our knowledge of metastatic tumor cell behavior and for the purpose of information exchange, cross-fertilization of ideas, and learning under intense and candid settings.
Throughout the years, there has been a tendency to classify cancer as a single disease – “cancer.” Today, it is often stated that cancer is a group of 100 diseases. The number 100 was probably selected to denote “many diseases.” At the close of the meeting, the participants were asked to summarize their views about the discussions held during the meeting. What became clear was that while investigators discussed different aspects of tumor biology, certain common features and problems in the study of cancer evolved as major themes during the meeting. One key issue raised by several of the participants was the fact that while tumors do not contain cells with uniform properties, common features of tumor behavior can be recognized. This is important because it suggests a more optimistic approach to the development of tumor therapy, as opposed to the pessimism that has pervaded the filed since the recognition of the problem of tumor diversity. Indeed, the commonality that one sees in tumors may be uniquely limited to individual approaches to the treatment of one cancer may not be relevant to another type of cancer.
This then, represents another focus of the meeting, namely, that one must look upon tumors as unique diseases and not address them with the broad name of cancer. The origins of neoplasia are likely very different as is their clinical behavior. It is logical therefore that approaches to tumor therapy will have to be focused to individual tumor types (and possibly subclassifications of individual types) rather than to broad, general approaches as has been the practice.
The concept that different cancers merit unique investigation has far reaching implications for how we devise our approaches to research in the biology of cancer. To date, the general approach to the study of neoplasia tended to examine many aspects of many tumors with the goal of finding a common theme for all tumors. Several of the participants pointed out that recent developments in cancer therapy, such as the successful use of interferon-gamma for the treatment of a rare tumor – hairy cell leukemia – but not other tumors, indicates that a more focused approach to the study of neoplasms may now be warranted. A focused approach is one where an individual tumor is studied in detail so as to develop an understanding of the mechanism by which this tumor type grows and develops, with the goal of developing a new therapeutic approach. Whereas the focused approach would have been frowned upon five to ten years ago, it is becoming clear that such directed research at individual tumors in specific laboratories may provide fruitful results.
The outcome of cancer is determined by the interaction of cancer cells with the organ environment. Understanding the basis for these interactions could clearly provide a unique avenue for cancer therapy. Several participants presented data demonstrating that when the balance between the cancer cell and its environment is disturbed, the growth and/or the metastatic potentials of the cancer can be arrested. Here again, the contribution of the organ environment to the growth of cancer cells or toward their differentiation into non-malignant cells can be related to the genetic predisposition of the host. This of course points out once again the variations in biological behavior of cancers among different patients are to be expected.
At the close of the meeting, the theme addressing the commonality in tumors recurred and the general consensus was that, despite the complexity of cancer biology, there is hope in defining common features in at least certain tumor types. If we begin to address these common features and direct our efforts to finding modalities of therapy directed toward these common characteristics of cancer behavior, we may well develop therapeutic means which are effective clinically, though we might not understand the detail of how therapy is working. Should we achieve this goal, then we would have the leisure of spending the next decades defining how the therapy is working while bringing relief to a large number of cancer patients.
From all of the above, it is clear that during the last few years, out knowledge of basic tumor biology has been increasing exponentially. Despite this fact, few opportunities exist where scientists who each contribute to the field of cancer biology can meet to compare data and unpublished results under settings which allow for a frank exchange of new unpublished data. The customary format of scientific meetings can be 200-4000 participants, or where many scientists to exhibit their data by means of a poster. Neither arrangement provides for intense dialog.
In general, the participants in this meeting felt that the ‘think tank’ approach, namely, a small meeting to address particular issues in tumor biology, was extremely effective in getting broad general discussions on major issues affecting cancer biology today. Being together in a beautiful surrounding with a small group allows scientists to meet each other on a personal level, and this, of course, encourages both discussion, and, ultimately, collaborations. Several collaborative studies have already resulted from this meeting, and the entire group felt that it would be of considerable value to continue such programs in future.
Retrospective Commentary (written Fall 1989)
One characteristic of normal embryo cells is their ability to undergo a series of events defined as differentiation. Thus, primitive cells can multiply but later assume unique properties that distinguish one cell from another. For example, epithelial cells of skin have morphology and function completely distinct from epithelial cells of kidney and colon. One characteristic of malignant cancer cells is their failure to undergo differentiation. It is this continuous cell division without a commitment to terminal differentiation (hence, cessation of growth) that clearly distinguishes a normal cell from a cancer cell.
This meeting actually predated many of the new developments in cancer research dealing with the topic of cancer progression from normal to benign to the malignant state. The relationship of genetic alterations in cells, production of stimulatory and inhibitory growth factors, and escape from immune recognition by the host, were discussed in the Think Tank. The explosive increase in data which is happening just now completely justified the selection of the topic for the second annual Forum.
Of the many benefits of the meeting, the interaction among scientists of slightly different disciplines and outlooks is most prominent. Several collaborative studies dealing with various aspects of tumor progression and differentiation have been initiated and completed. It is this cross-feeding and awareness of new and exciting data that are most welcome by leading researchers. The opportunity provided by the William Guy Forbeck Research Foundation to achieve these goals is both unique and gratifying.
Irwin D. Bernstein, MD
Children's Orthopedic Hospital
Leland W.K. Chung, PhD
University of Colorado
Donald S. Coffey, PhD
Johns Hopkins Medicine
Isaiah J. Fidler, DVM, PhD
MD Anderson Cancer Center
Philip Frost, MD, PhD
MD Anderson Cancer Center
Gloria Heppner, PhD
Michigan Cancer Foundation
John T. Kemshead, MD
Institute of Child Health
Robert S. Kerbel, PhD
Mount Sinai Hospital
Bruce Korf, MD, PhD
Boston Children's Hospital
David Solter, MD, PhD
The Wistar Institute
David Tarin, MD, PhD
University of Oxford
E. Lynette Wilson, PhD
University of Capetown