The first study group meeting in biological and clinical cancer research, sponsored by the Tumor Biology Program of the UICC and devoted to metastasis, was held in Annapolis, USA, on September 25-28,1983. Such study groups will provide a forum for basic cancer research workers on the one hand, and pathologists and clinicians on the other, to delineate common grounds, and should increase the awareness of new concepts in the two respective and complementary fields.
The formation of metastasis is most probably a multi-step phenomenon. In order to gain insight into the number and type of steps that are a prerequisite to the production of metastases, a series of in vivo andor in vitro models using animal andor human tumors has been designed. The study group was in general agreement that models should be used judiciously, and that their appropriateness depends solely on the nature of the question being addressed. Lectin-resistant mutants of mouse B16 melanoma, i.e. variants with a discrete alteration in a sugar transferase (fucosyltransferase) and a subsequent change in sialo-and fucoglycoproteins, were shown to have decreased metastatic capabilities. Dr. M. M . Burger (Basel) reported that B16-melanoma revertants could be isolated in which the biochemical defect had reverted entirely, and this correlated with increase in the metastatic phenotype.
Patterns of metastasis, i.e. the colonization of specific organs, are of predictive value for the clinician. Here again, models have been developed for brain, ovary, lung and liver metastasis. While Dr. G. L. Nicolson (Houston) and Dr. V. Schirrmacher (Heidelberg) have evidence supporting the notion that organ-specific adhesion may guide the cells to specific sites, Dr. M. M. Burger has reported growth-promoting effects of liver parenchymal cells in a given liver-tropic melanoma variant. Dr. F. K. Conley (Stanford) has been investigating KHT mouse sarcoma cells injected into the left ventricle which produce lung and brain metastases. Chronic infection of mice with Toxoplasma gondii protects mice from the development of metastases in the brain. This infection appears to attract mononuclear cells from the circulation into the brain parenchyma, suggesting that non-specific defense mechanisms may be active in limiting CNS metastasis of this tumor system.
A model for the study of breast cancer metastasis using the rat 13762NF mammary adenocarcinoma was described by Dr. G. L. Nicolson. This tumor is heterogeneous for various phenotypes, including spontaneous metastasis, and sensitivity to drugs, radiation, and heat. Some but not all of the selected lines demonstrated high capacity to metastasize to various organs from an implant growing in the mammary gland. In this tumor system, spontaneous metastasis does not correlate with loss of cell-associated fibronectin, but correlates well with cell-surface expression of two specific glycoproteins (gp80, gp580). Similar, but non-identical glycoproteins have been detected on human breast adenocarcinoma.
The appropriately manipulated, pathogen-free, athymic nude mouse could constitute a tool with which to ascertain the metastatic potential of human neoplasms. Dr. I. R. Hart (London) presented data obtained with human melanomas and prostate, colon, and renal carcinomas. Both the site of tumor cell injection and the hormonal status of recipient nude mice have profound effects on the metastatic behavior of the human tumor cells. However, the most important factor in determining the occurrence of spontaneous metastasis is the intrinsic characteristic of the tumor cells themselves. The nude mouse can also be used to select out preexisting subpopulations of metastatic cells from heterogeneous human neoplasms; this allows investigations dealing with the response of the metastatic human tumor cells to various therapeutic agents.
The first "human model" for directly testing the validity of the "seed and soil" hypothesis of Paget (1889) was presented by Dr. D. Tarin (Oxford). Data from 14 peritoneovenous shunt operations (Levin Shunt) in patients requiring relief from accumulation of ascites fluid due to untreatable peritoneal cancer were shown. Confirmation of Paget's classic hypothesis was provided by the finding that continuous seeding of viable, clonogenic tumor cells into the circulation did not lead in all cases to widespread metastases in organs normally not associated with these cancers. Despite the fact that large numbers of viable tumor emboli reached the lung microvasculature, in many such patients no macroscopic or microscopic lung metastases were found on autopsy, although many dormant tumor cell aggregates could be demonstrated. These data served as a basis for a discussion on the validity of assays for metastasis which introduce tumor cells directly into the circulation. In this "human model", as well as in many rodent systems, the mere entry of cells into the circulation does not guarantee the production of metastases. Tarin's data clearly demonstrate that both tumor cell properties (seed) and host factors (soil) influence the outcome of the process.
The development of heterogeneity in malignant populations could be due in part to the finding that in several mouse tumor system, highly metastatic cells exhibit an increased rate of spontaneous mutation as compared to non-metastatic counterparts. Dr. I. J. Fidler (Houston) discussed these data, and also presented evidence that in some mouse neoplasms of recent origin, metastases can well have a clonal origin, and that different spontaneous metastases proliferating in the same host can originate from different progenitor cells.