The role of the extracellular matrix (ECM) in the tumor microenvironment is not limited to being a barrier against tumor invasion. The ECM is a reservoir of cell binding proteins and growth factors that affect tumor cell behavior. It is also substantially modified by proteases produced by tumor cells or stroma cells. As a result of the activity of these proteases, cell-cell and cell-ECM interactions are altered, new biologically active ECM molecules are generated, and the bioavailability and activity of many growth factors, growth factor receptors, and cytokines are modified. ECM-degrading proteases also play a critical role in angiogenesis, where they can act as positive as well as negative regulators of endothelial cell proliferation and vascular morphogenesis. This review article summarizes some of the most relevant findings made over the recent years that were discussed at a workshop organized by the Path B Study Section of the National Institutes of Health in October 2002.

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Generalized leukemia was observed on day 3 following intra‐peritoneal inoculation of leukemic (L1210) ascites cells in CDF1 mice. On day 3 after tumor implantation, residual viable leukemic cells were detected in the peritoneal cavities and spleens of leukemic mice 6 h following treatment with 180 mg/kg of cyclophosphamide. Mice receiving weekly intraperitoneal injections of X‐irradiated leukemic (L1210) cells for 6 weeks were resistant to a challenge of tumor cells. When incubated in vitro, spleen and bone marrow cells of immune mice were able to inactivate viable leukemic cells, as evidenced by failure of tumor growth in mice inoculated with these cells. Leukemic mice injected with immune spleen or bone‐marrow cells from isogeneic mice following treatment with cyclophosphamide survived a 60‐day observation period. In one such experiment 90‐day survivors were able to resist re‐inoculation of tumor cells. Leukemic (DBA/2) mice inoculated with allogeneic spleen cells following cyclophosphamide treatment survived for longer periods than mice injected with isogeneic spleen cells.

The indications of immunologic dysfunction following low level exposure of rodents or even man to certain chemicals and drugs have raised concern regarding methodology and approaches for routine assessment of immunobiological effects. The immunogiological effect observed may either indicate impaired immunopotentiation or hypersensitization. The assays selected for testing should be relevant to the human experience and adaptable to certain practical considerations such as cost, reproducibility of data, ease of performance and application to routine toxicology studies. Using these considerations, a tier approach was proposed consisting of assays for screening for immunologic effects (Tier I) and assays to help define the mechanisms responsible for the immunobiological effects observed (Tier II). A tier of assays was also proposed for measuring the sensitization potential of certain compounds. Certain assays from the screening tier were assembled into a hypothetical and practical test battery to screen for immunological effects of a chemical with potential immunosuppressive properties. Information provided by this test battery should provide a reasonable and sensitive data base from which a standard of evaluation could be made regarding the safety of the test (1) compound.