Progression of mouse thymic leukemias in thymic microenvironments.
Mouse thymic leukemogenesis has been assumed to occur in multiple steps corresponding to the stages of normal T-cell lineage development. One of the roles of the thymus in leukemogenesis is to provide permissive microenvironments for the progression of developing leukemias from thymus-dependent to independent growth. We have devised a method to consistently isolate the symbiotic complex of leukemia cells and thymic epithelium-like stromal cells from primary leukemic thymuses. In such complexes, leukemia cells were able to proliferate in close association with thymic stromal cells in pseudoemperipolesis, i.e., a unique form of cell interaction which we defined. In normal thymus, subcapsular zone blasts, mitotically active early thymic lymphocytes, were able to form similar complexes with thymic stromal cells, but this property was lost as they differentiated into cortical small lymphocytes. These observations indicate that the stage of intrathymic progression of leukemias is critically linked with the stage of subcapsular zone blasts of normal thymic lymphopoiesis. Mechanism and regulation of the complex formation was analyzed by an in vitro assay. We found that many thymic microenvironment-dependent leukemia cells were reversibly stimulated to proliferate by various tumor-promoters sharing a cellular receptor for phorbol esters. Without support by adequate stromal cells or a tumor promoter, leukemia cells rapidly ceased to grow and died. The degree of growth stimulation was well correlated with their tumor-promoting activity in mouse skin. Action of tumor promoters on microenvironment-dependent leukemias seemed to be direct rather than mediated by lymphokines. Another remarkable effect of tumor promoters was their inhibition of complex formation, presumably by affecting the cytoskeleton.
D000818:Animals; D002450:Cell Communication; D007938:Leukemia / Q000209:etiology* / Q000648:ultrastructure; D051379:Mice; D013755:Tetradecanoylphorbol Acetate / Q000633:toxicity; D013950:Thymus Gland / Q000166:cytology / Q000502:physiology*; D013953:Thymus Neoplasms / Q000209:etiology*
D013755:Tetradecanoylphorbol Acetate