Role of thymic stromal cell dysfunction in the thymic involution of mammary tumor-bearing mice.

The growth of D1-DMBA-3 mammary tumors leads to a profound thymic atrophy in the hosts. In previous studies we have shown a minor increase in thymic apoptosis in tumor bearers and an early block in the maturation of double negative cells was observed in the thymuses of tumor-bearing mice. We now present evidence that in tumor bearers there is no increased apoptosis in the periphery that may enhance the migration of thymic precursors. Furthermore, using direct fluorescein labeling of thymocytes in vivo, no increased numbers of recent thymic emigrants could be detected. In addition, the thymic atrophy did not affect all thymus functions since the integrity of negative selection was preserved in tumor-bearing mice. Stromal cells derived from the thymuses from normal mice and tumor-bearers had decreased proliferation in the presence of culture supernatants from DA-3 cells, derived from the in vivo D1-DMBA-3 mammary tumors. Addition of known tumor derived factors to normal thymic stromal cells showed that, while granulocyte-macrophage colony stimulating factor and prostaglandin E2 did not cause any effects, phosphatidyl serine severely inhibited their proliferation. Importantly, we demonstrated that tumor bearers' stromal cells could not support the proliferation of thymuses from either normal or tumor-bearing mice, indicating that functional changes in the stromal cells may be involved in the abnormal thymic development occurring during mammary tumor development.