Pro-inflammatory condition-induced tumor dormancy in pre-metastatic reservoir thymus

Hypothesis: Cancer patients suffering from metastatic relapse is the major cause of death. This is attributed to some undetectable minimal number of tumor cells, which are able to resist radio-chemotherapy, being in dormant state at some organs of the body. The largest T-lymphoid organ, thymus, has just recently been suggested as this kind of organ to be a pre-metastatic reservoir for tumor cell dormancy, and eventually relapse. We hypothesize that infection-, drug- and aging-resulted thymic atrophy induces inflammatory conditions to create this tumor pre-metastatic reservoir. Materials and Methods: To test our hypothesis we utilized various cancer cell lines (both human- and mouse- derived) and inoculated them into different groups of mice to see how specific tumor microenvironments (young thymus/naturally and induced involuted thymus/T-and B-cell lacking) have an effect on cancer cells retention and survival during chemotherapy. Results: Our observations in tumor-inoculated mouse model show that various cancer cells could be retained in the thymus. This retention ratio (in the thymus vs. lymph nodes) was particularly high in the naturally-aging- or drug-caused atrophied thymus. We found that genotoxic chemotherapy (Doxorubicin) can lead to changes in thymic microenvironment, characterized by activation of p53 in thymic epithelial cells (TECs), induction of TEC senescence, and an increase of pro-inflammatory factors. These thymic conditions were able to confer tumor cell capacity to anti-apoptosis. We also found that dormant tumor cells in the thymus have a capacity to induce tumor recurrence in the distant organs. Conclusions: Our pilot experiments suggest that activation of p53 in TECs induced by DNA-damage upon Doxorubicin treatment promotes senescence, in which SASP (senescence-associated secretory phenotype) is activated, thereby leading to tumor cell dormancy/chemo-resistance. This work is clinically relevant because our findings may help to determine a new target to prevent tumor relapse after chemotherapy.