Chemotherapy-induced tumor dormancy and relapse

Abstract

Abstract Breast cancer mortality is due to distant recurrence of the disease as a result of awakening dormant tumor cells that were established by cancer therapies. The mechanisms through which dormant tumor cells are maintained or escape from dormancy, and relapse remain elusive. One such mechanism that may play a role in tumor dormancy maintenance or escape is autophagy; a process important in all cells for the removal of damaged proteins and organelles. Although autophagy is a mechanism of tumor suppression, it also confers stress tolerance that enables tumor cells to survive under adverse conditions. Here, we wanted to determine the role of autophagy in tumor dormancy and sensitivity of dormant tumor cells to immunotherapy, i.e., IFN-gamma treatment. A mouse mammary carcinoma (MMC) cell line was established from the neu over-expressing FVBN202 transgenic mouse. We also used Adriamycin (ADR) for the establishment of chemotherapy-induced tumor dormancy, and blocked autophagy by chloroquine (CQ). We demonstrated that a transient blockade of autophagy by CQ during ADR treatment prolonged tumor dormancy, in vitro, but not in vivo. Also, we determined that dormant tumor cells established by ADR or ADR+CQ were more sensitive to IFN-gamma induced apoptosis compared with non-dormant, proliferating tumor cells. These observations suggest that autophagy could participate, in part, in tumor dormancy without affecting the sensitivity of dormant cells to IFN-gamma treatment.