Abstract
Abstract : In breast cancer, myeloid cells recruitment into tumors following radiation therapy and chemotherapy is frequently observed in pre-clinical models. We therefore sought to determine the significance of myeloid cell recruitment following chemotherapy treatment and their role in therapeutic resistance. Using intravital imaging of tumors in live mice, we observed that the tumors of the polyoma middle T antigen (PyMT) mouse model of luminal breast cancer show a stage-dependent sensitivity to treatment with doxorubicin. Doxorubicin treatment recruits CCR2+Gr1+7/4+CD11b+ immature myeloid cells with monocytic morphology. Inhibition of this recruitment via orthotopic transplantation of Ccr2+/+ cancer cells from PyMT mice into Ccr2-/- mice enhances the response to doxorubicin. Furthermore, changes in tumor vasculature and tumor grade accompany this improved response, indicating that CCR2 signaling may play important roles in tumor proliferation and differentiation, angiogenesis, in addition to therapeutic response. The data herein presented show that antagonism of CCR2 signaling in combination with cytotoxic chemotherapy treatment may be a potentially powerful therapeutic strategy for the treatment of breast cancer.
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