Breast cancer is the leading cause of death in female
cancer patients due to the lack of effective treatment for
metastasis. Macrophages are the most abundant immune cells in the primary and metastatic
tumors, and contribute to
tumor initiation, progression, and
metastasis.
Emodin has been found to exert anti-
tumor effects through promoting cell cycle arrest and apoptosis, and inhibiting angiogenesis, but its effects on tumor-associated macrophages during
cancer metastasis have not been investigated. Mice inoculated with 4T1 or EO771
breast cancer cells orthotopically were treated with
Emodin after the primary
tumors reached 200 mm3 in size. Primary
tumor growth, lung
metastasis, and macrophage infiltration in the lungs were analyzed. In vitro experiments were performed to examine the effects of
Emodin on macrophage migration and M2 polarization, and the underlying mechanisms.
Emodin significantly suppressed
breast cancer lung
metastasis in both orthotopic mouse models without apparent effects on primary
tumors. Reduced infiltration of F4/80+ macrophages and Ym1+ M2 macrophages in lungs was observed in
Emodin-treated mice. In vitro experiments demonstrated that
Emodin decreased the migration of macrophages toward
tumor cell-
conditioned medium (TCM) and inhibited macrophage M2 polarization induced by TCM. Mechanistically,
Emodin suppressed STAT6 phosphorylation and C/EBPβ expression, two crucial signaling events in macrophage M2 polarization, in macrophages treated with
IL-4 or TCM. Taken together, our study, for the first time, demonstrated that
Emodin suppressed pulmonary
metastasis of
breast cancer probably through inhibiting macrophage recruitment and M2 polarization in the lungs by reducing STAT6 phosphorylation and C/EBPβ expression.