Tumor-associated macrophages (TAMs) are the key effector cells in the tumor microenvironment and induce neoangiogenesis, matrix remodeling, and
metastasis while suppressing the
tumor immune system. These protumoral macrophages display an M2 phenotype induced by
IL-4 and
IL-13 cytokines. In this study, we hypothesized that the inhibition of the
signal transducer and activator of transcription 6 (Stat6) pathway, a common downstream signaling pathway of
IL-4 and
IL-13, may be an interesting strategy by which to inhibit TAM differentiation and, thus, their protumorigenic activities. In vitro inhibition of the Stat6 pathway by using
small interfering RNA or the pharmacologic inhibitor,
AS1517499, inhibited the differentiation of mouse RAW264.7 macrophages into the M2 phenotype, as demonstrated by the reduction of Arg-1 (arginase-1) and Mrc-1 (
mannose receptor 1) expression and
arginase activity. In vivo,
AS1517499 significantly attenuated
tumor growth and early liver
metastasis in an orthotopic 4T1 mammary
carcinoma mouse model. Furthermore, in another experiment, we observed an increase in the intrahepatic
mRNA expression of F4/80 (
EGF-like module-containing
mucin-like
hormone receptor-like 1; total macrophages) and M2 macrophage markers [
Ym-1 (
chitinase 3-like
protein 3) and Mrc-1] and metastatic niche markers [ Mmp-2 (matrix metalloproteinase-2), Postn (
periostin), and Cd34] in mice with increasing growth of primary
tumors. Of interest, these markers were found to be reduced
after treatment with
AS1517499. In summary, inhibition of the Stat6 pathway in TAMs is a vital therapeutic approach to attenuate
tumor growth and
metastasis by inhibiting TAM-induced protumorigenic and prometastatic activities.-Binnemars-Postma, K., Bansal, R., Storm, G., Prakash, J. Targeting the Stat6 pathway in tumor-associated macrophages reduces
tumor growth and metastatic niche formation in
breast cancer.