BMP4 Inhibits Breast Cancer Metastasis by Blocking Myeloid-Derived Suppressor Cell Activity

Abstract

The TGFb growth factor family member BMP4 is a potent suppressor of breast cancer metastasis. In the mouse, the development of highly metastatic mammary tumors is associated with an accumulation of myeloid-derived suppressor cells (MDSC), the numbers of which are reduced by exogenous BMP4 expression. MDSCs are undetectable in na€ ve mice but can be induced by treatment with granulocyte colony-stimulating factor (G-CSF/Csf3) or by secretion of G-CSF from the tumor. Both tumor-induced and G-CSF-induced MDSCs effectively suppress T-cell activation and proliferation, leading to metastatic enhancement. BMP4 reduces the expression and secretion of G-CSF by inhibiting NF-kB (Nfkb1) activity in human and mouse tumor lines. Because MDSCs correlate with poor prognosis in patients with breast cancer, therapies based on activation of BMP4 signaling may offer a novel treatment strategy for breast cancer. Cancer Res; 74(18); 5091-102. Ó2014 AACR.

Carbonic Anhydrase IX Promotes Myeloid-Derived Suppressor Cell Mobilization and Establishment of a Metastatic Niche by Stimulating G-CSF Production

“…3F). These data suggest that CAIX expression is required for the production of G-CSF in breast tumors and that tumor-derived G-CSF is responsible for the mobilization of granulocytes to the lungs of tumor-bearing mice, observations that are consistent with previous reports demonstrating that G-CSF levels are critical for CD11b þ Gr1 þ mobilization (12,(27)(28)(29)(30).…”

“…G-CSF can induce T-cell tolerance and has been shown to drive MDSC development from human hematopoietic stem cells cultured in vitro (31,49). Including our data, there is an increasing list of preclinical studies implicating G-CSF in tumor progression and metastasis (12,24,27,29,30,42,50), and it is plausible that immune modulation is a contributing factor. Together, these studies suggest further investigation into the G-CSF-driven MDSC expansion in patients with cancer is needed.…”

“…The prevailing body of preclinical evidence suggests that in tumor-bearing mice, granulocytes, which include G-MDSC, are found in the metastatic niche where they assist in the establishment of metastases (6,12,29,30,32,33,(41)(42)(43). However, it has also been suggested that mobilized neutrophils have antimetastatic activity in the lung premetastatic niche (34).…”

“…G-CSF may not be well known for its chemoattractant properties; however, recent studies have demonstrated that treating tumor-free mice with recombinant G-CSF alone results in the accumulation of MDSC in organs where G-CSF expressing tumors are likely to metastasize (12,29). Furthermore, blocking the action of circulating G-CSF or its receptor with antibodies is sufficient to reduce the accumulation of these cells in the lungs of tumorbearing mice, and in fact attenuate metastasis formation (12,30).…”

Distinctive properties of metastasis-initiating cells

“…Therefore, mesenchymal-like DTCs, which often have elevated expression of TGF-β, may escape attack by CTLs upon arrival in distant tissues. In contrast, BMP4, another member of the TGF-β family, functions as a metastasis suppressor in breast cancer by blocking G-CSF-induced expansion of myeloid-derived suppressor cells (MDSCs) (Cao et al 2014). As another mechanism to compromise the function of innate immune cells during metastasis, melanoma cells express FcγRIIb that negatively regulates B-cell recognition and humoral immunity to promote liver metastasis (Cohen-Solal et al 2010).…”