Breast tumor cell TACE-shed MCSF promotes pro-angiogenic macrophages through NF-κB signaling

Abstract

Most deaths associated with breast cancer, the most common malignancy in women, are caused by metastasis. Tumor associated macrophages significantly contribute to breast cancer progression and development of metastasis through the promotion of angiogenesis which involves a central regulator of macrophage functions: nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB). Macrophages are activated by macrophage colony stimulating factor (MCSF) and chemokine (C-C motif) ligand 2 (CCL2) to secrete angiogenic factors including vascular endothelial growth factor (VEGF). The release of MCSF from tumor cells is mediated by ectodomain shedding through tumor necrosis factor alpha converting enzyme activation (TACE). Here we determined whether tumor cells TACE-shed MCSF promotes angiogenesis through activation of the NF-κB pathway in macrophages and the subsequent release of VEGF. These interactions were modeled in vitro using a panel of mammary cells mimicking the breast cancer progression from normal murine mammary gland cells to metastatic 4T1 cells along with J774 macrophages, all derived from BALB/c mice. TACE and MCSF expressions were higher in metastatic cells compared to epithelial cells (p < 0.05). Tumor conditioned medias activated the expression of VEGF by macrophages through stimulation of the NF-κB pathway and resulting macrophage secretions that promoted high levels of endothelial cell tubes. Furthermore, the combinations of CCL2, also highly expressed by tumor cells, and MCSF promoted pro-angiogenic macrophages. These results highlight the key role of tumor cell TACE-shed MCSF and secreted CCL2 in stimulating pro-angiogenic macrophages.

Apigenin inhibits TNFα/IL-1α-induced CCL2 release through IKBK-epsilon signaling in MDA-MB-231 human breast cancer cells

“…Meanwhile, the collective activity of TANS and MDSCS both yield the perpetual release of CCL2 and M-CSF fostering synergistic infiltration of TAMS. TAMS, upon arrival, can then lead to even more release of promoting cytokines: TGF-beta, MMPs, VEGF, CM/M-CSF, CCL 17, IL-13 and CCL2 which secure pro-angiogenic tumor processes [46]. In aggressive malignancies, metastatic MAMs arrive at secondary sites and in turn recruit inflammatory CCR2 bearing monocytes by CCL2, which in themselves release CCL3 and express CCR1, amplifying tumor potential [47].…”

Signal regulatory protein α associated with the progression of oral leukoplakia and oral squamous cell carcinoma regulates phenotype switch of macrophages

“…Besides, TAM increased their tumoricidal activity after targeted deletion or inhibition of IKKβ [40]. In spite of the fact that NF-κB is viewed as a noteworthy pro-inflammatory transcription factor, recent studies have demonstrated that NF-κB activation also controls anti-inflammatory pathways, especially in macrophages [41]. When NF-κB signaling is repressed particularly in TAMs, they get to cytotoxic to tumor cells and switch to a “classically” activated phenotype [9].…”

Role of tumor associated macrophages in tumor angiogenesis and lymphangiogenesis

“…Alternatively, VEGF-A expression can be induced by tumor-released CSF-1 (M-CSF), which acts through NF-κ B activation and, in combination with CCL2, promotes pro-angiogenic functions of macrophages (Eubank et al, 2003; Wyckoff et al, 2004). Moreover, irradiation stimulates tumor cells to produce higher levels of CSF-1 resulting in the enhanced infiltration of pro-angiogenic myeloid cells into the tumor site (Rego et al, 2013; Xu et al, 2013). Upon secretion from cells, VEGF-A associates with extracellular matrix (ECM) and its soluble form can be released by enzymatic cleavage of ECM by matrix metalloproteinases (MMPs) (Lee et al, 2005).…”