Abstract
BackgroundMounting evidence suggests that complement components promote tumor progression via modulating immune suppression, angiogenesis, or tumor cell proliferation. However, the role of C3a-C3aR signaling in regulating lung metastasis of breast cancer remains unknown.MethodsWe performed various ex-vivo and in-vivo assays. Genetic and pharmacological C3aR blockade models were applied to investigate the role of C3a-C3aR in metastasis of breast cancer.ResultsC3a-C3aR signaling in CAFs facilitates the metastasis of breast cancer. Mechanically, C3a-C3aR signaling augments pro-metastatic cytokine secretion and extracellular matrix components expression of CAFs via the activation of PI3K-AKT signaling. Genetic or pharmacological blockade of C3aR signaling effectively inhibited lung metastasis of breast cancer in mouse models.ConclusionsC3a-C3aR signaling in CAFs facilitates the metastasis of breast cancer. Targeting C3aR signaling is a potential anti-metastasis strategy for breast cancer therapy.
Highlights
Mounting evidence suggests that complement components promote tumor progression via modulating immune suppression, angiogenesis, or tumor cell proliferation
C3aR deficiency reduced metastasis of breast cancer to the lungs Previously, we and others demonstrate that C3aR signaling promote tumor growth by promoting immune inhibition [6, 10]
To investigated whether C3aR signaling contributed to metastasis, we orthotopicaly injected 4 T1 cells, which closely mimics stage IV of human breast cancer, into mammary fat pad of Balb/c C3aR+/+ mice and C3aR−/− mice, respectively
Summary
Mounting evidence suggests that complement components promote tumor progression via modulating immune suppression, angiogenesis, or tumor cell proliferation. The role of C3a-C3aR signaling in regulating lung metastasis of breast cancer remains unknown. In addition to participating in innate immunity, many complement proteins facilitate cross-talk between the immune cells and tumor cells in the tumor microenvironment (TME) [5,6,7]. A growing body of evidence suggests that tumor metastasis is dependent on tumor cells themselves, but is regulated by the tumor microenvironment (TME) [17]. Carcinoma associated fibroblasts (CAFs) are the largest populations of tumor cells which accumulate in TME [18, 19]
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