Lung mesenchymal stromal cells influenced by Th2 cytokines mobilize neutrophils and facilitate metastasis by producing complement C3

Abstract

Pre-metastatic niche formation is critical for the colonization of disseminated cancer cells in distant organs. Here we find that lung mesenchymal stromal cells (LMSCs) at pre-metastatic stage possess potent metastasis-promoting activity. RNA-seq reveals an upregulation of complement 3 (C3) in those LMSCs. C3 is found to promote neutrophil recruitment and the formation of neutrophil extracellular traps (NETs), which facilitate cancer cell metastasis to the lungs. C3 expression in LMSCs is induced and sustained by Th2 cytokines in a STAT6-dependent manner. LMSCs-driven lung metastasis is abolished in Th1-skewing Stat6-deficient mice. Blockade of IL-4 by antibody also attenuates LMSCs-driven cancer metastasis to the lungs. Consistently, metastasis is greatly enhanced in Th2-skewing T-bet-deficient mice or in nude mice adoptively transferred with T-bet-deficient T cells. Increased C3 levels are also detected in breast cancer patients. Our results suggest that targeting the Th2-STAT6-C3-NETs cascade may reduce breast cancer metastasis to the lungs.

The secretion profile of mesenchymal stem cells and potential applications in treating human diseases

“…Interestingly, the C3 production by MSCs is stimulated by Th2 cytokines. 149 Hence, the secreted factors by MSCs may serve as the essential signals to remodel the tumor microenvironment.…”

Comprehensive analysis identifies histone 2A ubiquitination as a marker for aging and pan-cancer prognosis

“…Specifically, the class 2 tumors were more active in terms including nucleotide excision repair, DNA repair, base excision repair, DNA replication, mismatch repair and homologous recombination (Fig 4c). In addition, like LUAD, the infiltration score of Th2 cells which promoted tumor immune evasion and metastasis in class 2 tumors were also dramatically higher than class 1 tumors in pan-cancer (Fig 4c) [21-23].…”

Potential role of PRKCSH in lung cancer: bioinformatics analysis and a case study of Nano ZnO

“…55 A recent study found that targeting the Th2-STAT6-C3-NET (neutrophil extracellular trap) signalling axis effectively inhibited breast cancer metastasis to the lungs. 56 Another study reported that p53 mutations may promote malignancy in solitary fibrous tumours by regulating the NAB2-STAT6 fusion gene at the transcriptional level. 57 Thus, in the future, other signalling pathways regulated by PRKCSH or Nano ZnO in lung cancer should be investigated further.…”