Mast cell exosomes promote lung adenocarcinoma cell proliferation – role of KIT-stem cell factor signaling

Abstract

BackgroundHuman cells release nano-sized vesicles called exosomes, containing mRNA, miRNA and specific proteins. Exosomes from one cell can be taken up by another cell, which is a recently discovered cell-to-cell communication mechanism. Also, exosomes can be taken up by different types of cancer cells, but the potential functional effects of mast cell exosomes on tumor cells remain unknown.Methods and resultsExosomes were isolated from the human mast cell line, HMC-1, and uptake of PKH67-labelled exosomes by the lung epithelial cell line, A549, was examined using flow cytometry and fluorescence microscopy. The RNA cargo of the exosomes was analyzed with a Bioanalyzer and absence or presence of the c-KIT mRNA was determined by RT-PCR. The cell proliferation was determined in a BrdU incorporation assay, and proteins in the KIT-SCF signaling pathway were detected by Western blot. Our result demonstrates that exosomes from mast cells can be taken up by lung cancer cells. Furthermore, HMC-1 exosomes contain and transfer KIT protein, but not the c-KIT mRNA to A549 cells and subsequently activate KIT-SCF signal transduction, which increase cyclin D1 expression and accelerate the proliferation in the human lung adenocarcinoma cells.ConclusionsOur results indicate that exosomes can transfer KIT as a protein to tumor cells, which can affect recipient cell signaling events through receptor-ligand interactions.

Exosomes as miRNA Carriers: Formation–Function–Future

“…Tetraspanins [64] were reported as highly abundant components in exosomes from different tumor entities such as lymphoma [65,66], colon carcinoma [67], melanoma [68], gastric adenocarcinoma [69], lung adenocarcinoma [70,71], and gastrointestinal stromal tumor [72]. CD63 is suggested as a surface marker [65,66] and it locates mainly in MVBs and lysosomes.…”

“…Besides, CD63 also binds with the kit receptor tyrosine kinase [74], which has been found to be enclosed in gastrointestinal stromal cell–derived exosomes and associates with tumor cell invasion [72]. That is generally inconsistent with the report that mast cell–derived exosomes transport tyrosin kinase to lung cancer cells and promote cell growth [70]. These pieces of evidence indicate that CD63 contributes not only receptor-ligand–mediated exosomal uptake but also scrutinizes exosome sequestration, which ultimately determines exosome functionality.…”

Interleukin-1β provided by KIT-competent mast cells is required for KRAS-mutant lung adenocarcinoma

“…The data presented here are novel and unprecedented and explain previous clinical and preclinical observations and in vitro functional findings. [28][29][30][31] Our in vivo results are important additions to the field, since MC play divergent tumorpromoting or gate-keeping roles in different cancers. [20][21][22][23]33 The reasons for this may be multiple, including the different tumor models employed and the multifaceted phenotypes of MC in the various bodily anatomic compartments.…”

“…26,27 MC have been identified in human and murine LADC, and have been found to promote lung adenocarcinoma cell growth in vitro and to be associated with poor patient survival. [28][29][30][31] We recently showed that KRAS mutations in tumor cells and host co-opted MC cooperate to promote the development of an inflammatory chemokine signaling network that culminates in metastatic malignant pleural effusions. [32][33][34] However, the functional role of MC in KRAS-mutant LADC development remained elusive.…”

Mast cells and exosomes in hyperoxia-induced neonatal lung disease

“…Exosomes are known to contain mRNA, miRNA, DNA, and protein from the host cells, which can be transferred to recipient cells (71). The release of mast cell proteases like chymase and tryptase have been linked to tissue destruction in the lung (38) and heart (53,73).…”