Tumor cell-activated CARD9 signaling contributes to metastasis-associated macrophage polarization.
M YangJ-H ShaoY-J MiaoW CuiY-F QiJ-H HanXin LinJ DuPublished in: Cell death and differentiation (2014)
Macrophages are critical immune effector cells of the tumor microenvironment that promote seeding, extravasation and persistent growth of tumor cells in primary tumors and metastatic sites. Tumor progression and metastasis are affected by dynamic changes in the specific phenotypes of macrophage subpopulations; however, the mechanisms by which tumor cells modulate macrophage polarization remain incompletely understood. Caspase recruitment domain-containing protein 9 (CARD9) is a central adaptor protein of innate immune responses to extracellular pathogens. We report that increased CARD9 expression is primarily localized in infiltrated macrophages and significantly associated with advanced histopathologic stage and the presence of metastasis. Using CARD9-deficient (CARD9(-/-)) mice, we show that bone marrow-derived CARD9 promotes liver metastasis of colon carcinoma cells. Mechanistic studies reveal that CARD9 contributes to tumor metastasis by promoting metastasis-associated macrophage polarization through activation of the nuclear factor-kappa B signaling pathway. We further demonstrate that tumor cell-secreted vascular endothelial growth factor facilitates spleen tyrosine kinase activation in macrophages, which is necessary for formation of the CARD9-B-cell lymphoma/leukemia 10-mucosa-associated lymphoid tissue lymphoma translocation protein 1 complex. Taken together, our results indicating that CARD9 is a regulator of metastasis-associated macrophages will lead to new insights into evolution of the microenvironments supporting tumor metastasis, thereby providing targets for anticancer therapies.
Keyphrases
- nuclear factor
- immune response
- tyrosine kinase
- vascular endothelial growth factor
- signaling pathway
- single cell
- induced apoptosis
- poor prognosis
- toll like receptor
- acute myeloid leukemia
- binding protein
- diffuse large b cell lymphoma
- dna methylation
- gene expression
- mesenchymal stem cells
- protein protein
- epithelial mesenchymal transition
- cell proliferation
- oxidative stress
- genome wide
- adipose tissue
- amino acid
- inflammatory response
- pi k akt
- epidermal growth factor receptor
- long non coding rna
- case control
- antimicrobial resistance