Identification of genes expressed in tumor-associated macrophages.
Most malignant tumors contain so-called tumor-associated macrophages (TAM) as a major component of their leukocytic infiltrate. To investigate the impact of the tumor microenvironment on activation and differentiation of macrophages, we established a 3-dimensional model system by culturing human monocytes within multicellular tumor spheroids. After 7 days, monocyte-derived TAM were isolated and analyzed for phenotypic alterations as compared to macrophages cultured without tumor cell contact. We found the known macrophage differentiation marker Carboxypeptidase M to be suppressed while CD14, HLA-DR, and CD16 were up-regulated. Using Differential Display, we identified several genes that were differentially expressed between TAM and control macrophages. Prolidase, a peptidase known to influence the chemoattraction of neutrophils and macrophage activity, was down-regulated in TAM. In contrast, the Toll-like receptor family-related molecules MD-1 and RP105 were up-regulated by tumor cell contact, both at the RNA and protein level. From our data we conclude that TAM represent a distict macrophage population characterized by low expression of differentiation-associated macrophage antigens but also by a constitutive state of activation.
Gottfried
Eva
E
Dept. of Hematology and Oncology, University of Regensburg, Germany.
Faust
Stefan
S
Fritsche
Jana
J
Kunz-Schughart
Leoni A
LA
Andreesen
Reinhard
R
Miyake
Kensuke
K
Kreutz
Marina
M
D015703:Antigens, CD / Q000235:genetics / Q000378:metabolism; D000954:Antigens, Surface / Q000235:genetics / Q000378:metabolism; D002478:Cells, Cultured; D004150:Dipeptidases / Q000235:genetics / Q000378:metabolism; D058851:GPI-Linked Proteins; D005786:Gene Expression Regulation; D006801:Humans; D015850:Interleukin-6 / Q000378:metabolism; D008264:Macrophages / Q000166:cytology / Q000201:enzymology / Q000276:immunology* / Q000378:metabolism*; D008666:Metalloendopeptidases / Q000235:genetics / Q000378:metabolism; D009000:Monocytes / Q000166:cytology / Q000276:immunology; D009369:Neoplasms / Q000276:immunology*; D010641:Phenotype; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism
D015703:Antigens, CD; D000954:Antigens, Surface; C092722:CD180 protein, human; D058851:GPI-Linked Proteins; D015850:Interleukin-6; C115213:LY86 protein, human; D012333:RNA, Messenger; D004150:Dipeptidases; C022449:proline dipeptidase; C058479:carboxypeptidase M; D008666:Metalloendopeptidases