Papillary carcinoma of the thyroid - Hepatocyte growth factor (HGF) stimulates tumor cells to release chemokines active in recruiting dendritic cells

Tissue distribution of dendritic cells was investigated in eight cases of p apillary carcinoma of the thyroid using immunohistochemistry. Most dendriti c cells had an immature phenotype (CD1a++, CD11c+, CD40+, CD86-, HLA-DR-) a nd were located at the invasion edge of the tumor. This pattern of distribu tion was profoundly different from that of CD68+ macrophages, which were ev enly distributed throughout the tumor. The ability of tumor cells to releas e chemotactic factors active on dendritic cells was investigated in primary cultures of the same cases of papillary carcinoma, and was compared to tha t of the corresponding normal thyroid cells obtained from the tumor-free co ntralateral lobe. Chemotactic activity of culture supernatants was tested a gainst dendritic cells in a chemotaxis chamber. It was found that papillary carcinoma cells were active in releasing chemotactic activity, that hepato cyte growth factor (HGF; 100 ng/ml) or interleukin (IL)-1 beta (10(3) U/ml) induced a fourfold increase in the amount of chemotactic activity released , and that normal thyroid cells obtained from the same patients were as eff ective as tumor cells. Characterization of chemokines at RNA level revealed that unstimulated cells contain large amounts of IL-8 and monocyte chemota ctic protein (MCP)-1 RNAs, and that stimulation with HGF or IL-1 beta induc ed RNAs for regulated upon activation normal T expressed and secreted (RANT ES), macrophage inflammatory protein (MIP)-3 alpha, interferon-gamma-induci ble protein 10 (IP-10), and, to a lesser extent, MIP-1 alpha and MIP-1 beta , The possibility that HGF/Met interaction has a biological role in vivo wa s investigated in serial sections of six tumors immunostained for CD1a+, Me t protein, and HGF. It was found that all six tumors were intensely and dif fusely positive for Met protein, that HGF staining was present in tumor cel ls of the advancing edge, and that HGF+/Met+ tumor cell nests were infiltra ted by CD1a+ dendritic cells. The foregoing observations are consistent wit h the possibility that HGF stimulation of Met+ tumor cells is one of the mo lecular mechanisms involved in the recruitment of dendritic cells.