Analysis of gene expression in the tumor-associated macrophage.
BACKGROUND
The tumor-associated macrophage (TAM) is at the front line of the host's defense against malignancy and provides an attractive target for immune-modulatory therapy. However, factors present within the tumor microenvironment can alter macrophage phenotype, preventing its cytotoxic activity and reducing its susceptibility to interferon-gamma and lipopolysaccharide-mediated stimulation.


METHODS
Macrophages were isolated from subcutaneous B16 melanoma tumors implanted in C57 BL/6 mice. Wound macrophages were harvested from subcutaneously-implanted PVA sponges, and resting peritoneal macrophages were harvested by peritoneal lavage. Gene expression was analyzed using an Atlas cDNA array (Clontech, Mountain View, CA).


RESULTS
TAM demonstrated a pattern of gene expression distinct from both wound and peritoneal macrophage. There is an increase in proliferation-associated genes and in genes encoding the ultrastructural proteins cofillin, zyxin, and vimentin more commonly associated with fibroblast-like cells. In addition, an observed decrease in expression of the CD14 gene, and increase in inhibitory pathways including osteopontin and its receptor CD44, the inositol 1,4,5-triphosphate receptor, and the receptors for interleukin-4 and granulocyte monocyte-colony stimulating factor could explain the resistance of TAM to lipopolysaccharide-mediated stimulation. There was also a significant decrease in the expression of the interferon-gamma second messenger, IRF-1.


CONCLUSIONS
This study has identified a number of pathways involved in the suppression of TAM function. Targeting of these pathways may allow for the generation of more effective immune-modulatory anti-neoplastic therapy.
Duff
Michael D
MD
Department of Surgery, Weill Medical College of Cornell University, New York Presbyterian Hospital, New York, New York, USA. mduff100@hotmail.com
Mestre
Juan
J
Maddali
Sirish
S
Yan
Zhao Ping
ZP
Stapleton
Philip
P
Daly
John M
JM
D000818:Animals; D049109:Cell Proliferation; D005109:Extracellular Matrix / Q000378:metabolism / Q000473:pathology; D005260:Female; D020869:Gene Expression Profiling; D008264:Macrophages / Q000378:metabolism* / Q000473:pathology; D017737:Macrophages, Peritoneal / Q000378:metabolism* / Q000473:pathology; D008546:Melanoma, Experimental / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D020411:Oligonucleotide Array Sequence Analysis; D010533:Peritoneal Lavage; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D012878:Skin Neoplasms / Q000378:metabolism* / Q000473:pathology; D015503:Surgical Sponges / Q000009:adverse effects; D014947:Wounds and Injuries / Q000209:etiology / Q000378:metabolism* / Q000473:pathology
D012333:RNA, Messenger