Molecular mechanisms regulating TNF-alpha production by tumor-associated macrophages.
The molecular mechanisms that regulate the production and/or functional activity of intratumoral tumor necrosis factor-alpha (TNF-alpha) remain poorly defined. To begin to address this issue we have examined the level of TNF-alpha mRNA and protein produced by macrophages present within immunogenic Fsa-R and non-immunogenic Fsa-N tumors grown in syngeneic Lps(d) C3H/HeJ and Lps(n) C3H/HeN mice. The results obtained indicate that macrophages isolated from tumors grown in Lps(d) C3H/HeJ mice express 5-10-fold less TNF-alpha than equivalent cells present in tumors grown in Lps(n) C3H/HeN mice. These data suggest that the mechanisms that operate within the tumor microenvironment to induce the production of TNF-alpha act, at least in part, via the same signal transduction pathway that is defective in Lps(d) C3H/HeJ mice. Interestingly, despite such differences in TNF-alpha production, tumors inoculated into C3H/HeJ and C3H/HeN mice grew at a similar rate and contained an almost identical proportion of macrophages. Moreover, tumor cells purified from tumors grown in C3H/HeJ and C3H/HeN mice produced similar quantities of the TNF-alpha-inducible cytokine GM-CSF. Thus, although differences in the level of TNF-alpha produced within tumors grown in C3H/HeN and C3H/HeJ mice are readily demonstrable, such differences appear to have little direct impact on the outcome of tumor growth.
Dougherty
S T
ST
Terry Fox Laboratory, BC Cancer Agency, Vancouver, British Columbia, Canada.
Eaves
C J
CJ
McBride
W H
WH
Dougherty
G J
GJ
D000818:Animals; D005354:Fibrosarcoma / Q000378:metabolism; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000096:biosynthesis; D008264:Macrophages / Q000378:metabolism*; D051379:Mice; D008809:Mice, Inbred C3H; D009363:Neoplasm Proteins / Q000096:biosynthesis* / Q000235:genetics; D012333:RNA, Messenger / Q000378:metabolism; D014407:Tumor Cells, Cultured; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis* / Q000235:genetics
D009363:Neoplasm Proteins; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; D016178:Granulocyte-Macrophage Colony-Stimulating Factor