The effects of tumor-promoting phorbol esters on human granulopoiesis in
vitro
R Sullivan, RA Brodie, NE Larsen, PJ Gans and LA McCarroll
In order to determine whether the tumor-promoting phorbol esters are
capable of inducing normal human committed granulocytic-monocytic
progenitor cells (CFUc) to proliferate and differentiate in the absence of
granulocyte-monocyte colony-stimulating activity (CSA), we studied the
effects of these compounds on human granulopoiesis in vitro. We found that
when light-density human marrow cells or peripheral blood leukocytes were
depleted of adherent cells and then incubated in semisolid tissue culture
medium under conditions optimal for CFUc growth, phorbol myristate acetate
(PMA) and its congeners produced no measurable stimulatory effect on the
proliferation of CFUc in the absence of added CSA. Likewise, when
light-density marrow cells that had not been depleted of adherent cells
were plated in the cultures, no stimulation of CFUc colony growth resulted
from the addition of PMA. However, when light-density peripheral blood
leukocytes were used as a target source of CFUc without first subjecting
them to adherence separation, enhanced proliferation and differentiation of
CFUc were noted in cultures that contained PMA. To investigate the
possibility that CSA production by monocytes in these cultures in response
to activation by PMA might account for the enhanced colony formation that
we observed, we incubated isolated peripheral blood monocytes in short-
term liquid suspension cultures and found that in the presence of PMA,
large quantities of CSA were secreted into the surrounding medium. Finally,
we noted that when marrow cell suspensions were suboptimally stimulated by
low concentrations of CSA added to the cultures, the effects of PMA on CFUc
proliferation were unpredictable, enhancing colony formation in some cases
and inhibiting it in others. Our data indicate that although the
tumor-promoting phorbol esters do not appear capable of directly
stimulating the proliferation or differentiation of human CFUc in the
absence of CSA, they may do so indirectly by causing auxiliary cells such
as monocytes to secrete CSA.
Volume 64,
Issue 2,
pp. 526-533,
08/01/1984
Copyright © 1984 by The American Society of Hematology
