C. Bauluz et al., AUGMENTED EXPRESSION OF CYTOKINES IN MOUSE EPIDERMAL TUMOR-CELLS AND ITS POSSIBLE INVOLVEMENT IN THE INDUCTION OF HEMATOPOIETIC ALTERATIONS, Molecular carcinogenesis, 11(3), 1994, pp. 155-163
Mice with skin tumors induced either by 7,12-dimethylbenz[a]anthracene
complete carcinogenesis or subcutaneous injection of a carcinogenic k
eratinocyte cell line showed moderate to severe splenomegaly as a resu
lt of an increase in splenic granulocyte-macrophage and erythroid (ery
throid burst-forming unit) progenitors. To test whether the observed a
lterations involve the release of soluble factors by the epidermal com
ponent of skin tumors, we used an in vitro approach. A series of mouse
keratinocyte cell lines resembling progressive stages of skin carcino
genesis and carrying either normal or activated Ha-ras genes were assa
yed for their ability to produce the factors required for colony growt
h of hematopoietic-committed progenitors. Only the conditioned media o
f keratinocytes harboring activated Ha-ras genes were able to support
the growth of granulocyte-macrophage colony-forming units. In addition
, preincubation of normal bone-marrow cells with conditioned media fro
m the transformed epidermal cell lines stimulated in vitro amplificati
on of the hematopoietic granulocyte-macrophage progenitor compartment.
To identify the possible factors responsible for the activities detec
ted in the keratinocyte-conditioned media, we performed northern blot
analysis using the cytokine probes granulocyte colony-stimulating fact
or, macrophage colony-stimulating factor, granulocyte-macrophage colon
y-stimulating factor, stem cell factor, interleukin-1 alpha, interleuk
in-3, and tumor necrosis factor-alpha. The cell lines expressed differ
ent cytokine mRNA combinations that positively correlated with the col
ony-stimulating activity detected in the corresponding conditioned med
ium. These results suggest that transformed epidermal tumor cells in v
ivo may alter normal hematopoiesis as a consequence of the production
of cytokines that act in autocrine or paracrine loops probably related
to tumor growth. (C) 1994 Wiley-Liss, Inc.