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Astrocyte-Derived
Cytokines Contribute to the Metastatic Brain Specificity of Breast Cancer
Cells |
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Angels Sierra,
Janet E. Price, Marta GarcAaia-Ramirez, Olga Mendez, Lluis Lopez, and Angels
Fabra |
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Departament
de Cancer i Metastasis (AS, MG-R, OM, LL, AF), Institut de Recerca Oncologica,
Hospital Duran i Reynals, Ciutat Sanitaria i Universitaria de Bellvitge,
Barcelona, Spain; and Department of Cell Biology (JP), University of Texas,
M. D. Anderson Cancer Center, Houston, Texas |
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The occurrence of breast
cancer metastases is preferential to certain organs. Astrocytes may play
an important role in the development of brain metastases, as these cells
have been shown to respond to extracellular stimuli by producing many cytokines
and growth factors that can modulate tumor cell proliferation, growth, and/or
metastases. To test this hypothesis, we analyzed the responses of the human
breast cancer cell line MDA-MB-435 and its metastatic sublines to astrocyte
primary cultures from newborn rat cerebra. Astrocyte purity of the glial
cell cultures was demonstrated by glial fibrillary acidic protein and rat
neural antigen-2 (Ran-2) immunopositive staining. The 435-Br1 cell line,
which was derived from a brain metastases in a nude mouse, showed increased
adhesion to astrocytes and enhanced growth in vitro in the presence of media
from Con A-stimulated astrocytes, relative to the parental MDA-MB-435 and
the lung metastasis-derived variant 435-Lung2. Furthermore, the growth-stimulatory
effect was partially reversed by anti-IL-6, anti-transforming growth factor
beta (anti-TGF beta), and anti-IGF-I antibodies, indicating that these metastatic
cells use exogenous cytokines as paracrine growth factors. In an attempt
to elucidate the role of several biologic-response modifiers produced by
astrocytes, we tested the responses of MDA-MB-435 cells to purified cytokines
and growth factors. We found that the addition of recombinant human or mouse
IL-6 produced a variety of responses in the different 435 metastatic variants.
Furthermore, IL-6 receptor (IL-6R) expression was slightly increased in
the 435-Br1 cells, and exogenous IL-6 rescued 435-Br1 cells from apoptosis
in serum-depleted cultures. No apoptotic protective effect was observed
in either MDA-MB-435 parental cells or 435-Lung2 cells. Thus, responses
to exogenous IL-6 might determine the differences among these metastatic
variants by extending cell survival of selected subpopulations, giving them
the opportunity to respond to growth factors or otherfavorable conditions
that might be present. These results suggest that cytokines produced by
glial cells in vivo may contribute, in a paracrine manner, to the development
of brain metastases by breast cancer cells. |
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