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Transforming
Growth Factor-[beta] Stimulates Urokinase Expression in Tumor-Associated
Macrophages of the Breast |
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Ralf Hildenbrand,
Christian Jansen, Georg Wolf, Beatrix Bohme, Stefan Berger, Gunter von Minckwitz,
Albrecht Horlin, Manfred Kaufmann, and Hans Jochen Stutte |
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Departments
of Pathology (RH, CJ, GW, SB, AH, HJS) and Gynecology (GM, MK), University
Frankfurt am Main, and Chemotherapeutisches Forschungsinstitut (BB), Georg
Speyer Haus, Frankfurt, Germany |
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Recent studies have shown
that urokinase (uPA) is an independent prognostic marker in breast cancer.
uPA plays a key role in the degradation of tumor matrix and promotes tumor
progression. Macrophage expression of uPA appears to be important in this
context. Our objective in the present study was to provide evidence that
tumor growth factor-[beta] (TGF-[beta]) released from breast cancer cells
markedly up-regulates uPA expression in tumor-associated macrophages (TAMs).
TAMs from 32 breast carcinomas were cultured. Blood monocytes from healthy
donors and breast cancer patients as well as tissue macrophages from patients
with fibrocystic changes of the breast were also examined. After TGF-[beta]
incubation, uPA levels were tested by ELISA, and uPA mRNA levels were determined
by Northern blot analysis. TGF-[beta] receptor and uPA cell surface fluorescence
intensities were determined by flow cytometry; TGF-[beta] receptors were
determined by Western blot analysis. Protein kinase-C dependence was also
examined, and immunohistochemical stainings for uPA and TGF-[beta] were
performed. We have demonstrated that TGF-[beta] markedly up-regulates basal
uPA expression (mRNA and protein) in TAMs but only modestly increases uPA
production in blood monocytes and tissue macrophages. Exposure of macrophages
to TGF-[beta]1 led to a rapid and sustained increase in uPA mRNA levels,
which was independent of de novo protein synthesis and completely inhibited
by actinomycin D. H7 markedly reduced the ability of TGF-[beta] to stimulate
uPA expression. Likewise, okadaic acid potentiated the ability of TGF-[beta]
to up-regulate macrophage uPA expression. We suggest that TAMs are more
responsive to TGF-[beta] stimulation than are blood monocytes and tissue
macrophages because of different TGF-[beta] receptor densities. TGF-[beta]
stimulates transcription of the uPA gene, increases uPA-mRNA stability,
and activates uPA expression via protein kinase-C-dependent mechanisms.
The ability of TGF-[beta] to induce macrophage uPA expression may rovide
an indirect mechanism by which this growth factor stimulates angiogenesis.
It may be, therefore, that TAMs promote tumor progression and tumor angiogenesis. |
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