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J. Exp. Med.,
Volume 188, Number 4, August 17, 1998 755-763
By
From the Department of Cell Biology, The University of Texas M.D. Anderson Cancer Center,
Houston, Texas 77030
We determined whether tumor cells consistently generating granulocyte/macrophage colony-
stimulating factor (GM-CSF) can recruit and activate macrophages to generate angiostatin and,
hence, inhibit the growth of distant metastasis. Two murine melanoma lines, B16-F10 (syngeneic to C57BL/6 mice) and K-1735 (syngeneic to C3H/HeN mice), were engineered to produce GM-CSF. High GM-CSF (>1 ng/106 cells)- and low GM-CSF (<10 pg/106 cells)-producing clones were identified. Parental, low, and high GM-CSF-producing cells were injected
subcutaneously into syngeneic and into nude mice. Parental and low-producing cells produced rapidly growing tumors, whereas the high-producing cells produced slow-growing tumors.
Macrophage density inversely correlated with tumorigenicity and directly correlated with
steady state levels of macrophage metalloelastase (MME) mRNA. B16 and K-1735 subcutaneous (s.c.) tumors producing high levels of GM-CSF significantly suppressed lung metastasis of
3LL, UV-2237 fibrosarcoma, K-1735 M2, and B16-F10 cells, but parental or low-producing
tumors did not. The level of angiostatin in the serum directly correlated with the production of
GM-CSF by the s.c. tumors. Macrophages incubated with medium conditioned by GM-CSF-
producing B16 or K-1735 cells had higher MME activity and generated fourfold more angiostatin than control counterparts. These data provide direct evidence that GM-CSF released from a primary tumor can upregulate angiostatin production and suppress growth of metastases.
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