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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.

Key Words: angiogenesis • angiostatin • granulocyte/macrophage colony–stimulating factor • metastasis • tumor

Abbreviations used: BCE, bovine capillary endothelial cell(s); bFGF, basic fibroblast growth factor; FBS, fetal bovine serum; GAPDH, glyceraldehyde 3-phosphate dehydrogenase; H, high (levels of GM-CSF– producing); LBS-1, plasminogen lysine–binding site 1; L, low (levels of GM-CSF–producing); MME, macrophage metalloelastase; PEM, peritoneal exudate macrophage(s).

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