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© The Rockefeller University Press, 0022-1007/1998/8/755/ $5.00
The Journal of Experimental Medicine, Volume 188, Number 4, August 17, 1998 755-763

Articles

Angiostatin-mediated Suppression of Cancer Metastases by Primary Neoplasms Engineered to Produce Granulocyte/Macrophage Colony–stimulating Factor

Zhongyun Dong, Junya Yoneda, Rakesh Kumar, and Isaiah J. Fidler

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

Address correspondence to Zhongyun Dong, Department of Cell Biology, Box 173, University of Texas M.D. Anderson Cancer Center, 1515 Holcombe Blvd., Houston, TX 77030. Phone: 713-792-8523; Fax: 713-792-8747; E-mail: zdong{at}notes.mdacc.tmc.edu

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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