TY - JOUR
T1 - Angiostatin-mediated suppression of cancer metastases by primary neoplasms engineered to produce granulocyte/macrophage colony-stimulating factor
AU - Dong, Zhongyun
AU - Yoneda, Junya
AU - Kumar, Rakesh
AU - Fidler, Isaiah J.
PY - 1998/8/17
Y1 - 1998/8/17
N2 - 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.
AB - 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.
KW - Angiogenesis
KW - Angiostatin
KW - Granulocyte/macrophage colony-stimulating factor
KW - Metastasis
KW - Tumor
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U2 - 10.1084/jem.188.4.755
DO - 10.1084/jem.188.4.755
M3 - Article
C2 - 9705957
AN - SCOPUS:0032541472
SN - 0022-1007
VL - 188
SP - 755
EP - 763
JO - Journal of Experimental Medicine
JF - Journal of Experimental Medicine
IS - 4
ER -