Consistent interactions between tumor cell IL-6 and macrophage TNF-α enhance the growth of human prostate cancer cells in the bone of nude mouse.
To test the hypothesis that tumor-associated macrophages (TAMs) enhance the growth and metastasis of human prostate cancer in the bone, we evaluated the effects of decreasing interleukin-6 (IL-6) production by tumor cells and TAMs in a mouse model of bone metastasis. Human PC-3MM2 cells that produce IL-6 were transfected with lentivirus containing IL-6 small hairpin RNA (shRNA) or nonspecific RNA and injected into the tibias of nude mice treated intraperitoneally every 5days for 5weeks with phosphate-buffered saline (PBS), liposomes containing PBS, or liposomes containing clodronate (to decrease the number of macrophages). Transfection of PC-3MM2 cells with IL-6 shRNA significantly decreased cellular expression of IL-6 and the number of TAMs and osteoclasts in bone tumors, which correlated with significant decreases in tumor size, bone lysis, and incidence of lymph node metastasis. Treatment of mice with clodronate liposomes significantly decreased the number of TAMs and osteoclasts in the bone tumors, the expression of IL-6 in the PC3-MM2 cells, and the production of tumor necrosis factor (TNF)-α by TAMs. These findings correlated with a significant decrease in tumor size, bone lysis, and lymph node metastasis. Knocking down IL-6 in tumor cells and decreasing TAMs was associated with the lowest incidences of bone tumors and lymph node metastasis. These results suggest that TAMs enhance the growth of prostate cancer cells in the bone.
Department of Cancer Biology, Cancer Metastasis Research Center, The University of Texas M. D. Anderson Cancer Center, Houston, TX 77030, USA.
Seung Wook
SW
Kim
Jang Seong
JS
Kim
John
J
Papadopoulos
Hyun Jin
HJ
Choi
Junqin
J
He
Marva
M
Maya
Robert R
RR
Langley
Dominic
D
Fan
Isaiah J
IJ
Fidler
Sun-Jin
SJ
Kim
D000818:Animals; D001859:Bone Neoplasms / Q000276:immunology* / Q000556:secondary; D002277:Carcinoma / Q000276:immunology* / Q000556:secondary; D002450:Cell Communication / Q000187:drug effects / Q000235:genetics / Q000276:immunology; D045744:Cell Line, Tumor; D004002:Clodronic Acid / Q000008:administration & dosage / Q000378:metabolism; D006801:Humans; D015850:Interleukin-6 / Q000235:genetics / Q000276:immunology / Q000378:metabolism; D008081:Liposomes / Q000378:metabolism; D008264:Macrophages / Q000187:drug effects / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D008297:Male; D051379:Mice; D008819:Mice, Nude; D010010:Osteoclasts / Q000276:immunology / Q000378:metabolism* / Q000473:pathology; D011471:Prostatic Neoplasms / Q000276:immunology* / Q000473:pathology; D034741:RNA, Small Interfering / Q000235:genetics; D047368:Tumor Burden / Q000187:drug effects / Q000235:genetics; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology / Q000378:metabolism
D015850:Interleukin-6; D008081:Liposomes; D034741:RNA, Small Interfering; D014409:Tumor Necrosis Factor-alpha; D004002:Clodronic Acid
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