Dormancy of micrometastases: balanced proliferation and apoptosis in the presence of angiogenesis suppression.
In cancer patients, dormant micrometastases are often asymptomatic and clinically undetectable, for months or years, until relapse. We have studied dormant lung metastases under angiogenesis suppression in mice. The metastases exhibited rapid growth when the inhibition of angiogenesis was removed. Tumour cell proliferation, as measured by bromodeoxyuridine incorporation and immunohistochemical staining proliferating cell nuclear antigen, was not significantly different in dormant and growing metastases. However, tumour cells of dormant metastases exhibited a more than threefold higher incidence of apoptosis. These data show that metastases remain dormant when tumour cell proliferation is balanced by an equivalent rate of cell death and suggest that angiogenesis inhibitors control metastatic growth by indirectly increasing apoptosis in tumour cells.
Holmgren
L
L
Department of Surgery, Children's Hospital, Boston, Massachusetts, USA.
O'Reilly
M S
MS
Folkman
J
J
D000818:Animals; D000903:Antibiotics, Antineoplastic / Q000494:pharmacology / Q000627:therapeutic use; D017209:Apoptosis; D018827:Carcinoma, Lewis Lung / Q000188:drug therapy / Q000473:pathology / Q000556:secondary / Q000601:surgery; D002455:Cell Division / Q000187:drug effects; D003510:Cyclohexanes; D005354:Fibrosarcoma / Q000188:drug therapy / Q000473:pathology / Q000556:secondary / Q000601:surgery; D008168:Lung / Q000473:pathology; D008175:Lung Neoplasms / Q000098:blood supply / Q000188:drug therapy / Q000473:pathology* / Q000556:secondary*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009362:Neoplasm Metastasis / Q000473:pathology*; D009389:Neovascularization, Pathologic / Q000503:physiopathology*; D000077609:O-(Chloroacetylcarbamoyl)fumagillol; D009929:Organ Size; D018809:Proliferating Cell Nuclear Antigen / Q000032:analysis; D016196:S Phase; D012717:Sesquiterpenes / Q000494:pharmacology / Q000627:therapeutic use; D014407:Tumor Cells, Cultured
D000903:Antibiotics, Antineoplastic; D003510:Cyclohexanes; D018809:Proliferating Cell Nuclear Antigen; D012717:Sesquiterpenes; D000077609:O-(Chloroacetylcarbamoyl)fumagillol