Endostatin inhibits murine colon carcinoma sinusoidal-type metastases by preferential targeting of hepatic sinusoidal endothelium.
An angiogenic response originating from peritumoral sinusoids and portal tracts that leads to the formation of metastases with sinusoidal- and portal-type angiogenic patterns, respectively, occurs during the course of liver colonization by murine 51b colon carcinoma (51b-CC) cells. We found a 5-fold increase in endogenous endostatin levels from hepatic blood over baseline (25 +/- 6 ng/mL) when micrometastatic foci had a detectable size and a 14-fold increase when macrometastases were developed. Despite this endogenous endostatin production, subcutaneous administration of recombinant human endostatin (rh-E; 50 mg/kg) decreased metastasis number by 60% when dosed from days 1 to 20 after 51b-CC cell injection, by 40% when given from days 10 to 20, and by 30% when administered as a single dose 30 minutes before 51b-CC cell injection compared with controls. In addition, administration of rh-E from days 10 to 20 decreased overall metastasis volume by 90% compared with controls. rh-E increased the number of necrotic sinusoidal-type metastases by 7-fold and decreased their intrametastatic CD31(+)-microvessel density by 80% without affecting portal-type metastases. Flow cytometry showed rh-E binding to mouse liver sinusoidal cells but not to CD45(+) cells (leukocytes and Kupffer cells) or 51b-CC cells. Furthermore, rh-E induced sinusoidal endothelium cell apoptosis. In conclusion, despite the direct correlation between metastasis development and endogenous endostatin generation in the liver, administration of rh-E inhibited micrometastasis generation and macrometastasis growth very efficiently. The antiangiogenic mechanism was selective for sinusoidal-type metastases, in which the neovasculature originating from sinusoidal endothelium cells was targeted by rh-E.
Solaun
Miren S
MS
Biomedical Research and Technological Development Institute, INBIOMED Foundation, San Sebastian Technological Park, Gipuzkoa, Spain.
Mendoza
Lorea
L
De Luca
Marco
M
Gutierrez
Virginia
V
López
Mari-Paz
MP
Olaso
Elvira
E
Lee Sim
B Kim
BK
Vidal-Vanaclocha
Fernando
F
D000818:Animals; D000970:Antineoplastic Agents / Q000097:blood / Q000494:pharmacology*; D002448:Cell Adhesion / Q000187:drug effects; D002455:Cell Division / Q000187:drug effects; D003094:Collagen / Q000097:blood / Q000494:pharmacology*; D024042:Collagen Type I / Q000378:metabolism; D003110:Colonic Neoplasms / Q000473:pathology*; D043169:Endostatins; D004727:Endothelium / Q000098:blood supply / Q000473:pathology; D008114:Liver Neoplasms, Experimental / Q000098:blood supply / Q000188:drug therapy* / Q000556:secondary*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D009336:Necrosis; D009368:Neoplasm Transplantation; D009389:Neovascularization, Pathologic / Q000188:drug therapy; D010446:Peptide Fragments / Q000097:blood / Q000494:pharmacology*; D011485:Protein Binding / Q000187:drug effects; D011994:Recombinant Proteins / Q000097:blood / Q000494:pharmacology; D013154:Spleen; D014407:Tumor Cells, Cultured / Q000166:cytology / Q000637:transplantation
D000970:Antineoplastic Agents; D024042:Collagen Type I; D043169:Endostatins; D010446:Peptide Fragments; D011994:Recombinant Proteins; D003094:Collagen