title: Prevention of cancer recurrence in tumor margins by stopping microcirculation in the tumor and tumor-host interface.
abstract: Combretastatins interrupt blood flow of solid tumor vascular networks and lead to necrosis by blocking nutrients. However, tumors recover from tumor blood flow interruption-induced damage and develop viable rims. To investigate why cancer recurs and its prevention, we used a combretastatin derivative, Cderiv (=AC7700), and analyzed changes in tumor-host interface (T-HI) vessels, which were closest to cancer cells in the tumor margin after tumor vessel disruption, and the microenvironment surrounding them. Treatment with Cderiv (10 mg/kg) interrupted tumor blood flow in all regions of LY80 (a variant of Yoshida sarcoma) tumor, but not T-HI vessel blood flow. The same Cderiv dose given 72 h after 5 Gy irradiation stopped T-HI vessel blood flow and prevented cancer recurrence. Treatment in the reverse order, however, did not affect T-HI vessel blood flow. The greatest difference between the two treatments was the occurrence of gradual T-HI edema with the former. Severe T-HI edema compressed T-HI blood vessels, so that circulation stopped. Thus, the distance between a tumor margin and its nearest functioning host vessel became much larger, and the tumor marginal region became a microenvironment that lacked a nutritional supply. Cancer cells in tumor margins received nutrients through two circulation routes: tumor vessels and T-HI vessels. Our starvation methods, which involved treatment with Cderiv 72 h after 5 Gy irradiation, blocked both circulation routes and may have great potential as a clinical strategy to prevent cancer recurrence.
authors: Division of Cancer Science, Department of Vascular Biology, Institute of Development, Aging and Cancer, Tohoku University, Sendai, Japan.
authors: Katsuyoshi
authors: K
authors: Hori
authors: Hirotoshi
authors: H
authors: Akita
authors: Hiroi
authors: H
authors: Nonaka
authors: Akira
authors: A
authors: Sumiyoshi
authors: Yasuyuki
authors: Y
authors: Taki
mesh_terms: D020533:Angiogenesis Inhibitors / Q000494:pharmacology*; D000818:Animals; D001632:Bibenzyls / Q000494:pharmacology*; D045744:Cell Line, Tumor; D059248:Chemoradiotherapy; D004354:Drug Screening Assays, Antitumor; D004487:Edema / Q000139:chemically induced / Q000378:metabolism; D008297:Male; D009364:Neoplasm Recurrence, Local / Q000517:prevention & control*; D009368:Neoplasm Transplantation; D051381:Rats; D012039:Regional Blood Flow / Q000187:drug effects; D012517:Sarcoma, Yoshida / Q000098:blood supply / Q000473:pathology / Q000628:therapy*; D059016:Tumor Microenvironment / Q000187:drug effects
chemical_list: D020533:Angiogenesis Inhibitors; D001632:Bibenzyls; C571791:Cderiv
keywords: Combretastatins; radiotherapy; tumor blood flow; tumor vessels; viable rim