Prevention of cancer recurrence in tumor margins by stopping microcirculation in the tumor and tumor–host interface

Authors

  • Katsuyoshi Hori,

    Corresponding author
    1. Division of Cancer Science, Department of Vascular Biology, Institute of Development, Aging and Cancer, Tohoku University, Sendai, Japan
    • Correspondence

      Katsuyoshi Hori, Department of Vascular Biology, Division of Cancer Science, Institute of Development, Aging and Cancer, Tohoku University, 4-1 Seiryomachi, Aoba-ku, Sendai, Miyagi 980-8575, Japan.

      Tel: 81-22-717-8532; Fax: 81-22-717-8533;

      E-mail: k-hori@idac.tohoku.ac.jp

    Search for more papers by this author
  • Hirotoshi Akita,

    1. Division of Craniofacial Development and Regeneration, Tohoku University Graduate School of Dentistry, Sendai, Japan
    Search for more papers by this author
    • This author retired from Tohoku University by retirement age in 2013.
  • Hiroi Nonaka,

    1. Department of Functional Brain Imaging, Institute of Development, Aging and Cancer, Tohoku University, Sendai, Japan
    Search for more papers by this author
  • Akira Sumiyoshi,

    1. Department of Functional Brain Imaging, Institute of Development, Aging and Cancer, Tohoku University, Sendai, Japan
    Search for more papers by this author
  • Yasuyuki Taki

    1. Department of Nuclear Medicine and Radiology, Institute of Development, Aging and Cancer, Tohoku University, Sendai, Japan
    Search for more papers by this author

  • Funding Information

    Ministry of Education, Science, Sports and Culture, Japan.

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.

Ancillary