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.

Accurate early prediction of tumour response to PDT using optical coherence angiography

“…Numerous recent studies, for example by Kutsuyoshi et al . 28 , have analogously demonstrated that blocking both blood circulation routes (tumour and peri-tumourous vessels) has great potential as a clinical strategy to prevent cancer recurrence.…”

Meeting the needs of breast cancer: A nucleolin’s perspective

“…The low extent of the antivascular effect might support the similar tumor viable rim area between mice treated with the Doxorubicin formulations and non-treated mice (Figure 3.6B). Additionally, nontumoral vessels from surrounding tissues are also expected to provide nutrient and oxygen supplies to cells in the peritumoral region 451,452 . Altogether, these factors likely contributed to the maintenance of viable areas in the tumor mass that fuels its expansion and invasion (Figure 3.6A), and could be responsible for the tumor regrowth observed in some Caelyx®treated mice.…”

Inoculated Cell Density as a Determinant Factor of the Growth Dynamics and Metastatic Efficiency of a Breast Cancer Murine Model

“…The low extent of the antivascular effect might support the similar tumor viable rim area between mice treated with Caelyx® and non-treated mice (Fig 4D). Additionally, non-tumoral vessels from surrounding tissues are also expected to provide nutrient and oxygen supplies to cancer cells [71, 72]. These factors likely contributed to the maintenance of tumor viable areas that fuels its expansion and invasion (Fig 4C), and could be responsible for the tumor regrowth observed in some Caelyx®-treated mice.…”