Dietary restriction reduces angiogenesis and growth in an orthotopic mouse brain tumour model - PubMed (original) (raw)

Dietary restriction reduces angiogenesis and growth in an orthotopic mouse brain tumour model

P Mukherjee et al. Br J Cancer. 2002.

Abstract

Diet and lifestyle produce major effects on tumour incidence, prevalence, and natural history. Moderate dietary restriction has long been recognised as a natural therapy that improves health, promotes longevity, and reduces both the incidence and growth of many tumour types. Dietary restriction differs from fasting or starvation by reducing total food and caloric intake without causing nutritional deficiencies. No prior studies have evaluated the responsiveness of malignant brain cancer to dietary restriction. We found that a moderate dietary restriction of 30-40% significantly inhibited the intracerebral growth of the CT-2A syngeneic malignant mouse astrocytoma by almost 80%. The total dietary intake for the ad libitum control group (n=9) and the dietary restriction experimental group (n=10) was about 20 and 13 Kcal x day(-1), respectively. Overall health and vitality was better in the dietary restriction-fed mice than in the ad libitum-fed mice. Tumour microvessel density (Factor VIII immunostaining) was two-fold less in the dietary restriction mice than in the ad libitum mice, whereas the tumour apoptotic index (TUNEL assay) was three-fold greater in the dietary restriction mice than in the ad libitum mice. CT-2A tumour cell-induced vascularity was also less in the dietary restriction mice than in the ad libitum mice in the in vivo Matrigel plug assay. These findings indicate that dietary restriction inhibited CT-2A growth by reducing angiogenesis and by enhancing apoptosis. Dietary restriction may shift the tumour microenvironment from a proangiogenic to an antiangiogenic state through multiple effects on the tumour cells and the tumour-associated host cells. Our data suggest that moderate dietary restriction may be an effective antiangiogenic therapy for recurrent malignant brain cancers.

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Figures

Figure 1

Energy intake in male C57BL6/J mice bearing the intracerebral CT-2A brain tumour. DR was initiated on day 1 and tumours were implanted on day 8. Values are expressed as means±s.e.m. and _n_=the number of tumour-bearing mice examined in each group.

Figure 2

Influence of DR on the intracerebral growth of the CT-2A brain tumour. DR was initiated 7 days before tumour implantation and was continued for 14 days after implantation as shown in Figure 1. Values are expressed as means±s.e.m. and _n_=the number of tumour-bearing mice examined in each group. The dry weight of the treated tumours was significantly lower than that of the control tumours (P<0.001, two tailed _t_-test).

Figure 3

Influence of DR on microvessel density and apoptosis in the CT-2A brain tumour. DR was initiated 7 days before intracerebral tumour implantation and was continued for 11 days. H&E stained tumour sections in an AL mouse (A) and in a DR mouse (B) (100×). Factor VIII immunostaining from the tumour grown in an AL mouse (C) and in a DR mouse (D) (200×). TUNEL positive apoptotic cells (arrows) from the tumour grown in an AL mouse (E) and in a DR mouse (F) (400×). Each stained section was representative of the entire tumour. All images were produced from digital photography.

Figure 4

Tumour cell-induced vascularity in the in vivo Matrigel plug assay. CT-2A tumour cells in Matrigel were injected s.c. in the flank of a BALB/c-SCID mouse as described in Materials and Methods. DR treatment was initiated 7 days prior to tumour cell injection. The Matrigel plugs with surrounding skin were removed on day 7 after implantation and photographed at 12.5×.

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Dietary restriction reduces angiogenesis and growth in an orthotopic mouse brain tumour model - PubMed (original) (raw)