Endothelial cell proliferation as a novel approach to targeting tumour therapy

Abstract

THE proliferation rate of vascular endo-thelial cells in tumours exceeds that in most adult normal tissues by a very large factor, often greater than 20 (Figure). This enormous differential offers a potential route for aiming tumour therapy at solid tumours by means of a targeted systemic toxin, with little risk of damage to most of the normal tissues. It has long been recognized that one of the major differences between solid tumours and adult normal tissues is the pattern and rate of development of the vascular network. New vessel formation in tumours is rapid, but it is insufficient, particularly in a 3-dimensional arrangement , to provide an adequate nutrient supply to all the tumour cells (Hirst et al., 1982). For this reason many tumour cells are non-proliferating because of nutrient deprivation, and hypoxic because of oxygen depletion by the metabolizing tumour cells around each capillary. This produces resistance to both chemotherapy and radiotherapy. A great deal of research is devoted to finding ways of improving the oxygenation, proliferative status and drug delivery in such tumours. recognized the special ability of tumour cells to promote new vessel formation via the tumour angiogenesis factor (TAF). They have proposed methods ofpreventing tumour growth by interfering with angio-genesis, including an immunological technique for inactivating TAF by producing an anti-TAF antibody which would prevent further capillary proliferation. Elsewhere, little attention has been paid to the enormous differential between the proliferation characteristics of the tumour vasculature and the normal tissue vasculature. Tannock (1970), Hirst & Denekamp (1979) and Hirst et al. (1982) have compared the proliferation rate of the capillary endothelium in tumours with that of the tumour cells themselves. They concluded that the rate of endothelial proliferation limits tumour cell production even though as many as 18% of the endothelial cells can be in DNA synthesis at any one time. Other studies have concentrated on the very low proliferation rate of endothelial cells in a variety of normal tissues (see reviews by Tannock & Hayashi, 1972; Hirst et al., 1980). However, the remarkable difference in proliferation rates between endothelium in tumours and in normal tissues does not seem to have been previously commented upon or identified as a potential route for directing therapy at a tumour. The Table summarizes the published labelling index (LI) for normal tissue and tumour endothelium, and illustrates the large difference between them. The values shown were obtained by scoring auto-radiographs …