New perspectives in clinical oncology from angiogenesis research

TUMOUR BURDEN AFFECTS TUMOUR ANGIOGENESIS SINCE THE early 197Os, the conventional wisdom in angiogenesis research was that the neovascularisation in a given tumour bed was an isolated event, unrelated to other turnours. In the past 2 years, it has been recognised that total tumour burden can affect angiogenesis in remote metastases. This recognition came about because of the demonstration by O’Reilly and associates [l] that a primary tumour could suppress angiogenesis in its metastases and that this would iead to inhibition of growth of the metastases. This process was found to be mediated by a novel endogenous angiogenesis inhibitor, angiostatin, generated by the primary tumour [ 11. Angiostatin is a 38 kD protein with homology to the first four kringle structures of plasminogen. It is a specific inhibitor of endothehal cell proliferation. Three converging lines of experimental work led up to O’Reilly’s discovery of angiostatin. The first was that, during the 198Os, my laboratory had been trying to understand how certain primary tumours could suppress the growth of their metastases. Since the turn of the century, clinicians and laboratory investigators have recognised that certain human and animal primary tumours could suppress the growth of their metastases [2-81. Furthermore, Prehn argued with compelling data that the rate of tumour growth was inversely proportional to total tumour burden, regardless of how the tumour was distributed, e.g. single tumour versus multiple implants or metastases [9, lo]. Oncologists have observed that very large tumours may grow very slowly and that ‘debulking’ of a large tumour mass may render the residual tumour more susceptible to cytotoxic chemotherapy. Many explanations have been offered to explain these phenomena, including mechanisms based on immunity (concomitant immunity), hormonal interactions and metabolic changes (accumulation of catabolites). The second line of experiments was a collaboration with Douglas Hanahan (of the University of California, San Francisco). We were studying the mechanism of the switch to the angiogenic phenotype by beta cell carcinomas arising de nowo in the pancreatic islets of transgenic mice [ 11, 121. Two angiogenic proteins, aFGF (acidic fibroblast growth factor) and VEGF (vascular endothelial growth factor) revealed similarly high levels of expression by these islets, before and after the angiogenic switch [13, 141. This provocative result forced us to think that the angiogenic switch could not be explained entirely by positive regulators of angiogenesis, but could also involve some role by negative angiogenic regulators. The third line of experiments was reported in 1989, from Noel Bouck’s laboratory at Northwestern University Medical School, Chicago, Illinois, U.S.A. 1151. Thrombospondin was identified as a negative regulator of angiogenesis that was downregulated during the switch to the angiogenic phenotype in transformed fibroblasts. Subsequently, thrombospondin was shown to be upregulated in human tumour cells by the restoration of ~53 tumour suppressor function, thus negating the angiogenesis inducers that the cells themselves produced as well as added bFGF, leading to blocked angiogenesis [ 161. It immediately occurred to us that a primary tumour elaborating both angiogenic stimulators and ‘left-over’ inhibitor(s) could generate accumulating levels of the putative inhibitor in the circulation, if such an inhibitor had a longer half-life in the circulation than the stimulator. Thus, when O’Reilly found that angiostatin accumulated in the serum and urine of tumour-bearing mice, but disappeared from serum and urine after removal of the tumour, this suggested a role for angiostatin as a mediator of the suppression of metastases by the primary tumour. It became clear that a primary tumour could influence the growth of a metastasis by inhibiting angiogenesis in the metastasis, without communicating directly with its tumour cells.