Positive and negative angiogenic factors in patients with malignant disease

Abstract: In this thesis, the levels of positive and negative angiogenic factors were studied in tissue, serum and urine from patients with malignant disease. The angiogenic factors VEGF (vascular endothelial growth factor) and bFGF (basic fibroblast growth factor) were studied in breast carcinomas. In one of the materials studied, we did not find a correlation between any of these factors and the number of microvessels in the tumors. A correlation was found, however, between strong staining of bFGF in the stromal compartment of breast carcinomas and the levels of a metalloprotease expressed by stromal fibroblasts, stromelysin-3. In a material of small (< 1cm), mammographically detected breast carcinomas, low intratumoral microvessel densities were detected. Small breast tumors were found to show low expression of VEGF by immunohistochemical staining. These findings are of interest, since they imply that the excellent prognosis of patients with small breast carcinomas may be related to the limited angiogenic potential of their tumors. Other groups have reported that tissue VEGF is a prognostic marker for some malignancies. Determination of serum VEGF has also been suggested to be of prognostic value. In the present study, we examined the relationship between tissue and serum VEGF using samples from patients with head and neck carcinoma. We found no correlation between the levels of tissue and serum VEGF in the same patients. Serum levels of VEGF were generally increased in patients with malignant tumors. Serum VEGF levels correlated with tumor stage in patients with head and neck carcinoma. Serum VEGF may turn out to be a useful tumor marker for some malignancies. In our material, we found that VEGF and bFGF were not coexpressed in the same sera. Western blotting experiments demonstrated, for the first time, the presence of angiostatin, an inhibitor of angiogenesis, in the urine of some patients with solid tumors. N-terminal sequencing suggested that the structure of angiostatin from cancer patients is similar to that described in Lewis carcinoma bearing mice. The levels of urine angiostatin were found to be dependent on kidney function. In conclusion, increased levels of VEGF, bFGF and angiostatin could be demonstrated in samples from cancer patients. Although these factors are likely to have important physiological functions, the prognostic value of their determination in cancer patients remains to be established.