Beta-fibroblast growth factor expression in human and murine squamous cell carcinomas and its relationship to regional endothelial cell proliferation.

Abstract

Surgical biopsies from ten head and neck squamous cell carcinomas were labeled in vitro with bromodeoxyuridine. In histological sections, bromodeoxyuridine-positive nuclei and beta-fibroblast growth factor (beta-FGF) were stained using immunohistochemistry. In clearly discernible clusters of tumor cells, the cytoplasm shows strong positive beta-FGF staining, whereas other tumor regions are completely beta-FGF negative. Within positively stained areas, the tumor cell bromodeoxyuridine labeling index is higher in comparison to beta-FGF-negative areas by a factor of 5 +/- 0.8. This is reflected in a positive correlation of the tumor cell labeling index and the relative extent of beta-FGF-positive tumor areas. Viable tumor areas bordering on necrosis, which are known to be hypoxic, are beta-FGF negative. The average tumor endothelial cell labeling index was 1.8 +/- 0.6%, as compared to 0.16% in adjacent normal mucosa. Since endothelial cell pulse labeling indices are too low for a further quantitative analysis, the relationship of beta-FGF expression and endothelial cell turnover was studied in more detail in two fairly well-differentiated murine squamous cell carcinoma lines (AT 84 and AT 478). Labeling indices were higher and endothelial cell doubling times were significantly shorter in beta-FGF-positive as compared to beta-FGF-negative tumor areas (AT 84, 9.3 h versus 25.4 h; AT 478/25, 6.8 h versus 16 h). Thus, the discrete expression of beta-FGF is associated with regional differences in endothelial cell kinetics. In two generations of the tumor line AT 478, characterized by different volume doubling times of 18 days (AT 478/25) and 36 days (AT 478/4), beta-FGF-positive areas represent 75.5 +/- 6% and 19.7 +/- 7% of the viable tumor tissue, respectively. This indicates a correlation between beta-FGF production of tumor cells and growth rate.