Relationship of endothelial cell proliferation to tumor vascularity in human breast cancer

Current studies of tumor angiogenesis rely on the concept that endothelium proliferates 30-40 times faster in tumors than in normal tissues. This evidence is based on histological autoradiographic data largely from animal studies. To assess endothelial cell proliferation in human cancer we used the more sensitive and specific technique of immunohistochemistry. We measured the frequency and distribution of endothelial cell proliferation and examined their relationship to tumor cell proliferation. For the first time, we also correlated endothelial and tumor cell proliferation with tumor vascularity. Twenty breast carcinomas from patients exposed to bromodeoxyuridine 3-8 h prior to surgery were double immunostained using antibodies to CD31 (as a marker of endothelium) and bromodeoxyuridine (as a marker of proliferation). The labeling index (LI) for both tumor and endothelial cells was determined and tumor vascularity was assessed by counting the number of CD31 positive vessels. Endothelial cell proliferation was predominantly at the tumor periphery while tumor cell proliferation occurred throughout the lesion. The mean LIs for endothelium and tumor were 2.2% (range, 0.8-5.3) and 7.3% (range, 1.3-17.1), respectively. There was no correlation between tumor and endothelial cell LI (P = 0.414) or between the tumor LI or endothelial cell LI and tumor vascularity (P = 0.08 and P = 0.39, respectively). These findings suggest that previous studies in animal tumors have significantly overestimated endothelial cell proliferation and that its importance in tumor angiogenesis may be related more to continual remodeling and migration of vessels than to proliferation alone.