Despite ongoing clinical trials, the efficacy of
anti-angiogenic drugs for the treatment of
brain metastases (BM) is still questionable. The lower response rate to anti-angiogenic
therapy in the presence of BM than in metastatic disease involving other sites suggests that BM may be insensitive to these drugs, although the
biological reasons underlining this phenomenon are still to be clarified. With the aim of assessing whether the targets of anti-angiogenic
therapies are actually present in BM, in the present study, we analyzed the microvessel density (MVD), a measure of neo-angiogenesis, and the vascular phenotype (mature vs. immature) in the
tumor tissue of a series of BM derived from different primary
tumors. By using immunohistochemistry against
endoglin, a specific marker for newly formed vessels, we found that neo-angiogenesis widely varies in BM depending on the site of the primary
tumor, as well as on its histotype. According to our results, BM from
lung cancer displayed the highest MVD counts, while those from
renal carcinoma had the lowest. Then, among BM from
lung cancer, those from large cell and
adenocarcinoma histotypes had significantly higher MVD counts than those originating from
squamous cell carcinoma (p=0.0043; p=0.0063). Of note, MVD counts were inversely correlated with the maturation index of the
endoglin-stained vessels, reflected by the coverage of smooth muscle actin (SMA) positive pericytes (r=-0.693; p<0.0001). Accordingly, all the
endoglin-positive vessels in BM from pulmonary
squamous cell carcinoma and
renal carcinoma, displayed a mature phenotype, while vessels with an immature phenotype were found in highly vascularized BM from pulmonary large cell and
adenocarcinoma. The low MVD and mature phenotype observed in BM from some primary
tumors may account for their low sensitivity to anti-angiogenic
therapies. Although our findings need to be validated in correlative studies with a clinical response, this should be taken into account in therapeutic protocols in order to avoid the adverse effects of useless
therapies.