Tumor angiogenesis in primary and metastatic colorectal cancers

Angiogenesis is needed to sustain growth of both primary and metastatic lesions; however, comparisons in microvessel density between a primary tumor and its metastases have not been widely performed. We studied microvessel density in primary colorectal cancers and their liver metastases.

Sections from 32 primary lesions and 53 hepatic metastases were immunostained with a monoclonal antibody for von Willebrand's factor, an endothelial cell marker. Blood vessels were quantified under x 100 magnification using both conventional light microscopy and computer-assisted image analysis. Primary and metastatic angiogenesis scores (AS), i.e., vessel counts, were analyzed with respect to tumor size, hepatic multicentricity, synchronicity, resectability, and patient survival. Using computer-assisted calculations, the same analyses were performed using blood vessel to tumor surface area ratios, vessel wall thickness, and intensity of immunostaining.

Angiogenesis scores were significantly lower in metastatic lesions compared with their primary tumors (P < 0.0001). Primary AS did not correlate with metastatic tumor size, resectability, multicentricity, or patient survival. Metastatic AS strongly predicted patient survival (P < 0.0009) but with a negative coefficient, i.e., higher scores were associated with improved survival. Metastatic AS were higher in resectable than in nonresectable metastases and in solitary than in multiple metastases; however, these trends were not statistically significant. Metachronous liver lesions had significantly higher angiogenesis scores than synchronous metastases (P < 0.04). Similar trends were seen using computer-assisted image analysis.

These results indicate that in presence of an established metastasis, there is a weak angiogenic relationship between a primary tumor and its metastasis. Heterogeneity in metastatic lesions cannot be explained solely by studying angiogenesis in primary tumors. Microvessel density in a primary tumor may not be useful as an independent prognostic indicator in late stages of disease. In such cases, assessment of microvessel density in a metastatic tumor whenever possible may be an indicator of prognosis.