Metastasis of cancer cells in humans occurs mainly via the blood and lymphatic systems. Whereas the role of angiogenesis in cancer metastasis has been well studied, the mechanisms of escape of tumour cells — from the primary tumour to distant sites, via the lymphatic system — are less well understood. In the 7 June issue of Science, Timothy Padera et al. discuss the contribution of the lymphatic system to tumour metastases in mice, focusing on the differences between lymphatics within the tumour and at the tumour edge. The authors used cutaneous melanoma and fibrosarcoma xenografts that were engineered to overexpress VEGFC, a member of the vascular endothelial growth factor (VEGF) family that is involved in stimulating the formation of lymphatic vessels. They also studied tumours in patients with lung cancer. Unlike previous studies, which have concentrated on using either molecular markers or functional assays to investigate lymphangiogenesis, this research combines the two approaches.

Although the expression of VEGFC in the experimental tumours correlated with the incidence of lymph-node metastases and increased staining of lymphatic markers in and around the tumours, functional lymphatic vessels were not found within the tumours. However, these VEGFC-overexpressing tumours all had functional lymphatic vessels in the tumour margin, which is defined as <100 μm from the tumour edge. The vessels in the tumour margins were dilated, and Padera et al. propose that this explains the increase in lymph-node metastases that arise from these tumours. The authors conclude that functional lymphatics in the tumour margin are therefore sufficient for lymphatic metastasis.

To further support their claim, Padera et al. studied a group of 22 patients with lung cancer. The patients had interstitial hypertension, greatly reduced lymphatic function in their tumours and almost no intratumoral lymphatic staining. However, nearly half the patients had metastases in regional lymph nodes, confirming the observations in mice that lymphatic vessels in the tumour margin are sufficient for tumour spread.

So how can these findings help treatment of patients with cancer? The authors suggest that the tumour margins should be treated aggressively by local treatment, such as surgery and radiation, to combat lymphatic dissemination. In addition, the role of VEGFC in lymphangiogenesis makes it a potential target for combating lymphatic metastasis.