Basic principles of the molecular biology of cancer II: angiogenesis, invasion and metastasis

Progression of malignancy is associated with invasion into surrounding normal tissues and spread, via blood vessels and lymphatic channels, to distant sites (metastasis). Metastases are responsible for 90% of cancer-related death, with opportunities for resection exceptional and long-term control with other treatment modalities uncommon. Altered expression of adhesion molecules, including cadherins and intergrins, permits cellular detachment from the primary tumour mass, through changes in adhesion specificity and direct signalling to intracellular pathways (‘inside-out’ signalling). Tumour and conscripted host cells produce matrix-degrading proteases that disrupt the architecture of surrounding tissue and release matrix-bound growth factors that support invasion. Migrating malignant cells must gain entry into the bloodstream or lymphatic vessels (intravasation), survive transport in the circulation and exit at secondary sites (extravasation). Recent studies have confirmed the importance of post-extravasation interactions between tumour cells and the new environment, including resistance to host apoptotic stimuli, to successful metastatic colonization. An important factor in cancer growth, invasion and metastasis is the recruitment of new blood vessels from the existing vasculature (angiogenesis). Tumour and host cell-derived pro-angiogenic factors bind to receptors on nearby blood vessels and induce the activation, proliferation and migration of endothelial cells towards the tumour. Angiogenesis is also crucial to metastatic growth at secondary sites. This contribution reviews current knowledge regarding the processes of angiogenesis, invasion and metastasis. Elucidation of the mechanisms underpinning these processes is imperative to allow accurate staging of patients and to permit the identification of novel therapeutic targets.