A final set of factors that contribute to the progression of cancer includes genes that affect the growth and spread of tumors. Oxygen and nutrients, which are essential to the survival and growth of tumors, are supplied by blood vessels, and the growth of new blood vessels (angiogenesis) is important to tumor progression. Angiogenesis is stimulated by growth factors and other proteins encoded by genes whose expression is carefully regulated in normal cells. In tumor cells, genes encoding these proteins are often overexpressed compared with normal cells, and inhibitors of angiogenesis-promoting factors may be inactivated or underexpressed. At least one inherited cancer—von Hippel–Lindau disease, in which people develop multiple types of tumors—is caused by the mutation of a gene that affects angiogenesis.

In the development of many cancers, the primary tumor gives rise to cells that spread to distant sites, producing secondary tumors. This process of metastasis, which is the cause of death in 90% of human cancer deaths, is influenced by cellular changes induced by somatic mutation. As discussed in the introduction to this chapter, the palladin gene, when mutated, contributes to the metastasis of pancreatic tumors. By using microarrays to measure levels of gene expression in tumors, researchers have identified other genes that are transcribed at a significantly higher rate in metastatic cells than in nonmetastatic cells. For example, one study detected a set of 95 genes that were overexpressed or underexpressed in a population of metastatic breast-cancer cells that were strongly metastatic to the lung, compared with a population of cells that were only weakly metastatic to the lung. Genes that contribute to metastasis often encode components of the extracellular matrix and the cytoskeleton. Others encode adhesion proteins, which help hold cells together.

Advances in sequencing technology have now made it possible to completely sequence the DNA of tumor cells to see how their genomes differ from those of normal cells. In one experiment, researchers sequenced the entire genome of cells from a metastasized breast-cancer tumor and compared it with the genome of noncancer cells from the same person. They also compared the genome of the metastasized tumor with the genome of the primary tumor (from which the metastasis originated), which had been removed from the patient nine years earlier. The researchers found 32 different somatic mutations in the coding regions of genes from the metastasized tumor cells, 19 of which were not detected in the primary tumor. This finding suggests that the metastasized tumor underwent considerable genetic changes during its nine-year evolution from the primary tumor. In contrast, another study of a breast-cancer metastasis found only two mutations that were not present in the primary tumor, but in this case, the metastasis had evolved in only one year.