Chance, in the form of random genetic change, does not explain how cell populations at the center of a tumor come to differ from those at the edge. At least, chance by itself fails to account for the distinctive “center” and “edge” tumor phenotypes, even though random mutations do accumulate during tumor development. Chance has a partner: environmental selection.

This Darwinian assertion comes from scientists based at the Moffitt Cancer Center. They deployed a mathematical model based on evolutionary theories to show that certain tumor subpopulations can be predicted and do not develop randomly as previously thought.

The idea that randomness rules phenotype development in tumors rests on an implicit assumption: cancer cells never evolve to a fitness maximum. Cancer cells, according to this idea, can always acquire mutations that increase proliferative capacity.

To test the idea, the Moffitt scientists devised a model based on the evolutionary concept that cancer cells can invest resources in reproduction or the ability to survive, but not both. The model showed that cells at the edge of a tumor invest their limited resources into cellular characteristics that promote invasion and the ability to use resources from the surrounding environment, such as blood vessels. Exterior cells develop these characteristics despite their association with a higher risk of cell death.

Alternatively, cells within the interior of a tumor are surrounded by many other cells and are farther away from the resources present within the environment. Therefore, interior cells develop characteristics that allow them to compete with neighboring cells for the limited resources that are available to them.

This work was reported in the June issue of the journal Cancer Research, in an article entitled, “Darwinian Dynamics of Intratumoral Heterogeneity: Not Solely Random Mutations but Also Variable Environmental Selection Forces.” The article described how the Moffitt scientists used evolutionary game theory to demonstrate that local cancer cell populations will rapidly converge to the fittest phenotype given a stable environment.

In addition, the article indicated that these findings were confirmed by gene expression patterns. Specifically, model predictions were tested through detailed quantitative image analysis of phenotypic spatial distribution in histologic sections of 10 patients with stage 2 invasive breast cancers.

Cells within the interior of a tumor have characteristics that are more static, including less proliferation and more cell death. Alternatively, the cells around the exterior of a tumor have higher rates of proliferation and are more likely to be producing an acidic environment, which is consistent with the need for cells on the edge of a tumor to grow and invade into the surrounding normal tissue.

“CAIX, GLUT1, and Ki67 were upregulated in the tumor edge consistent with an acid-producing invasive, proliferative phenotype,” wrote the article’s authors. “Cells in the tumor core were 20% denser than the edge, exhibiting upregulation of CAXII, HIF-1α, and cleaved caspase-3, consistent with a more static and less proliferative phenotype. Similarly, vascularity was consistently lower in the tumor center compared with the tumor edges.”

These results, according to the article’s authors, suggest that at least some of the molecular heterogeneity in cancer cells in tumors is governed by predictable regional variations in environmental selection forces. This result argues against the assumption that cancer cells can evolve toward a local fitness maximum by random accumulation of mutations.

“Interestingly, differences within a single population are seen in biological invasions in nature,” noted the study’s senior author, Robert A. Gatenby, M.D., senior member and chair of the Department of Diagnostic Imaging and Interventional Radiology at Moffitt. “For example, the cane toad has been invading Australia for many years. The cane toads at the edge of the invasion have bigger legs presumably because they are adapted to moving farther and faster.”

“However,” added Dr. Gatenby, “the characteristics of the invading cane toads that have allowed them to move farther and faster also come with a price: severe spinal arthritis is found in 10% of the larger-legged toads.”

The Moffitt researchers hope that by understanding the characteristics of invading tumor cells that it may be possible to find and target their Achilles heel to promote the evolution of noninvasive characteristics and slow tumor growth.








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