Evolution is driving therapeutic resistance to cancer therapies

Nov 19 2006

The dynamics of evolution are fully in play within the environment of a tumor, just as they are in forests and meadows, oceans and streams. This is the view of researchers in an emerging cross-disciplinary field that brings the thinking of ecologists and evolutionary biologists to bear on cancer biology.

Insights from their work may have profound implications for understanding why current cancer therapies often fail and how radically new therapies might be devised.

A review by researchers at The Wistar Institute of current research in this new field, published online November 16, will appear in the December issue of the journal Nature Reviews Cancer.

"A tumor cell population is constantly evolving through natural selection," says Carlo C. Maley, Ph.D., an assistant professor in the Molecular and Cellular Oncogenesis Program at Wistar whose own research focuses on this area. He is senior author on the new review. "The mutations that benefit the survival and reproduction of cells in a tumor are the things that drive it towards malignancy.

"Evolution is also driving therapeutic resistance," Maley adds. "When you apply chemotherapy to a population of tumor cells, you're quite likely to have a resistant mutant somewhere in that population of billions or even trillions of cells. This is the central problem in oncology. The reason we haven't been able to cure cancer is that we're selecting for resistant tumor cells. When we spray a field with pesticide, we select for resistant pests. It's the same idea."

Maley notes that there are three necessary and sufficient conditions for natural selection to occur and that all are met in a population of tumor cells. The first requirement is that there be variation in the population. This variation is evident in tumors, which are a mosaic of many different genetic mutants.

The second condition is that the variation must be heritable. This, too, can be seen within a tumor-cell population. When mutant tumor cells divide to replicate, the daughter cells share the same mutations.

The final condition is that the variation has to affect fitness, the survival and reproduction of the cells. All of the characteristics that are considered hallmarks of cancer affect fitness, according to Maley. Among these are that cancer cells no longer heed normal growth inhibition signals in their environment, they no longer require an external signal to divide as healthy cells do, and they are able to suppress a vital set of internal instructions that require cells to self-destruct when their genes are mutated beyond repair. This protective cell-suicide program carried by normal cells is known as apoptosis.

Seeing a tumor in this light opens a window on new therapeutic strategies.

"It's not just a metaphor to say tumor cell populations are evolving," Maley says. "Evolution is going on in the tumor. So let's think about how we might want to influence that evolution. Can we push it down paths that might be more beneficial to us?"

One idea might be to develop new drugs that would act as benign cell boosters. Such drugs would specifically target the more benign cells in a tumor to increase their relative fitness over their malignant neighbors. This would allow the benign cells to outcompete the malignant cells, leading to a less aggressive, less dangerous tumor.

"Another idea we're pursuing is what we call the sucker's gambit," Maley says. "In this case, you try to increase the fitness of chemosensitive cells so that they outcompete any resistant cells that are in the tumor. And then you apply your chemotherapy. So you sucker the tumor into a vulnerable state and then you hit it with your therapy."

In their review, Maley and his coauthors also explored how the ecological ideas of competition, predation, parasitism, and mutualism unfold in tumors. Here again, they found that the concepts from another field helped to illuminate cancer biology.

Mutant cells compete with each other for needed resources. The immune system often kills tumor cells like a predator hunting prey, and the tumor cells that develop defenses against the predation are the ones that survive and reproduce.

An example of parasitism in the tumor environment can be seen in angiogenesis, in which a subset of tumor cells send chemical signals to stimulate the host to generate new blood vessels to supply the tumor with nutrients. The neighboring cells that aren't investing resources in producing the signals take advantage of the nutrients nonetheless.

Mutualism describes a situation in which two organisms interact in a mutually beneficial way. Tumor cells send signals to stimulate the growth of the cells that form the scaffold in which the tumor cells grow, known as fibroblasts. The fibroblasts, in turn, send signals to the tumor cells to stimulate their growth. Recent studies suggest, too, that the fibroblasts in a tumor microenvironment begin to acquire mutations of their own.

"They're co-evolving, and it becomes a dynamic, runaway process," Maley says.