Evolutionary models of cancer cell cooperation could suggest new, non-toxic therapies.
Image: Laboratory of Kenneth Pienta, Johns Hopkins
What if there were a precise moment of weakness in the development of cancer within an individual? Like, the moment where a tumor steps out onto its porch first thing in the morning to let the dog out, still clad in the night's frayed underwear and without the benefit of a first cup of coffee? The tumor squints at the sky, scratches its balls, and whoosh, it's soaked in a hurricane of cytotoxins. The chances of beating that cancer might be a bit better then as opposed to, say, when it's at the gym or had three drinks at the bar.
A tumor should theoretically have such a moment, according to Johns Hopkins University researchers behind a new open-access study published in the journal Interface Focus. The study describes the potential use of game theory to beat one of cancer's most persistent challenges: keeping it from spreading from its first site of attack and threatening the whole organism. Once cancer has moved on, or become metastatic, it becomes much more difficult to cure.
Using game theory in cell biology isn't a brand new concept. The theory generalizes to, basically, the study of decision making; how different agents strategize resources to maximize something, like money or votes. The "games" in game theory are really mathematical objects. It applies to biology, as it applies to economics or political science, because maximization is often involved in evolutionary survival. Examples include the one-to-one sex ratios found in animal species, explained as a game where numbers of children and grandchildren are maximized as unreproducing members are minimized, as well as the notion of biological altruism, in which agents seem to be acting in the interests of other organisms at the expense of themselves, but are more working toward later reciprocation: scratching each others' backs.
Tumors have their own game. This game is played between tumor cells that are oxygen-rich and tumor cells that are oxygen-poor. The two sets behave differently in one very critical way: poor cells use glucose for energy through a process of fermentation, producing lactate, while rich cells use that lactate with oxygen to produce more glucose, which is passed back to the poor cells to turn into energy. This is a symbiosis unique to cancer cells in large part; an adaptation that allows the malignant cells to generate the massive amounts of energy needed to spread and conquer an organism. "Tumor cells reprogramme their metabolism and cooperate with each other to meet the challenge of uncontrolled proliferation," the paper explains.
This capability for extreme power generation is also part of what makes cancer cells so difficult to beat and, as the cells burn through so much extra glucose, cancer wastes away the body, depleting its defenses as an added bonus. Energy that might go toward fighting the proliferation of cancerous tissue instead gets soaked up by that tissue as it strives to grow as fast as possible.
The "game" for cancer cells is maximizing the relationship between mutation rates and the levels at which these two energy-creation schemes are intertwined, or, more specifically, the critical transitions between the processes. These critical transitions are when one stable state of a cancer cell is either dropped or elevated to another stable state, a realm of intermediate states regulated by signals indicating changes in the tumor's mutation rate. If some shit is about to go down and conditions are changing, leading to a change in the oxygen-poor and -rich balance, a new state is likely.
That's the conclusion of this particular game theory experiment: as cells seek to maximize energy production as mutation rates change, a switch is flipped in the metabolic relationship between these two kinds of cells. The transition isn't immediate, and the researchers think that this window is not only where the cancer cells are most vulnerable, but also when tumors are planning big moves. Wreck this intercellular partnership, and you starve the tumor of the energy it needs to become even more dangerous.
Even more optimistically, if we could understand and manipulate this metabolic relationship, we're likely to hit entirely new treatment strategies. New ways of interfering among cancer cells, possibly disrupting the concentrations of lactate among them, suggest "new non-toxic therapeutic strategies" for beating tumors, according to the paper. Doctors "could push a tumor to a condition where cells are not cooperating with each other," Hopkins researcher Ardeshir Kianercy explained in a university statement. "And if they become non-cooperative, they are most likely to stay in that state and the tumor may become more vulnerable to anti-cancer therapies."