By: Ross Keller, 4th year PhD candidate in the Biomedical Sciences Graduate Program

Cancerous cells. (Creative Commons)

The War on Cancer series has so far covered: How Can We Win?, Targeted Therapy, and Tumor Relapse.

In this fourth part of the War on Cancer, I will discuss a phenomenon that has only recently been pushed to the forefront of cancer biology, and it both complicates and opens new doors to treatment strategies. That concept is “tumor heterogeneity”—a tumor that is comprised of multiple types of transformed cells.

The traditional view of tumor formation is simple: DNA within a single cell is damaged, causing it to escape biological constraints and proliferate unchecked. Many tumors do behave like this. However, it has recently come to light that tumors can also be much more complicated. They can be populated by not just a single cell population, but a multitude of cell populations, causing some tumors to behave more like complex ecological systems rather than simple out of control cell divisions.  In fact, some very basic ecology concepts you’ve learned in high school biology may be surprisingly similar to how researchers are beginning to view tumors today.

One way tumors behave as an ecological system is via “branched evolution” [1]. A single cell may be initiated, but as a tumor grows, mutations are continuing to be accumulated. Eventually a tumor cell may acquire a number of mutations that allows that cell and its clones to move away from the original population and form a niche of their own.

Think of a cancer cell like an insect: if one leaves the ecosystem, another will take over. (Creative Commons)

This is the same idea as many species evolving from a common ancestor and populating a habitat. For example, a forest may be populated by several species of insects, all from a common ancestor, but each species populates a different niche of the forest. Think of each cell type as a separate species of insect and all the insects in the forest as the whole tumor. If only one species is removed from the forest, another will take its place. A tumor can function the same way, and the practical effects of this type of evolution within a tumor is that separate portions of a tumor may not be an identical cell type just as different insects exist in different regions of the forest. This complicates treatment because, as I mentioned before, targeted therapy is designed to target one specific cell population. If the tumor is actually multiple populations, multiple targeted drugs will be needed.

A recent paper written by colleagues of mine [2] identifies another way cancer cells can behave that follows an ecological principle: cooperation. The world around us is filled with different species cooperating to gain a selective advantage together—bees and flowers, squirrels and trees, or humans and the bacteria that digests our food. The list goes on. All these species cooperate and gain an advantage because of it, and tumor cells can do the same thing. One cell cooperates with a different, genetically distinct cell, and this cooperative event actually promotes tumor growth.

Imagine a cancer cell like a single tree. Instead of attacking one tree, perhaps we should be attacking the interaction between this tree with its surroundings. (Creative Commons)

This presents both a problem and an opportunity for treating cancer. If a tumor is found to exhibit cooperation, it may not be sufficient to target only one cell in the pair, meaning a separate, targeted drug may be necessary. However, it may also be possible to target the interaction itself to help shrink the tumor. This would exploit a new vulnerability and may help patient outcome in the future.

A third way in which tumors can behave as an ecological system is highlighted in another very recent paper [3]. Here, tumors act as an ecosystem, with one subpopulation promoting growth of all the others by controlling the overall environment of the tumor.

Think of it this way: imagine several species of non-native animals and a group of humans are put on an island—the humans and each animal species represent tumor cells. The humans keep themselves and the animals alive by planting food that both the animals and the humans eat. As a result, the humans and the animals survive. In this instance, taking a single animal species off the island would not collapse the ecosystem. It would be the humans that need to be removed to cause collapse. Tumors can function the same way. A specific “driver” cell type would need to be targeted to combat the tumor. This complicates treatment options because finding out which cell type is the driver can be challenging. It is something that will need to be overcome to treat cancer in the future.

Overall, thinking of a tumor as an ecosystem rather than a single cell outgrowth is a relatively new concept. In fact, this notion has yet to be considered in the design of treatment options for cancer patients. As we learn more about these phenomena and develop new strategies, however, it will be of great benefit to patients. Perhaps it’s time we begin considering tumors in a new way: as ecosystems of their own.

1. Gerlinger M, Rowan AJ, Horswell S, Larkin J, Endesfelder D, Gronroos E, Martinez P, Matthews N, Stewart A, Tarpey P, et al.: Intratumor heterogeneity and branched evolution revealed by multiregion sequencing. N Engl J Med 2012, 366:883-892.
2. Cleary AS, Leonard TL, Gestl SA, Gunther EJ: Tumour cell heterogeneity maintained by cooperating subclones in Wnt-driven mammary cancers. Nature 2014, 508:113-117.
3. Marusyk A, Tabassum DP, Altrock PM, Almendro V, Michor F, Polyak K: Non-cell-autonomous driving of tumour growth supports sub-clonal heterogeneity. Nature 2014.