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MUSINGS OF A CANCER DOCTOR: Invasive Species

Sledge, George W. JR., MD

doi: 10.1097/01.COT.0000459159.04990.18
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Figure

Figure

No birds sing on the island of Guam. Sometime in the 1940s the brown tree snake, native to Australia and New Zealand, arrived there, probably in the cargo hold of a passing ship. It had no natural predators, and was let loose on an island rich in wildlife. It proliferated madly, causing the extinction of numerous vertebrate species as it spread.

GEORGE W

GEORGE W

Something very similar is happening in Florida. The Burmese python, introduced by the pet trade, was first sighted in the Everglades in the 1980s. By 2000 or so there were well-established reproductive populations, and between 2000 and 2010 these grew exponentially. There are now estimated to be somewhere between 30,000 and 300,000 Burmese pythons in southern Florida, with effects on wildlife similar to those in Guam, writ large. These pythons are now genetically distinct from the pythons of Burma, but remarkable in their own lack of diversity: a clonal population run wild.

Or, if you appreciate unintended irony, take the case of Darwin's frogs, the Chilean amphibian first described by the great evolutionary biologist during his voyage of discovery on HMS Beagle. Darwin's frogs (Rhinoderma rufum is the proper scientific name) have likely gone extinct, the result of the introduction of a toxic fungal species, Batrachochytrium dendrobatidis.

Batrachochytrium dendrobatidis causes chytridiomycosis, a disease characterized by the inability to breathe, hydrate, osmoregualte, or thermoregulate correctly. It is sweeping around the globe, wiping out amphibian species wherever it lands: as many as 30 percent of amphibian species worldwide may be affected. Amphibians have been around for 365 million years, but their biodiversity is collapsing due to an invasive species.

The brown tree snake and the Burmese python and chytridiomycosis are part of a growing, and global problem: the spread, through human agency, of invasive species. These invasive species are an important part of what has been labeled “the sixth extinction.”

The previous five great extinctions (such as the meteor that wiped out the dinosaurs) were caused by cataclysmic natural events. The sixth extinction is on us: the species have spread sometimes through intent (the Burmese python) and sometimes by mistake (the brown tree snake), but always through human intervention.

The results have been devastating, with loss of biodiversity on a worldwide scale. They are also very expensive: one estimate puts the economic burden of the 6500 harmful invasive species in the United States at $100 billion per year. Not too different from the cost of cancer care in the U.S., I would guess, or at least the same order of magnitude.

Analogies are always dangerous, because biology is so particular and contextual, but the invasive species studied by wildlife ecologists seem, well, almost like cancer. They spread from their initial ecosystem, establish themselves at a distant site, proliferate madly, and push aside the normal hosts, in the process reconfiguring the microenvironment of the distant site. Uncontrolled, they eliminate their hosts.

This connection has not been lost on either ecologists or cancer researchers, both of whom now make use of each other's scientific approaches. It is one of the delights of science that we can make important contributions through repurposing insights from one field to another, and the cancer-wildlife ecology connection is a good example of this phenomenon.

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Shannon Index

Take the Shannon index. Claude Shannon was one of the greatest, and least recognized, 20th century scientists. He is, for practical purposes, the father of information theory, and his work underlies much of the computer technology we take for granted. Shannon was interested in entropy (information loss) in strings of transmitted text, and his Shannon index was designed to measure the degree of that entropy.

Wildlife ecologists use the Shannon index to measure species biodiversity. A big issue surrounding the introduction of invasive species involves its effects on the overall biodiversity of an ecosystem. If the brown tree snake assassinates Guam's birdlife, the biodiversity of the island diminishes, an impoverishment that ultimately affects us all. One can measure biodiversity using the Shannon index, the equation for which, for those who are interested, is as follows:

Figure

Figure

The Shannon index has been applied to cancer ecosystems as well. Intratumor diversity differs among cancers. For instance, among breast cancers, triple negative breast cancers are more genotypically diverse than luminal breast cancers, and their “biodiversity,” as measured by the Shannon Index, may predict patient survival. Distant metastatic deposits (the true “invasive species”) tend to have a greater degree of diversity than the primary tumor, perhaps a reflection of the treatments they have been exposed to. Vanessa Alemendro's recent CancerResearch paper (Cancer Res 2014;74:1338-1348) is a nice starting point on this topic. Similar results have been seen in Barrett's esophagus, where the Shannon index of a lesion predicts progression to frank esophageal cancer.

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Evolutionary Imbalance Hypothesis

A colleague recently referred to Charles Darwin as “the first and best oncologist.” The Shannon index/biodiversity story is further evidence that this is true. Recently two evolutionary biologists, Dov Sax of Brown University and Jason Fridley of Syracuse University, have proposed what they call the Evolutionary Imbalance Hypothesis of invasive species.

The EIH goes something like this: species from regions with deep and diverse evolutionary histories are more likely to be successful invaders of regions with less deep, less diverse evolutionary histories.

Sax and Fridley have put EIH to the test through statistical analysis of multiple “host” and “recipient” ecosystems, looking both in the plant and animal kingdoms, and the hypothesis always appears to ring true. Humans have created several unintended experimental tests of EIH: digging the Suez and Panama canals exposed, in each case, a more evolutionarily diverse ecosystem to a less well-developed ecosystem. Guess who invaded whom?

EIH is nothing new, the authors point out: Darwin proposed it in 1859, saying that better tested species have “consequently been advanced through natural selection and competition to a higher stage of perfection or dominating power.” When I think of a nice, well-behaved tubular breast cancer, each cell looking like its neighbor, each with a low mutational load, and compare it with a high-grade, genomically diverse basal breast cancer, and the subsequent fate of their hosts, I can only repeat, “Darwin was the first and best oncologist.”

Ken Pienta's group at Hopkins has taken the connection even further, explicitly making the link between metastasizing cancers and invasive species. Invasive species, they point out in a recent paper (Journal of Cellular Biochemistry 2014;115:1478-1485), are ecosystem engineers, reconfiguring their microenvironment “as they construct a niche that is favorable to their own survival.”

This niche construction results in ecologic inheritance, “the inheritance, via an external environment, of one or more natural selection pressures previously modified by niche-constructing organisms.” Pienta's group has championed the use of mathematical approaches derived from the ecology literature (the Tilman equations for modeling the invasion of two species into a defined space) to describe bone marrow metastasis.

Tumors are great ecosystem engineers, through the secretion of cytokines and growth factors that permanently alter the neighborhood they live in, making life easier for their progeny. But whereas many invasive species eventually reach some sort of homeostasis with their new ecosystem, cancers rarely do so. Their ecosystem engineering, successful in the short term, ultimately results in environmental collapse, and the death of the host.

So are they “successful” invasive species, or not? It's all a matter of perspective, and the duration of the perspective. They are successful invaders right up to the patient's last breath.

And, at the need of the day, so what? Both of the groups mentioned above have suggested that we might use ecologic principles as part of a therapeutic attack on metastatic lesions. One wonders whether the recent immunologic approaches using checkpoint inhibitors (anti-PD1 and PDL-1) are a partial answer to the ecologic observations regarding tumor biodiversity: the more genomically and antigenically diverse a cancer (think melanoma and smoking-induce lung cancer), the more sensitive to immunotherapy? Is the Shannon index as a predictor of immunotherapy benefit? It's a thought.

Wildlife ecologists are just beginning to draw on the cancer experience, if my cursory review of their literature is correct. While they regularly refer to invasive species as a form of ecosystem cancer, they are just beginning to think about what it takes to wipe out these “cancerous” species. A recent press release by the US Geological Survey pointed out that the cancer model of “prevention, early detection, diagnosis, treatment options and rehabilitation” made perfect sense, and this combined approach is being used to combat invasive American bullfrogs in the Yellowstone River of the Northern Rockies. I just hope invasive American bullfrogs are easier targets than triple negative breast cancer.

Humans are the ultimate invasive species, and the one that allowed all the others to spread. We're responsible for the extinction (outside of 1.5% of our own genome) of our closest relatives, the Neanderthals, as well as the many other large mammalian and avian species that have disappeared since we conquered the world. We've provided the conduits for all the other invasive species that are performing ecosystem engineering on a global scale.

It would be easy to say that we are the ultimate cancer, the one doing its level best to foul its global environment. Indeed, many have said something like this. But if so, we are surely the first cancer with a conscience, and perhaps the only one ultimately capable of reining itself in before it kills its host.

Let's hope that the fields of wildlife ecology and cancer biology continue to cross-fertilize, to the benefit of both planetary and human ecosystems. Let's pray that we continue to be a “successful” invasive species.

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