Carlo Maley, researcher at the Biodesign Institute's Center for Evolution and Medicine and ASU's School of Life Sciences, brings a paleontological view of species extinction to bear on the challenges involved in driving populations of cancer cells to annihilation.Biodesign Institute at Arizona State UniversityCarlo Maley, a researcher at the Biodesign Institute's Center for Evolution and Medicine and Arizona State University's School of Life Sciences, has brought a paleontological view of species extinction to bear on the challenges involved in driving populations of cancer cells to annihilation – or at least improving patient prognosis through disease-limiting efforts.

In collaboration with international colleagues, Maley reports his findings in the current issue of the journal Nature Reviews Clinical Oncology.

“The two themes of this paper are how to drive cancer extinct and how to do better prognosis,” Maley said. In both cases, paleontological studies of species extinction can provide valuable insights.

Interminable threat

Though significant strides have been made in some areas, cancer’s tenacious resistance to eradication remains one of the great challenges for modern medicine, and a fresh perspective is desperately needed.

Researchers like Maley are bringing the tools of evolutionary biology and ecology to bear on the discipline of oncology. The basic idea draws on an intriguing analogy between species and cancers – each involve genetically diverse populations mutating and evolving under selective pressures in an effort to proliferate and survive extinction.

More than 99.9 percent of species once inhabiting the earth have gone extinct, though the process often occurs over many millions of years. Driving populations of cancer cells extinct in time to save a patient’s life is far more difficult to achieve, but the authors of the current study suggest we have much to learn by examining the factors responsible for driving species extinct, as well as the traits that make a species extinction-resistant.

From extinction to oncology

The new study highlights a number of key ingredients governing so-called “background extinctions,” which involve a single species. Background extinction is a constant, ongoing process that is distinct from mass extinction, which can lay waste to many species. From the standpoint of oncology, background extinctions are more relevant, as the aim of cancer treatment is to drive cancer cells extinct while leaving other cell types healthy and intact.

Some species however are more resilient to extinction. The study identifies two principle factors governing species resistance to extinction: evolveability and robustness to perturbations.

A species’ evolveability is governed by several considerations. The more genetically diverse a species is, the greater its ability to adapt to environmental change. Large population size is also beneficial, as it increases genetic diversity and improves survival likelihood through sheer numbers. 

Robustness to perturbations is similarly dependent on a variety of factors, including species geographic dispersal and the ease with which species are able to move, should changing environmental conditions require it. A species may also beat the odds depending on its degree of generalism. Highly specialized species dependent on a single resource are at greater extinction risk.

The authors note that two principle strategies exist for driving cancer cells extinct: altering their microenvironment and killing them directly. Most cancer therapy to date has relied heavily on the latter strategy. As Maley notes however, many researchers and clinicians have begun rethinking this approach, noting that aggressive efforts to exterminate rather than manage diseased cells may prove counterproductive by exerting selective pressure, which may enrich cancer cells that are resistant to a given treatment.

Indeed, destroying those cells responsive to treatment may actually act to clear geographic space and provide resistant cells with additional environmental nutrients, essentially super-charging aggressive cancer in what was meant to be an effort to destroy it.

Cancer cells are also capable of entering temporary states of quiescence, waiting out cancer therapy regimes, which tend to target aggressively proliferating cells. Like hibernating animals, quiescent cancer cells can reemerge when environmental conditions are more advantageous.

Press-pulse

Many complex factors contribute to a given species going extinct. In broad outline however, the process often occurs when a prolonged period of unrelieved stress weakens the species over time. This is followed by an abrupt event that renders the species unable to recover. The continuous stress is referred to as the “press” and the coup de grace leading to extinction is known as the “pulse.”

However, cancer treatment generally fails to mimic this natural course of extinction. Radiation and chemotherapy are not applied in a press-pulse regimen that would place cancer cells under relentless, diverse and sustained pressure.

The study emphasizes that a species extinction approach to cancer has important implications for disease prognosis. Cancer forms in a way that mirrors characteristics of species resistant to extinction, including rapid population growth, dispersed geographic range, high genetic diversity and ease of motility, all of which pose the most serious challenges to successful treatment under currently available therapies.

Save lives: destroy the environment

Cancer cells resemble species in another critical respect: they act to modify their environmental surroundings to suit their needs. One means of applying the lessons of species extinction to cancer therapy would involve a shift from targeting cancer cells to targeting the microenvironment surrounding and supporting them.

Such efforts might focus on the extracellular matrix and collagen surrounding cancer cells but could also target the host cells that produce these features, known as fibroblasts, or they might target host immune cells.

“There’s good evidence that cancer cells influence and change fibroblasts and co-opt immune cells – first shutting them down from clearing the cancer and then sending angiogenic signals, instructing them to grow blood vessels and help the cancer survive,” Maley says. “There’s a whole ecology of different cell types evolving and manipulating the microenvironment.”

Some of these insights are already being clinically tested, such as anti-angiogenic therapy, which attempts to target non-cancer cells playing a supportive role by furnishing cancerous cells with their blood supply. Altering temperature (hyperthermic therapy) or pH levels or disrupting growth and survival signals transmitted by normal cells during carcinogenesis likewise offer new techniques under active investigation.

The problem, according to researchers like Maley, is that such approaches are often used in isolation. If the model of species extinction advanced by paleontologists is indeed applicable to oncology, one key will be to apply many forms of stress to cancer cells continuously, in hopes of short-circuiting their recovery efforts and their successful development of treatment resistance.

This article is a shortened version of a longer one, read the full-length version here. The full study, “Can oncology recapitulate paleontology? Lessons from species extinctions,” can be viewed here.