One of my favorite parts of mathematical modeling is the opportunities it provides to carefully explore metaphors and analogies between disciplines. The connection most carefully explored at the MBI Workshop on the Ecology and Evolution of Cancer was, as you can guess from the name, between ecology and oncology. Looking at cancer from the perspective of evolutionary ecology can offer us several insights that the standard hallmarks of cancer approach (Hanahan & Weingerg, 2000) hides. I will start with some definitions for this view, discuss ecological concepts like mimicry and ecological engineers in the context of cancer, unify these concepts through the idea of morphostatic maintenance of tissue microarchitecture, and finish with the practical importance of diet to cancer.
A very energetic proponent of the connection between ecology and cancer is Joel Brown, who delivered the second talk on Tuesday, September 16th. To make the analogies easier to see, he focused on definitions. Brown is an evolutionary ecologist, so from his perspective “metastatic cancer is the evolution of a new single-celled, asexual protist”. This means that we need to understand evolution — the change in heritable characteristics of a population over time; and we need to understand ecology — interaction between organisms and their environment. Together: studying organisms, populations, communities, and ecosystems through the adaptation of the organisms. This gives us three tools to study cancer that we already use to study nature more generally: (1) looking at the recipe of inheritance with genetics, (2) tracing a historical process with phylogenetics, and (3) understanding the fit of form and function — adaptation.
In analogy to other biological systems, Brown sees the driver behind adaptation as natural selection: a force of evolution that promotes heritable traits (which we can more easily call ‘strategies’) that maximize the average growth rate in the population given the circumstances. He views the whole human body as an ecosystem with different organs, tissues, spatial locations within tissues, and matrix of healthy cells corresponding the the more specific circumstances. Surprisingly, in the application to chancer, the question of what constitutes a population — especially in clinical settings where many different cell-types with slight variations in both phenotype and genotype are interacting — is the more difficult one. Measuring these populations of cancer cells in patients to test our theories is even more difficult, a problem that is less common when studying more classical ecological systems like squirrels.
In the next talk after Brown, Ruchira Datta proposed more specific insights we could draw from ecology. She explored the connection between mimicry and a tumor’s interaction with the immune system. In the mimicry that ecologists are familiar with, a mimic emits a signal imitation the model, the dupe receives the signal and mistakes the mimic for the model, acting toward the mimic as if it was the model and thus providing the mimic with some advantage. In the case of cancer, she proposed the hypothesis that cancerous cells mimic the phenotype of wounded tissue, this dupes the immune system into executing a wound healing program, and thus leading the immune system to cooperate in carcinogenesis. In contrast to the popular view that “cancer is the wond that never heals” (Pierce & Speers, 1988; Riss et al., 2006), David Axelrod summarized Datta’s hypothesis as “cancer is the wound that keeps on healing”.
In the second to last talk of Monday, September 15th, Kenneth Pienta pushed further by introducing the analogy of cancer cells as ecological engineers (Pienta et al., 2008; Yang, et al., 2014). Pienta’s guiding question is: why do people die from solid tumors like those of prostate cancer? Although we know many of the immediate causes of death — metabolic death 40% of the time, embolus 20%, pain treatment 30% and respiratory failure 10% — the unifying ultimate cause is mysteries. Pietka believes that the mystery is cytokine overproduction, the oncological equivalent of ecology’s swamp gas that slowly poisons the patient. Cancer cells are ecological engineers that are building a ‘swamp’ in two different ways:
- Allogenic — like beavers, cancer cells mechanically alter their environment. This can be done by deforming the cell matrix they are embedded in, or by attracting new blood vessels that alter the local spatial heterogeneity and creating new static edges to exploit.
- Autogenic — like trees, changing themselves with growth over time. As the tumor grows in size, it changes the local architecture and pH concentrations through things like the Warburg effect from a lack of oxygenation.
The resulting niche helps the cancer cells more easily continue reproducing and avoiding our natural defenses.
An important aspect of cancer ecology to remember, is that human cells are largely organized in tissues and are not (maybe with the exception of blood) well modeled by an inviscid population. When we look at cancer cells, we need to understand not just the individual cells, but their interaction with their local architecture and environment. The overly reductionist textbook account of cancer — as presented by Hanahan & Weingerg’s (2000) hallmarks of cancer, for example — tends to mostly ignore this by focusing on individual mutations, and only mentioning tissue in the context of angiogenesis — the recruitment and formation of new blood vessels. An ecological perspective must depart from this viewpoint, and that is just what John Potter did in the third talk on Monday with his introduction of morphostats.
As regular readers of TheEGG can recall, Alan Turing’s most cited work was not in computer science, but in biology. In 1952, to understand the systematic break of spherical symmetry in embryos, Turing introduced the idea of morphogenes. The morphogenetic fields he defined help organize the dynamic tissue morphology of a growing embryo. In analogy to this, several researchers (Tarin, 1972; Potter, 2001; van den Brink, 2001; for an overview, see Potter, 2007) have suggested morphostatic fields as a way to maintain homeostatic tissue microarchitecture in adults, and a mechanism for resisting cancer. The offers a change in perspective by focusing on the microarchitecture rather than just differentiation of cells.
By corrupting the morphostatic control, cancer cells can recruit normal cells into tumours. This disrupted areas can quickly become the swamps of Pienta’s presentation. Since morphastatic control is believed to be related to wound healing (Potter, 2007), its large scale disruption might envision the sort of immune-system mimicry that Datta hypothesized. Most importantly, this focus on maintenance of the local environment can take us out of the world of abstract connections between ecology and oncology, and into the world of concrete interventions — nutrition.
It is important to remember that both development (the part that morphogenes are relevant to) and homoestatic maintenance (the part that morphostats are relevant to) are ruled not only by a genetic program but by the environment. An important and often overlooked part of the human cellular ecosystem is nutrition — in fact, it is often overlooked (or oversimplified) on purpose by doing studies on mice with fixed feed. These environmental effects of nutrition are often downplayed by the hallmarks of cancer approach, which tends to focus on carcinogens that facilitate mutations instead of general effects of nutrition on microarchitecture of the gut. Potter provided us with an onslaught of evidence that suggested that the dominant theory of carcinogenesis does not account for the drastic effects of nutrition on cancer progression and prevention (Hirayama, 1979; Reddy et al., 1980; Willett, 2000; Anand et al., 2008; Gonzalez & Riboli, 2010). I wish that I could go into more detail on this connection, but I’d rather not scare you off your dinner.
This is my third post of a series on the MBI Workshop on the Ecology and Evolution of Cancer. The previous posts were: Colon cancer, mathematical time travel, and questioning the sequential mutation model; Experimental and comparative oncology: zebrafish, dogs, elephants.
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