Life’s many histories open new approaches to cancer
Life’s many histories open new approaches to cancer
February 26, 2019
February 26, 2019
For most humans, a family of ten would be considered abundant. But for many other forms of life on earth, that’s.. well…chicken feed.
Take the ocean sunfish for example. At spawning time, a female will commonly disgorge some 300 million eggs into her liquid habitat, which are subsequently fertilized externally. Only a tiny fraction of these eggs will hatch and survive. The resulting fry, each the size of a pinhead, can eventually grow to the proportions of a rhinoceros.
Why do species differ so radically in the numbers of offspring they produce, their overall size, their lifespans, the resources they invest in their young and the percentage of their progeny that will survive to maturity?
Such questions have fascinated Athena Aktipis, a researcher at Arizona State University’s Biodesign Institute. One area of study, known as ‘life history theory,’ seeks to understand these discrepancies and the inventive strategies species deploy to adapt and thrive in their environments.
As Aktipis notes, the exploration of life histories not only expands our insight into mechanisms of evolution but may hold profound clues for the management of cancer. The disease is a kind of living laboratory for investigating mutation and natural selection—cornerstones of evolution—in action.
“A lot of tools from ecology and evolutionary biology have been developed over decades and they are just now starting to be applied to understanding cancer evolution in the ecology of our bodies,” Aktipis says.
Life history theory sheds new light on these evolutionary mechanisms and their complex interplay with species ecology, illuminating the delicate balancing act all organisms must perform to remain healthy and viable.
In addition to her appointment with the Biodesign Centers for Biocomputing, Security and Society and the Center Immunotherapy, Vaccines and Virotherapy, Aktipis is assistant professor in the ASU Department of Psychology and the Center for Evolution and Medicine. She directs the ASU Interdisciplinary Cooperation Initiative.
From the dark side
Like other living things, cancer cells pursue life history strategies designed to maximize their ability to survive and proliferate. Understanding the many factors influencing cancer life histories may help researchers develop innovative new tactics for combatting an illness that remains a leading killer, exceptionally resistant to defeat by conventional means.
Central to life history theory is the notion of biological trade-offs. When a given species opts for one life history over another, for example, a profusion of offspring rather than just a few, the choice typically comes with a variety of pros and cons. The ocean sunfish hopes that out of her enormous brood, a few will manage to survive to carry on the lineage. This is sometimes referred to as a fast life history.
Creatures following a fast life history will develop quickly, produce multiple offspring and invest minimal resources in caring for young. Such strategies are subtly fine-tuned through the process of evolution.
In contrast, primates like humans, along with lions, elephants and cape buffalo follow slow life histories, generally living much longer, developing later and producing a small number of offspring on whom they lavish significant resources in order to nurture and raise them to adulthood.
“Life history theory is a tool of ecology used to help understand why organisms have diverse strategies for surviving and reproducing,” Aktipis says. “As an organism, it’s like you have a bucket of coins. How much are you going to allocate for reproduction vs fast growth vs surviving and protecting yourself from threats in the environment?”
Lessons in life
In a new study, Aktipis, along with colleagues Amy Boddy and Weini Huang explore important life history trade-offs governing the behavior of cancerous cells within tumors. Specifically, the group examines trade-offs of survival vs. proliferation, proliferation vs. migration, and migration vs. survival as they relate to cancerous cells within tumors.
Their findings appear in the journal Current Pathobiology Reports.
As the authors emphasize, tumors are not uniform environments acting on their constituent cells, but varied landscapes or microenvironments. These may include regions of low but stable resource availability that tend to promote strong competition among cancer cells in the tumor interior as well as regions of high or fluctuating resource availabilities, more common at the margins of tumors, where greater coexistence among rapidly proliferating cells may dominate.
The life history strategies selected by given cells should generally reflect such factors as the availability of blood flow and nutrient resources, fluctuations in these availabilities, and extrinsic sources of mortality such as predation by the immune system and chemotherapy.
A critical point made in the new study is the fact that cancer life histories are not set in stone. They are highly dynamic phenomena, ceaselessly adjusting to new conditions of resource abundance and scarcity and threats lurking in the tumor microenvironment.
Researchers expect that slow life history strategies may produce a more stable or more slowly expanding tumor with a lower probability of killing the patient. Extending these ideas to the clinical setting may entail efforts to limit high cell mortality and environmental change, promoting instead a more stable and predictable environment with low extrinsic mortality, leading to long-term cancer control.
Clinical approaches to inducing slow life histories within tumors are currently being explored, for example so-called adaptive therapy, directed at maintaining a balance between drug-resistant and susceptible cells. Rather than attempting to thoroughly eradicate the tumor, which tends to select for treatment-resistance and loss of therapeutic control, adaptive therapy seeks to maintain the tumor, while keeping it from becoming lethal.
The new study outlines a useful framework for exploring the variables defining diverse life histories. Known as the Evo-Eco index, the classification system describes the dynamics of tumor trajectories in terms of two evolutionary measures: diversity and change over time; and two ecological factors: hazards and resources.
One of the most exciting potentials of the Evo-Eco approach is the ability to predict the likelihood of metastasis—the often-lethal spread of cells from the primary tumor to other parts of the body. According to life history theory, tumors with growth constraints, high population densities and patchy resource distributions will have a higher likelihood of metastasizing.
Ecological principles may potentially be applied to improve the effectiveness of cancer therapy. For example, it may be possible to modify the cancer microenvironment to reduce the risk of tumor growth and metastasis. Using trade-offs, researchers hope to enhance conditions for cell survival at the expense of rapid cellular proliferation, resulting in a slower-growing, more geographically stable and less virulent cancer.
Continuing research into the Evo and Eco underpinnings of life histories promises to further our understanding of foundational issues in evolutionary theory, while helping to develop an arsenal of new approaches for understanding and treating cancer.
Written by: Richard Harth