New book by ASU researcher explores cancer’s pervasive mysteries

Evolution is a propulsive force, working incessantly to reshape life on earth, from the lowliest single-celled organisms to the planet’s vast forests, insect and bird populations, oceanic life and diverse mammalian species.

Like all living things, cancer cells are also subject to the stringent dictates of evolution. Indeed, cancer has proven to be among the most adept players in nature’s ceaseless game. Evolution is the reason humans and other life forms are vulnerable to cancer and why the disease has been so challenging to cure.

In a new book, "Frontiers in Cancer Research: Evolutionary Foundations, Revolutionary Directions," (Springer, 2017), Carlo Maley, a researcher at Arizona State University's Biodesign Institute, illuminates some of the central issues in current cancer study, from the vantage point of evolutionary and ecological theory. The book features chapters written by a range of researchers at the vanguard of the field. Their aim is to highlight some of the most intriguing unanswered questions in cancer research and to propose evolution-based strategies for addressing them.

Ignoring evolutionary transformation — cancer’s primary weapon of destruction — has limited progress toward the successful treatment and possible prevention of cancer. By the same token, the authors argue, the rules of evolution, if properly understood and applied, may help science to outwit cancer, either driving it to extinction or curtailing its lethality.

The book begins with a call to arms in the fight against cancer: “Nearly everyone working on cancer biology is actually working on evolutionary biology, even if they do not realize it,” Maley said. “Unfortunately, we suffer from a paucity of evolutionary biologists and ecologists who are studying cancer.” The following chapters deliver a rallying cry for other innovative researchers to enter the field and contribute their talents.

Historically, biology has been a largely experimental discipline. Charles Darwin, however, provided a theoretical framework for understanding living systems, a master narrative capable of accounting for the diversity of earthly life, through simple laws. Intriguingly, the twin forces of chance mutation and natural selection also provide cancer cells with their tenacious ability to carve out a hospitable niche, compete for resources and expand their reign at the expense of their host.

The wide-ranging text covers the genetics of cancer populations, genetic diversity within tumors (intra-tumor heterogeneity), the expansion of mutant clones, cancer stem cells in the dynamics of tumors, the evolution of metastasis, and techniques for improving cancer therapy through monitoring cancer’s evolutionary response to treatment.

Additional chapters address the patterns of human cancer susceptibility due to a mismatch between modern environments and those in which our species evolved, as well as the evolution of cancer suppression mechanisms that have emerged in different species; particularly the large long-lived animals like elephants and whales that are better at suppressing cancers than humans. Perhaps these adaptations can provide new sights relevant for human therapy and cancer prevention.

The topic of cancer heterogeneity is a central theme of the book. The existence of a wide variety of mutant cells — usually present in the patient before initial diagnosis — presents the most formidable challenge to effective treatment. The authors propose that such diversity is so ubiquitous that it may be applied as a universal biomarker — an early warning beacon indicating the propensity for cancer development or the severity of the particular cancer diagnosis. Diversity may therefore provide a common denominator, useful for tracking and characterizing cancers through all their bewildering subtypes.

In addition to disease diagnosis, measures of cancer cell diversity may also help guide the course of therapy. Here, the authors stress a central misconception in conventional cancer treatment — one which persists in spite of evolutionary theory. Efforts to eradicate all cancerous cells in a diverse population effectively select for those cells resistant to treatment. Eliminating evolutionary competition between varying cell types allows resistant post-treatment cells to expand without limit, forming a sort of super-charged cancer, less susceptible to management.

The authors trace the history of the current impasse in cancer treatment, attributing it in part to the revolution in molecular biology, which may have unwittingly acted to sideline evolutionary approaches. Clinical methods that met with enormous success in treating viral and bacterial infections have proven largely impotent against the protean nature of cancer, which, unlike a foreign pathogen, is a moving target comprised of the host’s own cells.

As John W. Pepper of the National Cancer Institute writes in the book: “ ... cancer cells are genetically heterogeneous but fundamentally human, as opposed to infectious cellular diseases that are homogeneous and fundamentally non-human.” Clearly, a reevaluation of reductionist tactics will be critical in breaking the treatment stalemate. Magic-bullet approaches to cancer, the authors argue, have dominated clinical thinking but have largely amounted to dead ends.

The dynamic nature of evolution poses particular challenges for cancer research and treatment. Cancers are often diagnosed at a single time point, with one sample per tumor, an approach that masks the subtle evolutionary processes driving cancer progression. A transition to multiple sampling to yield a more representative, time-sensitive picture of tumor evolution is encouraged, though at present, this is often cost- and time-prohibitive.

A popular theory declares that not all cancer cells are created equal. Even cells that are genetically identical may behave differently. In this view, so-called cancer stem cells, which are distinct from neighboring cancer cells in that they are self-restoring, act to drive the progression of the disease, with surrounding cells acting merely as bystanders.  From the standpoint of treatment, cancer stem cells are of central concern and a failure to eradicate them will inevitably lead to regrowth of the tumor.

Chapter 8 is devoted to cancer’s most lethal attribute, its ability to spread from the region of primary malignancy to other areas of the body, a phenomenon known as metastasis. Indeed, most cancer fatalities are the result of metastasis. Here again, research has only scratched the surface in terms of understanding the subtle particulars driving this aspect of cancer. What seems clear is that metastasizing cells often display greater aggressiveness and adaptability compared with their primary tumor counterparts. Thwarting metastasis is therefore among the primary objectives of ongoing research, with evolutionary models paving the way for new insights.

Given the selective pressure exerted by anti-cancer drugs, which cause Darwinian dynamics to select for treatment-resistant cells, what alternatives exist? One of the most exiting clinical innovations resulting from an evolutionary re-thinking of cancer is described by Robert Gatenby, a pioneer in what is known as “adaptive therapy.”

The basic idea is to maintain cells in the tumor that remain sensitive to the therapy so that they can out-compete resistance cells. The goal is to maintain the tumor at a stable size. So, when the tumor shrinks in response to therapy, the oncologist lowers the dose, but when it grows, she raises the dose. The aim is to stabilize the tumor by insuring active intra-tumor competition, rather than attempt to kill a maximum number of cells via conventional chemotherapy or radiation.  The method is likened by Gatenby to the predator-prey arms race often seen in adaptive landscapes of differing species.

How can we deal with the evolutionary resilience of cancer? The sobering conclusion of the book stresses cancer’s virtually limitless capacity to reemerge in new, resistant guises due to compulsive evolution, a fact that may continue to sabotage our best efforts to shut it down. Prevention and the earliest possible interventions — when heterogeneity may still be limited — offer the best chances in the near term for beating this implacable illness. Time is the enemy.