Sherman Zhao, MD, PhD
Cancer as an interaction of macro- and micro-evolutionary process
It has been well established that environmental factors such as air, water, food, and other chemicals we live with in this world constitute the evolutionary dynamic. This could be viewed as the macro-environment in which the human body has been exposed, and this process can be called macro-evolution through which human become to exist and keep changing by adaptation. But what’s more important is our micro-environment in which the cells are living: surrounding cells, extracellular matrix, tissue fluids, and uncountable signalling molecules. Cell behaviours are strictly shaped by this micro-environment and the adaptation of cells to this environment can be called micro-evolution. The body of an animal can be viewed as a society or ecosystem whose individual members are cells, reproducing by cell division and organized into collaborative assemblies or tissues. Our concerns were similar to those of the ecologist: cell births, deaths, habitats, territorial limitations, the maintenance of population sizes, and the like. The topic of natural selection here for somatic cells in a healthy body is very peculiar, where self-sacrifice, rather than competition, is the rule: all somatic cell lineages are committed to die, leaving no progeny but dedicating their existence to support of the germ cells, which alone have a chance of survival. There is no mystery in this, for the body is a clone, and the genome of the somatic cells is the same as the genome of the germ cells; by their self-sacrifice for the sake of the germ cells, the somatic cells help to propagate copies of their own genes. Thus, unlike free-living cells such as bacteria, which compete to survive, the cells of a multicellular organism are committed to collaboration. Any mutation that gives rise to selfish behavior by individual members of the cooperative will jeopardize the future of the whole enterprise. Mutation, competition, and natural selection operating within the population of somatic cells are the basic ingredients of cancer: it is a disease in which individual mutant cells begin by prospering at the expense of their neighbors but in the end destroy the whole cellular society and die. The development of cancer is as a microevolutionary process. This process occurs on a time scale of months or years in a population of cells in the body, and it is dependent on the same principles of mutation and natural selection that govern the long-term evolution of all living organisms.
The macro-environment is relatively easy to adjust to lower the risk of developing cancer once we realized its role. However, micro-environment, which is far more complicated and elusive, is hard to be modified to become unsuitable for cancer cells to grow in.
Evolutionary Medicine
According to the principle of evolutionary medicine, nature does not strive for complexity or perfection—- it is blind and random. Variation of genetic material occurs randomly in species in every generation, through cellular DNA mutations, and that the survival or extinction of a given organism is a result of natural selection, based on its capacity to adapt and reproduce itself within its own environment. Cancer cells, carrying mutations that have the ability to divide indefinitely in the normal micro-environment have great survival advantages to their surrounding cells. Since the now adopted methods (kill cancer cells by cytotoxic agents/radiation) could not reverse this unexpected situation, maybe another way deserves try — turn the micro-environment into a condition that cancer cells no longer adapt. There are several studies demonstrate that botanicals could induce the differentiation of cancer cells. This throws a light on cancer treatment, a new field using chemicals to build a hostile environment which stop the cancer. This treatment maybe called adaptive therapy.
Adaptive Therapy
All the modalities deployed in the treatment of cancer, from chemicals to radiation to nanotechnology, the underlying strategy has remained the same: detect and destroy, to kill cancer cells as much as possible. But so far, the outcomes are far away from our expectation. When conceive of cancer as a dynamic, evolutionary system, it becomes understandable, and might give us a new idea to reach a comprehensive method to fight cancer. The goal of adaptive therapy is to enforce a stable tumor burden by permitting a significant population of chemosensitivity cells to survive so that they, in turn, suppress proliferation of the less fit but chemo resistant subpopulations. Recently, Dr. Robert A. Gatenby and his colleagues, present mathematical analysis of the evolutionary dynamics of tumor populations with and without therapy. Their solution, the theory of evolution, is based on three main principles—heredity, variation, and natural selection, and the promising results of their data seems that adaptive therapy is an alternative approach to treat cancer. In the model they applied, analytic solutions and numerical simulations show that, with pre-treatment, therapy-resistant cancer subpopulations are present due to phenotypic or microenvironmental factors; maximum dose density chemotherapy hastens rapid expansion of resistant populations. The models predict that host survival can be maximized if “treatment-for-cure strategy” is replaced by “treatment-for-stability.” Specifically, the models predict that an optimal treatment strategy will modulate therapy to maintain a stable population of chemosensitivity cells that can, in turn, suppress the growth of resistant populations under normal tumor conditions (i.e., when therapy-induced toxicity is absent). In vivo experiments using OVCAR xenografts treated with carboplatin show that adaptive therapy is feasible and, in this system, can produce long-term survival.
According to the evolutionary models, trying to wipe cancer out altogether actually makes it stronger by helping drug resistant cells flourish. Rather than fighting cancer by trying to eradicate its every last cell, he suggests doctors might fare better by intentionally keeping tumors in a long-term stalemate. We are looking forward to more intensive studies to confirm this hypothesis.