Commentary summary, February through July, 2024

 With this August post, Cancer Ecology Commentary concludes its survey of epigenetics, planning to shift focus in upcoming posts to examine another determinant in the health of life-communities, that of biodiversity. Before leaving the world of molecular biology, however, this might be a good time to review where we’ve been so far, summarizing earlier posts over the first half of this year. 

The Commentary began by reviewing an essay by Pulitzer Prize winning author and medical oncologist, Siddhartha Mukherjee, using a metaphor from cosmology, dark matter, to describe gaps in our understanding of human carcinogenesis. Mukherjee wrote of how mutagenesis, acting to either activate protooncogenes causing oncogene-driven growth autonomy or reciprocally to inhibit tumor suppressor genes, the normal genetic braking mechanism guarding against unrestrained growth, proved insufficient to account for certain experimental as well as clinical studies of cancer causation. The ‘dark matter’ proved to be the environment of an individual including those influences triggering chronic inflammation acting as a cofactor in catalyzing oncogenesis. 

This led to the question of just how is it that such extrinsic influences operate as carcinogenic cofactors. The research of Andrew Fineberg described how the epigenome, the set of chromatin and DNA modifications regulating gene network expression were an interface between the untoward influences of aging, diet, and environmental exposures and the disruption of controlled expression of these networks. He proposed a classification system outlining three sets of epigenetic regulators, the epigenetic modulators, modifiers and mediators, three levels of epigenetic control, that ordinarily govern gene expression, but which prove to be sensitive to environmental influence to account for neoplastic transformation. He explored how the normal cellular capability of lineage plasticity, the ability to change cell fate in time was mediated by the epigenome. This capability is ordinarily needed for coordinating development and organ repair of injury but which also proves to be vulnerable to certain perturbations allowing the emergence of pathologic phenotypic plasticity. 

Underlying this disturbance was a fundamental problem faced by any system of information storage, retrieval and transmission, that is information entropy. Such systems are inevitably faced with the occurrence of stochasticity, the randomness by which corrupting events interfere with signal transmission, first recognized by information age Einstein, Claude Shannon. At the cellular level, the more often a stem cell is called upon to respond to injury, the more often that cell, relying on the information contained within the epigenome, must in response open that information library, the genome, but in the process risking that the information needed for injury response will become garbled. Information entropy, a statistical measure to quantitate epigenetic incoherence connects this impairment to other forms of physical entropy occurring in nature, a deep relationship with one of nature’s fundamental laws, the 2nd law of thermodynamics. 

Measures of epigenetic entropy are proving to be a useful yard stick for estimating risk of pathologic lineage plasticity. Barrowing a model from developmental biology, the integrity of stem cell differentiation channels along a gradient to account for normal organogenesis might also be subject to stochasticity. Epigenetic entropy then would serve as an index of the width of those channels with wider channels permitting more developmental variation. Fineberg employed another model from physics, that of an inverse relationship between the probability of a statistical distribution of elements of a system and its associated quasi-potential energy. As first described by Ludwig Boltzmann, the probability of finding a system in any particular state diminishes as the energy of that system increases. Gene regulatory networks can be thought of as systems capable of occupying diverse states. By translating the probability of a network being in a particular state into its associated quasi-potential energy he was able to quantitatively estimate that network’s entropy and thus the associated likelihood for aberrant cell state transition. 

As the barriers for random cell state transition are lowered, a function of increasing entropy, the greater the chances are, under the influence of ambient the selection pressures found within proto-cancer ecosystem, that promiscuous ‘sampling’ of adjacent phenotypes will from time to time occur and periodically achieve enhanced cell fitness. Oncologists will recognize those transitions, referred to as Cancer Hallmarks as described by Douglas Hanahan and Robert Weinberg as empowering cancer development and progression. They are recognizable in the clinic and are the defining elements of cancer behavior. From the cancer ecology perspective however, they may be potential targets for ecologically directed therapy. 

A dramatic example of this process was recently described by Eric Gardener and colleagues examining a highly lethal phenotypic transition observed in certain adenocarcinomas arising from the lung or prostate marked by a histologic transition from adenocarcinoma to the neuroendocrine phenotype. In the lung, pathologists recognize this transition as producing small cell lung cancer. Using recombinant genetic engineering of a murine model of lung cancer, the investigators were able to demonstrate an accompanying molecular transformation occurring during the histologic transition characterized by a change in sensitivity between two oncogenes, EGFR and MYC, reflecting likely epigenetic reprogramming of the neoplasm in response to the selection pressure of targeted therapy. 

Summarizing the Commentary’s examination of epigenetics, we can point to two intersecting pathways underling the development of cancer. First, mutagenesis classically acts through gene mutation producing oncogenes and impeding tumor suppressor genes to fuel intrinsic growth autonomy. Additionally, impairment in sets of genes regulating epigenetic control of gene expression networks, either from mutagenic events or stemming from extrinsic cell influence of the environment causes epigenetic dysregulation. This impairment is measurable through epigenetic entropy, that is the level of corruption of accurate information transfer and leads to pathologic lineage plasticity and selection pressure-determined enhanced cell fitness. Those extrinsic influences include aging, nutrition and untoward environmental exposure, often channeled though the development of chronic inflammation represents the ‘Dark Matter’ of carcinogenesis as described by Mukherjee. These last factors are the focus of cancer ecologists seeking to define the character of the cancer ecosystem, that is the environment in which a cancer occurs. Study of the cancer ecosystem in turn provides a window through which we can view cancer evolution and formulate strategies to amend the ecosystem in order to impede cancer development and progression.