John D. Nagy, Kalle Parvinen, Scott T. Bickel, Anne Seppnen: September 2016

*This document is intended to narrate and summarize the research conducted by Nagy, Parvinen, et. al. These notes are my personal interpretation of the information which may serve as the basis for continuing research with Dr. John D. Nagy as we attempt to answer further questions on the evolution and spatial dynamics of angiogenesis in tumor  development. 

Notes from: September 30, 2017
Abstract & Introduction
"Angiogenesis and dysregulated tissue homeostasis (proliferation) are canonical characteristics of cancer. Both traits are thought to arise by clonal selection. However, natural selection's role in generating the angiogenic switch is not well understood. Here we show that the angiogenic switch is likely to evolve by early positive selection on angiogenic ability which eventually becomes reversed to negative selection in older tumors. Importantly, this reversal is itself driven by directional selection on proliferation ability. We study an established, general mathematical model of tumor growth with angiogenesis. In the model, competing clones vary their ATP allocation to proliferation, angiogenic signaling, and cell maintenance in a realistic way. Adaptive dynamics analysis of this coevolutionary dynamic predicts that early tumors, in which proliferation rates have not yet approached their evolutionary endpoint, experience positive selection for angiogenesis, conforming to observations of the angiogenic switch in real tumors. However, as selection drives proliferation towards its ESS, the once-favored angiogenic clones become susceptible to \free-rider" mutants, which reallocate metabolic energy from angiogenesis production to proliferation. Selection on angiogenic ability therefore switches from positive to negative. The ultimate result would be necrosis by vascular hypoplasia, a sort of "tumor-on- a-tumor" predicted in previous work. Simulations from an analogous stochastic model, however, show that these deterministic endpoints are rarely realized. Selection acts much more strongly on proliferation than on angiogenesis. As a result, tumors often reach lethal size before negative selection on angiogenesis has much impact. Throughout its clinical existence, a tumor's angiogenic phenotype tends to ride along with a selective sweep acting on proliferative ability. This model yields experimentally testable predictions and highlights the importance of understanding coevolution of cancer hallmarks."
This paper assumes angiogenic factors are a public good, meant to increase vasculature within tissues thus providing oxygen for cell function and survival.
Def: Clonal Selection Theory [cancer results when natural selection sorts among genetically distinct clones within developing and established tumors, favoring those with malignant traits.
This public good is assumed to be shared equally until "free-rider" clones (a concept derived from evolutionary game theory) arrive in the system and utilize the resources without contributing energy [in the form of ATP] to angiogenesis, and instead allocate resources towards proliferation.This focus on proliferation allows the cheating clones a selection advantage, which out-competes the advantage of their angiogenic counterparts.
As cheater clones populate the tumor, cells grow further away from the oxygen source (as they are not secreting angiogenic factors) to which focal necrosis becomes inevitable.
This necrosis harms the tumor, however this is irrelevant to the cheater as selection acts towards reproduction of the individual.Inq: How common are mutations that lead to a focus on proliferation? Hyp: This should be quite common seeing as the driving force behind selection is reproduction, so mutated cells introduced to the system might not have a genotype that abides to the normal functioning for the system.