Search

Abstract Background The advent of rapid and inexpensive sequencing technology allows scientists to decipher heterogeneity within primary tumours, between primary and metastatic sites, and between metastases. Charting the evolutionary history of individual tumours has revealed drivers of tumour heterogeneity and highlighted its impact on therapeutic outcomes. Discussion Scientists are using improved sequencing technologies to characterise and address the challenge of tumour heterogeneity, which is a major cause of resistance to therapy and relapse. Heterogeneity may fuel metastasis through the selection of rare, aggressive, somatically altered cells. However, extreme levels of chromosomal instability, which contribute to intratumour heterogeneity, are associated with improved patient outcomes, suggesting a delicate balance between high and low levels of genome instability. Conclusions We review evidence that intratumour heterogeneity influences tumour evolution, including metastasis, drug resistance, and the immune response. We discuss the prevalence of tumour heterogeneity, and how it can be initiated and sustained by external and internal forces. Understanding tumour evolution and metastasis could yield novel therapies that leverage the immune system to control emerging tumour neo-antigens.

Background: The advent of rapid and inexpensive sequencing technology allows scientists to decipher heterogeneity within primary tumours, between primary and metastatic sites, and between metastases. Charting the evolutionary history of individual tumours has revealed drivers of tumour heterogeneity and highlighted its impact on therapeutic outcomes.Discussion: Scientists are using improved sequencing technologies to characterise and address the challenge of tumour heterogeneity, which is a major cause of resistance to therapy and relapse. Heterogeneity may fuel metastasis through the selection of rare, aggressive, somatically altered cells. However, extreme levels of chromosomal instability, which contribute to intratumour heterogeneity, are associated with improved patient outcomes, suggesting a delicate balance between high and low levels of genome instability.Conclusions: We review evidence that intratumour heterogeneity influences tumour evolution, including metastasis, drug resistance, and the immune response. We discuss the prevalence of tumour heterogeneity, and how it can be initiated and sustained by external and internal forces. Understanding tumour evolution and metastasis could yield novel therapies that leverage the immune system to control emerging tumour neo-antigens. [ABSTRACT FROM AUTHOR]

I employ a mathematical model integrating the population and co-adaptive dynamics of an insect host and its specialist parasitoid wasp toinvestigate the competitive evolution of two forms of host resistance: concealment from adult parasitoid location and encapsulation of parasitoid eggs. When only one form of resistance is permitted to evolve, concealment always evolves to frequencies equal to or higher than encapsulation. When both forms of resistance evolve, the outcome depends on the capacity of the parasitoid to evolve counter-measures. Evolution of the host in the presence of the most virulent parasitoid clone results in no differences between the equilibrium frequencies of the two forms of resistance, unless host clone densities are somehow unequally perturbed. When the parasitoid is allowed to co-evolve, thefrequency of hosts concealing themselves exceeds the frequency of those capable of encapsulating parasitoid eggs. At equilibrium, there is generally a negative genetic correlation between resistance measures in the host population, and a positive one for counter-measures in the parasitoid population. The mechanism driving the asymmetries between the two forms of host defense is the loss of more reproductive effort by parasitoids when the host encapsulates as compared to when anencounter is missed due to concealment. I predict that hosts should pay greater costs to maintain concealment as compared to encapsulation when they are relatively common and/or parasitism rates relatively low; that is, when regulation of the host population tends to be influenced by other density dependent forces. [ABSTRACT FROM AUTHOR]