Classifying the evolutionary and ecological features of neoplasms

Abstract

Neoplasms change over time through a process of cell-level evolution, driven by genetic and epigenetic alterations. However, the ecology of the microenvironment of a neoplastic cell determines which changes provide adaptive benefits. There is widespread recognition of the importance of these evolutionary and ecological processes in cancer, but to date, no system has been proposed for drawing clinically relevant distinctions between how different tumours are evolving. On the basis of a consensus conference of experts in the fields of cancer evolution and cancer ecology, we propose a framework for classifying tumours that is based on four relevant components. These are the diversity of neoplastic cells (intratumoural heterogeneity) and changes over time in that diversity, which make up an evolutionary index (Evo-index), as well as the hazards to neoplastic cell survival and the resources available to neoplastic cells, which make up an ecological index (Eco-index). We review evidence demonstrating the importance of each of these factors and describe multiple methods that can be used to measure them. Development of this classification system holds promise for enabling clinicians to personalize optimal interventions based on the evolvability of the patient's tumour. The Evo- and Eco-indices provide a common lexicon for communicating about how neoplasms change in response to interventions, with potential implications for clinical trials, personalized medicine and basic cancer research.

Figure 1. The Evo-index and how it changes

a | The evolutionary index (Evo-index) is composed of two factors corresponding to heterogeneity over space (diversity, D) and heterogeneity over time (change over time, Δ). By ‘change’, we mean both change in the genetic, epigenetic and phenotypic alterations present in the population and change in the frequencies of those alterations in the neoplastic cell population. What measures of D and Δ are best is an open question. In addition, how these factors should be stratified into two, three or more classes is also an open question. Here, for simplicity, we provide examples of the kinds of dynamics that could be categorized into a simple 2 × 2 classification. b | The genetic composition of a tumour may change either slowly (Δ1) or rapidly (Δ2) in a variety of ways. On the left, a tumour may have low diversity (D1) at time 0 because it is a new tumour or there has been a recent homogenizing clonal expansion. That tumour may be quiescent and so appear substantially the same at time 1 (D1Δ1), or it may accumulate clones, some of which expand, to generate a diverse tumour by time 1 (D2Δ2). Alternatively, a tumour may be diverse (D2) at time 0 because it is old or has a high mutation rate and is evolving neutrally. At time 1, that tumour may have been homogenized by a selective sweep (D1Δ2) or may continue on its current trajectory with gradual turnover of its clones (D2Δ1).

Figure 2. Clonal divergence is independent of clonal structure

The cell lineages from two tumours may have the exact same clonal structure when they are sampled at the far right but have radically different degrees of genetic divergence. If one tumour (part a) has a higher mutation rate or has been accumulating genetic alterations for a longer period of time because those cells had a common ancestor, it will have a higher level of genetic divergence than another tumour (part b).

Figure 3. The Eco-index

sThe ecological index (Eco-index) is composed of two factors corresponding to the hazards (H) and resources (R) available to the neoplastic cells. These capture the broad categories of selective pressures on a population. We have included example phenomena in this figure that might be observed in the different combinations of the degrees of hazards and resources. For example, a tumour with low hazards (H1) and low resources (R1) might be relatively barren, with few infiltrating lymphocytes but also poor perfusion and few supporting cells. Such an environment would select for cells that can either survive on few resources or move to locate more resources. High levels of hazards (H2) should, according to life history theory, select for rapid proliferation, evasion of predation, migration away from the hazards and little investment in cell (and DNA) maintenance. High levels of resources allow neoplastic cells to rapidly proliferate. Thus, an H2R2 tumour would probably undergo massive cell turnover as cells are killed by the hazards and replaced by their rapidly proliferating sisters.

Figure 4. Changing the evolutionary class of a tumour through interventions

With the classification system outlined in TABLE 2, we could examine how different interventions move tumours between categories. a | In this example, chemotherapy can be mutagenic and can select for hypermutator clones, generating new clones and more diversity^,,. It can also kill endothelial cells and thus have an anti-angiogenic effect, resulting in a tumour (type 13) with one of the worst predicted prognoses. This may partly explain why tumours that recur after chemotherapy are so difficult to control. b | Immunotherapy, if successful, may increase the predation hazards to the tumour and perhaps select for a subclone, reducing diversity. Targeted therapy, unlike chemotherapy, probably does not cause significant DNA damage and may further genetically homogenize the tumour. Anti-angiogenic therapy is designed to restrict the resources of the tumour. At the end of this example sequence, the tumour is in the most manageable, least evolvable category (type 3 in TABLE 2). Of course, chemotherapy, immunotherapy and targeted therapy may have different effects depending on the details of those therapies and their interaction with the clones in the tumour and their ecosystem.