Tumor heterogeneity: causes and consequences

Abstract

With rare exceptions, spontaneous tumors originate from a single cell. Yet, at the time of clinical diagnosis, the majority of human tumors display startling heterogeneity in many morphological and physiological features, such as expression of cell surface receptors, proliferative and angiogenic potential. To a substantial extent, this heterogeneity might be attributed to morphological and epigenetic plasticity, but there is also strong evidence for the co-existence of genetically divergent tumor cell clones within tumors. In this perspective, we summarize the sources of intra-tumor phenotypic heterogeneity with emphasis on genetic heterogeneity. We review experimental evidence for the existence of both intra-tumor clonal heterogeneity as well as frequent evolutionary divergence between primary tumors and metastatic outgrowths. Furthermore, we discuss potential biological and clinical implications of intra-tumor clonal heterogeneity.

Fig. 1. Schematic view of monoclonal and multiclonal models of tumor progression

Increasing color intensity correlates with tumor progression, whereas different colors reflect different clones. A: Traditional, linear model of clonal succession, where progressive mutations in oncogenes and tumor suppressor genes drive linear succession of rounds of clonal expansion, manifested as tumor progression. B: Multi-clonal model of tumor progression: although all cells in tumors originate from a single initiated cell, the evolution of the tumor is more “messy”, with genetically divergent tumor clones co-existing within tumors for substantial periods of time. The population sizes and characteristics of clones change as tumors evolve, with some clone populations expanding in size and others remaining unchanged or becoming extinct. In advanced stages of tumor evolution, tumors might become dominated by single clones.

Fig. 2. The effect of clonal heterogeneity on the ability to explore the fitness landscape

Fitness landscape (see glossary) is represented as a 3-D topographical map. Higher elevation represents higher fitness. Crosses of different colors represent genotypes of tumor cell clones. New mutations, branching from parental genotypes (represented by dots), can only explore genotypic space in the vicinity of their parental genotypes. If one of the progeny genotypes lands on a hill, it will be subjected to positive selection, which will enable further evolutionary progression toward the fitness peak. A: Clonal heterogeneity increases the probability of tumor progression. Left: the genotypic vicinity of the green clone includes regions of lower fitness and one small fitness peak. The probability that the mutant progeny of this clone reaches the hill of a larger fitness peak is very low. Right: when a tumor is composed of several genetically distinct populations (red, blue, and green), new mutants spurring from these clones can “sample” a larger region of fitness landscape, increasing their probability of reaching the hill of a larger fitness peak. In this case, some of the mutations branching from the blue clone are subjected to positive selection, allowing them to ultimately reach the fitness peak (indicated by blue arrow). B: Cancer therapy might lead to dramatic alterations of the adaptive landscape (compare fitness landscape in parts B and A). As a result, fitness of a given clone can become either higher or lower. A genetically heterogeneous tumor has higher probability that at least one of its clones will end up in a region with higher fitness value in the altered landscape (red clone in this case), enabling its evolution toward the fitness peak.