From: Intra-tumor heterogeneity: lessons from microbial evolution and clinical implications
Factors in diversification | Effect on diversity | Evolutionary theory | Observed patterns in oncology | References |
---|---|---|---|---|
Biotic | Â | Â | Â | Â |
Mutation | ↑ | A higher mutation rate increases genetic variation and facilitates faster adaptation, with fitness cost as trade-off | Genomic instability is an important source of genetic alterations (nucleotide mutations, deletions, amplifications and chromosomal rearrangements) | |
Interspecific interactions | ↑↓ | Competitive intereactions may drive diversification under weak selection. Under strong selection, bottlenecks may reduce diversity | Tumor cells do interact with their environment, but the role of the microenvironment in driving genetic heterogeneity remains poorly understood | |
 | ↑↓ | Cooperative interactions drive diversification as structured environments mediate interactions between local cells creating heterogeneity across space | Tumors that grow at metastatic sites display organ-specific genetic alterations, which might be due to microenvironmental differences | |
Intraspecific interactions | ↑↓ | In a heterogeneous environment, localized interactions (competitive or cooperative) will increase diversity; in an homogenous environment, a single clone will tend to dominate | Intra-tumor heterogeneity exists at genotypic and at phenotypic levels (such as quiescent cells, differentiated cells, stem cells), which probably influence each other, in either a cooperative way (for example, generating specific niches) or a competitive way (for example, competition for limited resources or space) | |
Individual movement (migration/dispersal) | ↑ | Migrants will encounter different ecological conditions and thus will diverge from their primary population | Deep-sequencing data show that metastases do have unique mutations that are not detected in the primary tumor | |
Abiotic | Â | Â | Â | Â |
Heterogeneity in space | ↑ | A heterogenic environment provides multiple niches | Levels of oxygen and nutrients are not uniform throughout a tumor | |
Heterogeneity in time | ↑ | Different subclones will be favored over time. A more rapidly changing environment will maintain more subclones | A longitudinal study that included untreated CLL patients failed to observe a change in the relative presence of subclones in most cases within the time-frame of the study | |
Exposure to non-living antagonists | ↓ | Exposure to antagonists tend to create bottlenecks, limiting diversity and favoring only resistant clones | Drug treatment can create a bottleneck, selecting the survival of less sensitive clones, thereby decreasing heterogeneity |