Population dynamics inside cancer biomass driven by repeated hypoxia-reoxygenation cycles

Abstract

A computational analysis of genome-scale transcriptomic data collected on ~1,700 tissue samples of three cancer types: breast carcinoma, colon adenocarcinoma and lung adenocarcinoma, revealed that each tissue consists of (at least) two major subpopulations of cancer cells with different capabilities to handle fluctuating O₂ levels. The two populations have distinct genomic and transcriptomic characteristics, one accelerating its proliferation under hypoxic conditions and the other proliferating faster with higher O₂ levels, referred to as the hypoxia and the reoxygenation subpopulations, respectively. The proportions of the two subpopulations within a cancer tissue change as the average O₂ level changes. They both contribute to cancer development but in a complementary manner. The hypoxia subpopulation tends to have higher proliferation rates than the reoxygenation one as well as higher apoptosis rates; and it is largely responsible for the acidic environment that enables tissue invasion and provides protection against attacks from T-cells. In comparison, the reoxygenation subpopulation generates new extracellular matrices in support of further growth of the tumor and strengthens cell-cell adhesion to provide scaffolds to keep all the cells connected. This subpopulation also serves as the major source of growth factors for tissue growth. These data and observations strongly suggest that these two major subpopulations within each tumor work together in a conjugative relationship to allow the tumor to overcome stresses associated with the constantly changing O₂ level due to repeated growth and angiogenesis. The analysis results not only reveal new insights about the population dynamics within a tumor but also have implications to our understanding of possible causes of different cancer phenotypes such as diffused versus more tightly connected tumor tissues.

Graphical abstract

Keywords

cancer population dynamics / intratumor heterogeneity / cancer cell subpopulations / hypoxia / reoxygenation / cancer evolution

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