Abstract
Polyploidization, a common event during the evolution of different tumours, has been proposed to confer selective advantages to tumour cells by increasing the occurrence of mutations promoting cancer progression and by conferring chemotherapy resistance. While conditions leading to polyploidy in cancer cells have been described, a general mechanism explaining the incidence of this karyotypic change in tumours is still missing. In this study, we tested whether a widespread tumour microenvironmental condition, low pH, could induce polyploidization in mammalian cells. We found that an acidic microenvironment, in the range of what is commonly observed in tumours, together with the addition of lactic acid, induced polyploidization in transformed and non-transformed human cell lines in vitro. In addition, we provide evidence that polyploidization was mainly driven through the process of endoreduplication, i.e. the complete skipping of mitosis in-between two S-phases. These findings suggest that acidic environments, which characterize solid tumours, are a plausible path leading to polyploidization of cancer cells.
Highlights
There are currently four known paths leading to tetraploid cells from diploid precursors[1]: cell-to-cell fusion, cytokinesis failure, mitotic slippage and endoreduplication
We report that lactic acidosis alone induced tetraploidization in transformed and non-transformed human cell lines in vitro
We showed that in vitro exposure of transformed or non-transformed human cells to fluctuating acidic environments was sufficient to trigger genome doubling through the process of endoreduplication
Summary
There are currently four known paths leading to tetraploid cells from diploid precursors[1]: cell-to-cell fusion, cytokinesis failure, mitotic slippage and endoreduplication While many of these processes occur in normal tissues and are part of the development of specialized cells, some of them have been shown or hypothesized to occur during tumour development. While non-transformed adult cells have an extracellular pH (pHe) of ~7.4, cancer cells have a lower average pHe of ~6.7–7.125, with pHe as low as 5.8 being reported[26] This acidic environment is primarily generated by a combination of two effects. Poor vascularization and blood perfusion of the tumour mass leads to reduced gas exchange and accumulation of H+ ions in the extracellular environment The combination of these two factors has been hypothesized to be at the basis of the observed reduced pHe in solid tumours[27]
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