Adaptation of Cancer Cells to Long-Term Starvation Shows Similar Properties as Starvation Adaptation in Bacteria (GASP)

Michael Klutstein
Faculty of Dental Medicine, Hebrew University of Jerusalem, The institute of Dental Sciences, Israel

Introduction:

The Growth Advantage in Stationary Phase (GASP) phenomenon, described in bacteria, reflects the versatility of bacteria to tolerate stressful conditions, including extreme starvation for long periods of time and the ability of cells from older cultures to utilize nutrients more efficiently. GASP is primarily a genetic adaptation phenomenon with mutations occurring in specific genes and pathways. Previously, we have shown that GASP exists in eukaryotes. We have shown that yeast strains exposed to long-term starvation show perturbed Target of Rapamycin (TOR) signaling and a hyper-mutator phenotype. These genetic adaptation is similar to the one described in bacterial cells where a hyper muttor phenotype and mutation of Simga S signaling were observed. Here, we set out to investigate whether the same principles apply to cancer cells exposed to long-term starvation and hypoxia. GASP may explain several adaptation described for cancer cells, specifically in the interior hypoxic region of a tumor.

Methods:

We subjected 10 cell lines to 4 months` starvation with no addition of fresh medium. In 6 of the cell lines cells survived. We thus set out to characterize the traits of the surviving cells by comparing survivors and parental cell lines. We subjected the cells to 10 different drugs, to heat shock, to hypoxia, and measured genomic stability and EMT gene expression pattern in the survivors and parental cells.

Results and discussion:

Survivors show some differences in drug sensitivity when compared with parental lines. When we examined more closely the HCT116 cell line, we saw that the 4 months` starved cell line is more heat shock resistant and more hypoxia resistant than the parental cell line. The survivor shows a marked elevation in genomic instability compared to parental line. In addition, the survivor overexpresses mesenchymal markers and underexpresses epithelial markers when compared to the parental line. These results show that starvation may have induced a genetic adaptation, which changes the epithelial stable HCT116 line into a more mesenchymal genomic-unstable line, with higher resistance to heat, hypoxia and several drugs. The differentiation of cancer cells from hypoxic regions to a more mesenchymal, stem-cell-like phenotype has been described before, and our novel system may provide means to study the mechanism by which it occurs.

Conclusion:

Cancer cells exposed to long-term starvation show phenotypes similar to bacteria and yeast exposed to long-term starvation and hypoxia.





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