Cancer Cells Resort to Cannibalism To Survive Chemo

Some cancer cells can survive chemotherapy by resorting to cannibalism.

By “consuming” neighboring cancer cells, some cells have found a way to obtain the energy they need to remain alive and induce relapse after a course of chemotherapy is completed, according to new findings published in the Journal of Cell Biology,

Breast cancer cells and doxorubicin

Doxorubicin (the chemotherapy drug used in this study) is as an anthracycline. This type of chemotherapy drug works by damaging the DNA in a cancer cell, achieved via three different mechanisms:  

• By binding to DNA via intercalation between base pairs on the DNA helix
• By preventing repair of DNA by inhibiting an enzyme called topoisomerase II
• By acting as a powerful iron-chelator. This property enables the formation of iron-doxorubicin complexes that can bind both the cell’s DNA and its membrane
  
  

Crafty cancer cells

However, some cells are able to survive initial treatment with doxorubicin, which can result in relapsed tumors. These “crafty” cells transform into senescent cells, entering a “dormant” state, whilst remaining metabolically active. Senescent cells can encourage the growth of a tumor by releasing tumor-promoting factors and inflammatory molecules.

This is particularly problematic when treating breast cancer cells that retain a “normal” copy of the TP53 gene. TP53 is mutated in just 30% of breast cancers – the remaining 70% with “normal” TP53 can escape death in response to chemotherapy-induced DNA damage. Breast cancer survival can be predicted by TP53 mutation status – those with TP53 wild-type tumors have poorer survival.

"Understanding the properties of these senescent cancer cells that allow their survival after chemotherapy treatment is extremely important," explains first author Crystal A. Tonnessen-Murray, in a recent press release.

Study design and findings

In the new study the team discovered that the breast cancer cells exposed to doxorubicin (or other chemotherapy drugs) which then transformed into senescent cells often engulfed their neighboring cancer cells.

“We used cells and tumors that express fluorescent proteins (e.g., GFP) of different colors to examine interactions between cells in treated tumors and also in treated cultures,” explains James G. Jackson, corresponding study author.

Jackson elaborates on some of the techniques used in the study: “We used confocal microscopy, which allows one to visualize a 3-dimensional representation of an image. This allowed us to determine if cells were under, on top of, or actually within another cell. We also used time lapse microscopy to generate movies of cells cannibalizing.”

This image of a breast tumor formed in mice and treated with the chemotherapy drug doxorubicin shows that some cancer cells (red nuclei) have been engulfed by other cancer cells (green cell membrane). Credit: Tonnessen-Murray et al., 2019

Tonnessen-Murray, et al. found that the senescent cells exhibiting the cannibalistic behavior activated a specific group of genes that are ordinarily switched on in macrophages,  a type of cell designed to engulf and digest “unwanted” material within the body including cellular debris, foreign particles, microbes and cancer cells.

“We used RNA sequencing and gene set enrichment analysis (GSEA) to determine that chemotherapy treated tumors in vivo and cell lines in vitro were highly enriched for macrophage-like programs of genes involved in engulfment and phagocytosis,” says Jackson.

This cannibalistic behavior wasn’t confined to breast cancer cells; other cancer cell types became capable of “eating” their neighbors once senescent and were able to survive in culture for longer than those senescent cells that didn’t engulf. Jackson elaborates: “In the publication, we show that a lung cancer cell line and an osteosarcoma cell line (bone cancer) also engulf after chemotherapy treatment.”


Credit: Tonnessen-Murray et al., 2019

Whilst these findings hold promise as a basis for new therapeutic opportunities, further research is necessary to determine if other cell types may also be potentially “fall victim” to these cannibalistic cancer cells.

Jackson touches on some of the study limitations: “Tumors are a complex mixture of cancer cells and stromal cells such as blood vessels and immune cells. It is not known what other cell types can be engulfed by the chemotherapy-treated cancer cells. The advantage gained by a cell that engulfs, and exactly how that contributes to relapse, needs deeper examination.” He also adds that the cells were not studied under the different types of nutrient deprivation or stress that a tumor experiences in vivo.

“Next steps include identifying therapies that can eliminate the cells that survive chemotherapy by entering the state of cellular senescence. We surmise the need to cannibalize other cells is a weakness that can be exploited,” concludes Jackson.

Reference: Tonnessen-Murray, et al. (2019) Chemotherapy-induced senescent cancer cells engulf other cells to enhance their survival. J. Cell Biol. DOI: 10.1083/jcb.201904051

James G. Jackson was speaking to Laura Elizabeth Lansdowne, Science Writer for Technology Networks.