Scientists in the US have developed a way of identifying chemicals that specifically seek and destroy cancer stem cells and showed it worked by finding a compound that was toxic only to breast cancer stem cells in mice.
The study was the work of first author Dr Piyush B Gupta, of the Massachusetts Institute of Technology (MIT), the Broad Institute of MIT and Harvard, both in Cambridge, Massachusetts, and colleagues, who wrote a paper about it in the 13 August online issue of the journal Cell.
Just like a healthy cell, a tumor cell is produced from a stem cell, a sort of “master cell” that has the potential to specialize into a range of cell types, except that cancer stem cells only produce cancer cells.
Cancer stem cells are of great interest to researchers keen to develop new treatments for cancer because if you can find a way to destroy them, you stop them turning in to cancer cells, which stops tumors growing.
However, cancer stem cells are also very resistant to chemotherapy and radiation, so we have to find another way to deal with them. One such way is to find compounds that only destroy these cancer stem cells and leave healthy cells alone.
Until now, it has not been possible to develop a reliable screen for chemicals that specifically target cancer stem cells because there aren’t many of them in a tumor, and they don’t stay stable long enough in culture to allow time to experiment on them.
However, Gupta and colleagues found a way to do this. At first they weren’t sure it would be possible.
First they took cultured breast cancer cells and coaxed them to increase the numbers of cells with stem-like properties, including the ability to resist standard cancer drugs.
Then they tested a panel of 16,000 natural and commercial compounds for their ability to kill only the stem-like cancer cells and not the already differentiated cancer cells. They found 32 candidates from this screening.
Gupta and colleagues then turned the 32 into a shortlist of compounds that were readily available in sufficient quantities that they could then test on normal cancer stem cells (as opposed to the stem-cell-like cells they had used in the first screening stage).
This stage revealed a clear winner: the compound salinomycin, which reduced the proportion of cancer stem cells by more than 100 times relative to paclitaxel, a commonly used breast cancer chemotherapeutic drug known under the brand name Taxol.
However, they were still not finished, there was one more important question: how fast did tumors develop from salinomycin-treated cancer stem cells compared to paclitaxel-treated ones? They injected samples of both treated cells into mice and found that salinomycin-treated cancer stem cells were less able to seed tumors than the paclitaxel-treated ones.
They also found that salinomycin treatment slowed the growth of the animals’ tumors.
Other studies into the properties of salinomycin, an antibacterial agent used in animal farming, suggest that treating human breast tumors with the compound results in loss of gene expression linked with cancer stem cell activity.
This study did not investigate how salinomycin worked to reduce the activity of cancer stem cells, but it is unlikely to be due to its antibiotic properties. There is also evidence that it inteferes with cell potassium levels.
Gupta said it wasn’t clear whether salinomycin itself would end up in the clinic as a treatment for breast cancer: there are lots of steps in the development of a new anti-cancer drug. However, it does already serve a useful purpose: as a tool for manipulating cancer stem cell numbers and seeing how it affects growth and spread of cancer in the lab.
Perhaps the greatest contribution of this study is the fact it offers a new way of developing anti-cancer drugs, as the researchers concluded:
“This study demonstrates the ability to identify agents with specific toxicity for epithelial CSCs [cancer stem cells].”
Until now, the rationale for killing cancer cells has been to target tumor cells with specific genetic alterations. But this study introduces another dimension, or variable to manipulate: as well as genetic alteration there is the opportunity to focus on the stage of development of cancer cells.
“Accordingly, future therapies could offer greater possibilities for individualized treatment by considering both the genetic alterations and differentiation states present within the cancer cells of a tumor at the time of diagnosis,” wrote the researchers.
Gupta and colleagues hope that one day cancer therapy might combine traditional cancer drugs (to kill the differentiated cancer cells, as now) and new drugs that target and destroy cancer stem cells that would otherwise get left behind.
“Identification of Selective Inhibitors of Cancer Stem Cells by High-Throughput Screening.”
Piyush B. Gupta, Tamer T. Onder, Guozhi Jiang, Kai Tao, Charlotte Kuperwasser, Robert A. Weinberg, and Eric S. Lander.
DOI:10.1016/j.cell.2009.06.034
Additional source: Cell Press.
Written by: Catharine Paddock, PhD