A common chemotherapy drug may boost breast cancer cells' ability to metastasize to the lungs, a new study carried out on mice suggests. Published in the International Journal of Molecular Sciences, the paper reveals how the drug modifies cells that line blood vessels in the lungs, making it easier for cancerous cells to penetrate and stick to them.
"The whole point of our pre-treatment model is to ask the question: Does chemotherapy affect normal cells in such a way that they will turn around and help cancer cells? The answer is yes,” said study author Tsonwin Hai in a statement. "It's a cautionary note for the use of chemotherapy."
The researchers first treated healthy mice with the chemotherapy drug cyclophosphamide (CTX), then waited four days for the animals to metabolize and excrete the medication. The mice were then injected with breast cancer cells, and the accumulation of these cells in the animals’ lungs was monitored.
Compared to a control group that hadn’t received CTX, treated mice had higher concentrations of cancer cells in the blood vessels of their lungs three hours after injection. The drug appeared to first increase the permeability of these blood vessels and then alter their underlying basement membrane, allowing cancer cells to stick to the insides of the vessels.
"The endothelial cells lining the inner side of the blood vessel are like a brick wall, and each brick is tightly adhered to the next one," said Hai. "What we found when we treated mice with chemotherapy is that it makes the vessel leaky, so the tight junction is not as tight anymore and the cancer cells can squeeze themselves through the brick layer.”
"We also found that chemotherapy modified the underlying basement membrane so once the cancer cells squeeze through, they find a place to grab onto."
The remodeling of the basement membrane appears to be regulated by an enzyme called matrix metalloproteinase-2 (MMP-2), levels of which were increased following CTX treatment. This, in turn, increased the exposure of two key peptides within the basement membrane, known as RGD and YIGSR, both of which bind to receptors on the surface of cancer cells.
These findings reveal how CTX makes it easier for breast cancer cells to enter the blood vessels of the lungs and to adhere to these vessels once inside. By clinging onto the inner lining, invading cells are able to avoid being flushed out by the blood, and can therefore establish themselves within the lungs.
"Our data revealed that chemo acts on non-cancer cells and sets in motion changes in the lung so that within three hours of cancer cells' arrival, they already can adhere very well,” said Hai. Putting it more bluntly, she explained that "the effect of chemotherapy on non-cancer cells actually changes those cells, and those changes help cancer cells to progress."