Liz Meszaros, MDLinx | August 11, 2017
Paclitaxel—a front-line chemotherapy drug—may set off a number of molecular-level changes that allow breast cancer cells to escape from the tumor, while creating changes in the lung that promote a more hospitable environment for cancer cells, according to results published in the Proceedings of the National Academy of Sciences.
Researchers used a mouse model of breast cancer to analyze breast cancer metastasis in humans.
“That chemotherapy can paradoxically promote cancer progression is an emerging revelation in cancer research. However, a molecular-level understanding of this devastating effect is not clear,” said Tsonwin Hai, PhD, professor of biological chemistry and pharmacology, The Ohio State University, Columbus, OH.
Dr. Hai and colleague documented such changes in tumor and lung that were dependent on Atf3, a gene turned on by stress. They found higher Atf3 gene expression in patients who had undergone chemotherapy than those who did not.
“This gene seems to do two things at once: essentially help distribute the ‘seeds’ (cancer cells) and fertilize the ‘soil’ (the lung),” said Dr. Hai.
She explained that at first, chemotherapy may send signals increasing the number of molecular doors through which the cancer cells can escape from the primary tumor into the bloodstream. Thus, they are free to travel to other organs.
“I think it’s an active process – a biological change in which the cancer cells are beckoned to escape into the blood — rather than a passive process in which the cancer cells get into the bloodstream because of leaky vessels,” said Dr. Hai, who is also a member of The Ohio State University Comprehensive Cancer Center.
In addition, Dr. Hai and colleagues found that paclitaxel also creates a cascade of events that makes the tissue environment in the lung fertile for circulating cancer cells.
“There are signals that help cancer cells enter the lungs and set up shop, that make the environment more immunologically tolerant to cancer cells,” she said, adding the caution that more work is needed before these effects in mice can be extrapolated to cancer treatment in humans.
“At this point, what our study and the recent literature on chemotherapy taught us is that it is prudent to keep our mind open, realizing that chemo can help treat cancer, but at the same time may increase the possibility of the spread of that cancer,” she noted.
But their identification of Atf3 in this process is new. Paclitaxel—essentially a stressor, exerts a pro-cancer effect, at least partially, by turning on Atf3.
“It’s possible there could be a treatment given in conjunction with the chemo that would inhibit this problem by dampening the effect of the stress gene Atf3,” said Dr. Hai.
In the future, this will become the focus of her research.
This study was supported by the US Department of Defense.