Is an anticancer drug helping cancer to spread?

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It sounds counterintuitive, but a new study shows that the side effects of a chemotherapy drug may enable breast cancer to spread.

Breast cancer survival rates have consistently been improving in recent years, and much of the progress is due to the effectiveness of chemotherapy.

However, previous studies have suggested that a chemotherapy treatment in breast cancer may have a counterintuitive effect, instead raising the risk of metastasis.

Earlier this year, one such study showed that chemotherapy may cause changes at the cellular level not only in a breast cancer mouse model, but also in a small number of breast cancer patients.

Now, a team of scientists led by Tsonwin Hai, a professor of biological chemistry and pharmacology at Ohio State University in Columbus, has built on this research by investigating the effects of the common chemotherapy drug paclitaxel on the spread of breast cancer cells to the lungs.

The drug paclitaxel is commonly used as a frontline medication in the treatment of several types of cancer, including ovarian, breast, and lung cancer.

The new study - which is published in the journal Proceedings of the National Academy of Sciences - uses a rodent model and data from breast cancer patients to uncover ways in which paclitaxel may enable breast cancer to spread.

Paclitaxel may activate Atf3 gene

The study analyzed human data and found that in those who had received chemotherapy, the gene Atf3 - a transcription factor activated by stress, implicated in the mechanism of cellular stress, and found in a variety of cancer cells - is overexpressed, compared with patients who were not administered chemotherapy.

The findings, therefore, suggest that paclitaxel may have a carcinogenic effect by activating this gene.

The lead researcher explains the role of this gene as revealed by the study, saying, "This gene seems to do two things at once: essentially help distribute the 'seeds' (cancer cells) and fertilize the 'soil' (the lung)."

The way that it does the former, the authors write, is by increasing "the abundance of the tumor microenvironment of metastasis" at the level of the primary tumor. This microenvironment is "a landmark microanatomical structure at the microvasculature where cancer cells enter the blood stream."

The way that it does the latter is by improving "the tissue microenvironment (the 'soil') for cancer cells (the 'seeds') to thrive" at the level of the metastatic lung. "These changes," the authors write, "include increased inflammatory monocytes and reduced cytotoxicity."

Speaking to Medical News Today about the findings, Prof. Hai says:

"What is surprising to us is the multitude of pro-cancer effects that paclitaxel has! It not only enhances the escape of cancer cells from the primary tumor but also facilitates the preparation of distant sites (lung in our case) in such ways that when the cancer cells arrive, they can set up shop and grow."

In other words, paclitaxel seems to set off a molecular chain reaction, the end result of which is the creation of a cancer cell-friendly environment in the lungs.

Chemotherapy is 'a double-edged sword'

The new research reinforces the findings of previous studies, adding unique insights into the Atf3 gene.

Speaking about the strengths and limitations of the study, Prof. Hai told MNT that although their research studied both primary tumors and metastatic sites, the study focused on how cancer cells can escape into the blood, "a highway for cancer cells to spread."

"However," Prof. Hai said, "the lymphatic vessel is another highway system for cancer cells to spread. We did not address this issue."

"What set our study apart from the others is twofold," said the lead investigator. "(a) the analyses of both the tumors and the metastatic sites (others primarily focused on one site or the other), and (b) the identification of Atf3, a stress gene, in this process (paclitaxel exerts its pro-cancer effects in an Atf3-dependent manner)."

However, the lead researcher told us, the "causal relationship" behind why chemotherapy causes cancer to spread has only been demonstrated in mice. The human data only provide "correlative evidence" that seems to support the mouse data.

"Therefore, at this point, we are not suggesting oncologists to change their clinical practices but would suggest that it is prudent to keep our mind open, realizing that chemotherapy can be a double-edged sword."

The lead researcher also ventures a possible explanation for the study's findings. She says, "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."

"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."

Prof. Tsonwin Hai

The researchers are hopeful that in the near future, their findings will help medical researchers to knock off the drugs' undesired effects while maintaining its anticarcinogenic properties.

"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," concludes Prof. Hai.

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