How a chemo drug can help cancer spread from the breast to the lungs

August 7, 2017, The Ohio State University

COLUMBUS, Ohio -The very same treatment that thwarts breast cancer has a dark side—it can fuel the spread of the disease to the lungs.

Researchers at The Ohio State University studied the cascade of events that lead to metastatic and found clues to why it happens, opening up the possibility of one day interfering with the medication's downsides while preserving its cancer-fighting properties in breast tissue.

The front-line chemotherapy drug paclitaxel sets off a variety of molecular-level changes that allow to escape from the tumor. At the same time, it creates an environment in the lung that is more hospitable to the cancer cells, facilitating the spread of the disease, the researchers found in a of breast cancer.

The study, which appears in the journal Proceedings of the National Academy of Sciences, includes an analysis of data from women with breast cancer that suggest the findings from mouse models could be relevant to breast cancer metastasis in humans.

"That chemotherapy can paradoxically promote is an emerging revelation in cancer research. However, a molecular-level understanding of this devastating effect is not clear," said Tsonwin Hai, the study's senior author and a professor of biological chemistry and pharmacology.

The changes in both the tumor and the lung documented in the study depend on a gene called Atf3, which is turned on by stress. In human data, the researchers found higher Atf3 gene expression in patients who had 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)," Hai said.

First, the chemo appears to send signals to increase the number of molecular doors through which the cancer cells can escape from the primary tumor into the bloodstream, freeing them to travel to other organs, the researchers found.

"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 Hai, a member of The Ohio State University Comprehensive Cancer Center.

This finding is bolstered by another recent study conducted at the Albert Einstein College of Medicine and published in Science Translational Medicine, which showed a similar result using imaging techniques to observe the tumor in mice, Hai said.

Second, the Ohio State researchers found that, beyond aiding cancer cell escape, paclitaxel creates a cascade of events that makes the tissue environment in the lung fertile ground 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," Hai said.

A molecular-level understanding of why chemotherapy sometimes increases risk of is in the early stages, Hai said.

She said it's important to recognize that the cancer cells in the study's mouse model are very aggressive and that it would be interesting to test whether paclitaxel also enhances the escape of at earlier stages in cancer progression.

Hai cautioned that much more work is required before extrapolating the findings in mice to human cancer treatment.

"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 said.

What set their study apart from other research in this area is the identification of the stress gene Atf3. They showed that paclitaxel—a stressor—exerts its pro-cancer effect at least in part 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," Hai said.

And that will be a focus of Hai's work in this area going forward, she said.

Explore further: Neoadjuvant chemotherapy induces breast cancer metastasis through a TMEM-mediated mechanism

More information: Yi Seok Chang el al., "Stress-inducible gene Atf3 in the noncancer host cells contributes to chemotherapy-exacerbated breast cancer metastasis," PNAS (2017). www.pnas.org/cgi/doi/10.1073/pnas.1700455114

Related Stories

Neoadjuvant chemotherapy induces breast cancer metastasis through a TMEM-mediated mechanism

July 6, 2017
(Medical Xpress)—A team of researchers working at the Albert Einstein College of Medicine in the U.S. has found evidence that suggests administering chemotherapy to breast cancer patients prior to surgery can put them at ...

The stress and cancer link: 'Master switch' stress gene enables cancer's spread

August 22, 2013
In an unexpected finding, scientists have linked the activation of a stress gene in immune-system cells to the spread of breast cancer to other parts of the body.

New bone-in technique tests therapies for breast cancer metastasis

April 21, 2017
A new laboratory technique developed by researchers at Baylor College of Medicine and other institutions can rapidly test the effectiveness of treatments for life-threatening breast cancer metastases in bone. The study appears ...

Low doses of common cancer drug may promote cancer spread

June 22, 2016
New research indicates that paclitaxel, which is the most commonly used chemotherapy for breast cancer, suppresses tumors when given at a certain dosage, but at low doses, it actually promotes cancer spread to the liver.

Scientists identify chain reaction that shields breast cancer stem cells from chemotherapy

February 22, 2017
Working with human breast cancer cells and mice, researchers at Johns Hopkins say they have identified a biochemical pathway that triggers the regrowth of breast cancer stem cells after chemotherapy.

ALK1 protein may play a role in breast cancer metastasis

June 15, 2015
Breast cancer patients with high levels of the protein activin-like receptor kinase (ALK1) in the blood vessels of their tumors were more likely to develop metastatic disease. This makes inhibition of the ALK1 pathway a possible ...

Recommended for you

Researchers identify a mechanism that fuels cancer cells' growth

November 14, 2018
Scientists at the UCLA Jonsson Comprehensive Cancer Center have identified sodium glucose transporter 2, or SGLT2, as a mechanism that lung cancer cells can utilize to obtain glucose, which is key to their survival and promotes ...

A new approach to detecting cancer earlier from blood tests: study

November 14, 2018
Cancer scientists led by principal investigator Dr. Daniel De Carvalho at Princess Margaret Cancer Centre have combined "liquid biopsy", epigenetic alterations and machine learning to develop a blood test to detect and classify ...

New antibody breakthrough to lead the fight against cancer

November 14, 2018
Scientists at the University of Southampton have developed a new antibody that could hold the key to unlocking cancer's defence against the body's immune system.

Photoacoustic imaging may help doctors detect ovarian tumors earlier

November 14, 2018
Ovarian cancer claims the lives of more than 14,000 in the U.S. each year, ranking fifth among cancer deaths in women. A multidisciplinary team at Washington University in St. Louis has found an innovative way to use sound ...

Solving the mystery of NPM1 in acute myeloid leukemia

November 13, 2018
Although it has long been recognized that mutations of gene NPM1 play an important role in acute myeloid leukemia, no one has determined how the normal and the mutated forms of the protein NPM1 function.

Cognitive decline—radiation—brain tumor prevented by temporarily shutting down immune response

November 13, 2018
Treating brain tumors comes at a steep cost, especially for children. More than half of patients who endure radiation therapy for these tumors experience irreversible cognitive decline, a side-effect that has particularly ...

0 comments

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.