Nav: Home

Senescence promotes chemotherapy side effects and cancer relapse

January 16, 2017

Standard chemotherapy is a blunt force instrument against cancer - and it's a rare cancer patient who escapes debilitating side effects from systemic treatments that mostly affect dividing cells, both malignant and healthy, throughout the body. Researchers at the Buck Institute and elsewhere now show that chemotherapy triggers a pro-inflammatory stress response termed cellular senescence, promoting the adverse effects of chemotherapy as well as cancer relapse and metastasis. Eliminating the senescent cells in mice prevented the side effects and relapse. The research is published in Cancer Discovery.

"While chemotherapy does save lives, it often comes with a very high price," said Judith Campisi, PhD, Buck faculty and senior scientist on the study. "Our work in mice studied the effects of chemotherapy on cancer relapse and other serious side effects. It provides a proof-of-principle that we hope can be translated into clinical practice."

Campisi's latest work highlights the two-faced nature of cellular senescence. It's a biological mechanism that puts a break on cancer by permanently stopping stressed cells from dividing, but it also contributes to aging and late-life cancers. That's because senescent cells are not benign - they secrete inflammatory molecules that damage neighboring tissues and cells. "Chemotherapy induces widespread senescence, contributing to persistent local and systemic inflammation," Campisi said. "That's why many patients feel so awful following treatment."

The research, led by Marco Demaria, PhD, a former postdoc in the Campisi lab, utilized transgenic mice that permit tracking and eliminating senescent cells. Results showed that eliminating chemotherapy-induced senescent cells reduced several short-and long-term effects of treatment, including bone marrow suppression, toxicity to the heart, cancer recurrence and metastasis, and physical activity and strength. Common chemotherapy drugs Doxorubicin, Paclitaxel, Temozolomide and Cisplatin were used to treat the mice.

Demaria, who is now a principle investigator at the European Research Institute for the Biology of Ageing, at the University Medical Center, Groningen, Netherlands, said some of the most striking results involved running speed - an indicator of fatigue in mice. "Eliminating senescent cells was sufficient to almost entirely rescue the decline in physical activity in the treated mice," he said. "Normally, mice spend 40 percent of their time running. After chemotherapy that activity dropped to 10 percent. When we knocked out the senescent cells the mice returned to normal running."

"Fatigue, which can be long-lasting, is a big deal for patients on chemotherapy," said Norman E. Sharpless, MD, Director of the Lineberger Comprehensive Cancer Center at the University of North Carolina in Chapel Hill and a co-author of the study, "Years later they often say that was the worst part of the treatment."

"Chemotherapy-induced bone marrow injury can lead to reduction in blood cell production, which can contribute to chemotherapy-induced fatigue," Said Daohong Zhou, MD, Associate Director for Basic Research of the Winthrop P. Rockefeller Cancer Institute at the University of Arkansas for Medical Sciences in Little Rock and a co-author of the study, "Eliminating senescent cells can promote bone marrow recovery after chemotherapy."

Sharpless looked at blood markers of cellular senescence in 89 women with breast cancer before they underwent chemotherapy aimed at curing their disease. "Women who went into chemotherapy with the highest existing burden of senescent cells experienced the most debilitating fatigue after treatment," he said. "It didn't really matter what particular drug was used - the results following chemotherapy tracked to the existing burden of senescent cells."

"We are excited about the potential applications of this work," said Campisi. "It would be a huge benefit if we could reduce the risk of cancer relapse and metastasis in patients. We also think it would be great to mitigate the other side effects of chemotherapy, the fear of which sometimes keep patients from seeking treatment."
-end-
Citation: Cellular senescence promotes adverse effects of chemotherapy and cancer relapse
DOI: 10.1158/2159-8290.CD-16-0241

Other Buck Institute researchers involved in the study include: Monique N. O'Leary, Su Liu, Fatouma Alimirah, Kristin Koenig, Catherine Le, Emmeline C. Academia, Sumner Kilmarx, Alexis Valdovinos, Brian K. Kennedy, and Simon Melov. Additional collaborators include Boshi Wang from the European Institute for the Biology of Aging, University of Groningen, Netherlands; Jianhui Chang, Lijan Shao, and Daohong Zhou from the Department of Pharmaceutical Sciences, University of Arkansas for Medical Sciences, Little Rock; Natalia Mitin from HealthSpan Diagnostics, Research Triangle Park, North Carolina; Allison M Deal, Shani Alston and Hyman Muss from the Lineberger Comprehensive Cancer Center and Department of Medicine, The University of North Carolina School of Medicine, Chapel Hill; and Alain de Bruin, Department of Pathobiology, University of Utrecht, Netherlands.

The work was supported by grants from the American Italian Cancer Foundation and the National Institutes of Health grants AG009909, AG017242, AG041122 and CA122023

Campisi and Zhou are co-founders of Unity Biotechnology which is developing drugs to eliminate senescent cells. Sharpless and Demaria have equity in the company. Sharpless is a founder and has a financial interest in HealthSpan Diagnostics. Mitin is an employee of HealthSpan Diagnostics. All other authors declare no financial interests.

About the Buck Institute for Research on Aging

The Buck Institute is the U.S.'s first independent research organization devoted to Geroscience - focused on the connection between normal aging and chronic disease. Based in Novato, California, the Buck is dedicated to extending "healthspan," the healthy years of human life, and does so by utilizing a unique interdisciplinary approach involving laboratories studying the mechanisms of aging and others focused on specific diseases. Buck scientists strive to discover new ways of detecting, preventing and treating age-related diseases such as Alzheimer's and Parkinson's, cancer, cardiovascular disease, macular degeneration, osteoporosis, diabetes and stroke. In their collaborative research, they are supported by the most recent developments in genomics, proteomics, bioinformatics and stem cell technologies. For more information: http://www.thebuck.org.

Buck Institute for Research on Aging

Related Breast Cancer Articles:

Breast cancer: AI predicts which pre-malignant breast lesions will progress to advanced cancer
New research at Case Western Reserve University in Cleveland, Ohio, could help better determine which patients diagnosed with the pre-malignant breast cancer commonly as stage 0 are likely to progress to invasive breast cancer and therefore might benefit from additional therapy over and above surgery alone.
Partial breast irradiation effective treatment option for low-risk breast cancer
Partial breast irradiation produces similar long-term survival rates and risk for recurrence compared with whole breast irradiation for many women with low-risk, early stage breast cancer, according to new clinical data from a national clinical trial involving researchers from The Ohio State University Comprehensive Cancer Center - Arthur G.
Breast screening linked to 60 per cent lower risk of breast cancer death in first 10 years
Women who take part in breast screening have a significantly greater benefit from treatments than those who are not screened, according to a study of more than 50,000 women.
More clues revealed in link between normal breast changes and invasive breast cancer
A research team, led by investigators from Georgetown Lombardi Comprehensive Cancer Center, details how a natural and dramatic process -- changes in mammary glands to accommodate breastfeeding -- uses a molecular process believed to contribute to survival of pre-malignant breast cells.
Breast tissue tumor suppressor PTEN: A potential Achilles heel for breast cancer cells
A highly collaborative team of researchers at the Medical University of South Carolina and Ohio State University report in Nature Communications that they have identified a novel pathway for connective tissue PTEN in breast cancer cell response to radiotherapy.
Computers equal radiologists in assessing breast density and associated breast cancer risk
Automated breast-density evaluation was just as accurate in predicting women's risk of breast cancer, found and not found by mammography, as subjective evaluation done by radiologists, in a study led by researchers at UC San Francisco and Mayo Clinic.
Blood test can effectively rule out breast cancer, regardless of breast density
A new study published in PLOS ONE demonstrates that Videssa® Breast, a multi-protein biomarker blood test for breast cancer, is unaffected by breast density and can reliably rule out breast cancer in women with both dense and non-dense breast tissue.
Study shows influence of surgeons on likelihood of removal of healthy breast after breast cancer dia
Attending surgeons can have a strong influence on whether a patient undergoes contralateral prophylactic mastectomy after a diagnosis of breast cancer, according to a study published by JAMA Surgery.
Young breast cancer patients undergoing breast conserving surgery see improved prognosis
A new analysis indicates that breast cancer prognoses have improved over time in young women treated with breast conserving surgery.
Does MRI plus mammography improve detection of new breast cancer after breast conservation therapy?
A new article published by JAMA Oncology compares outcomes for combined mammography and MRI or ultrasonography screenings for new breast cancers in women who have previously undergone breast conservation surgery and radiotherapy for breast cancer initially diagnosed at 50 or younger.
More Breast Cancer News and Breast Cancer Current Events

Trending Science News

Current Coronavirus (COVID-19) News

Top Science Podcasts

We have hand picked the top science podcasts of 2020.
Now Playing: TED Radio Hour

Listen Again: Reinvention
Change is hard, but it's also an opportunity to discover and reimagine what you thought you knew. From our economy, to music, to even ourselves–this hour TED speakers explore the power of reinvention. Guests include OK Go lead singer Damian Kulash Jr., former college gymnastics coach Valorie Kondos Field, Stockton Mayor Michael Tubbs, and entrepreneur Nick Hanauer.
Now Playing: Science for the People

#562 Superbug to Bedside
By now we're all good and scared about antibiotic resistance, one of the many things coming to get us all. But there's good news, sort of. News antibiotics are coming out! How do they get tested? What does that kind of a trial look like and how does it happen? Host Bethany Brookeshire talks with Matt McCarthy, author of "Superbugs: The Race to Stop an Epidemic", about the ins and outs of testing a new antibiotic in the hospital.
Now Playing: Radiolab

Dispatch 6: Strange Times
Covid has disrupted the most basic routines of our days and nights. But in the middle of a conversation about how to fight the virus, we find a place impervious to the stalled plans and frenetic demands of the outside world. It's a very different kind of front line, where urgent work means moving slow, and time is marked out in tiny pre-planned steps. Then, on a walk through the woods, we consider how the tempo of our lives affects our minds and discover how the beats of biology shape our bodies. This episode was produced with help from Molly Webster and Tracie Hunte. Support Radiolab today at Radiolab.org/donate.