For more information on our recent data notice, please click here

Menu
Search

Damage Control: Recovering From Radiation and Chemotherapy

Protein discovery could boost efficacy of bone marrow replacement treatments

April 30, 2014  |  

Researchers at the University of California, San Diego School of Medicine report that a protein called beta-catenin plays a critical, and previously unappreciated, role in promoting recovery of stricken hematopoietic stem cells after radiation exposure.

The findings, published in the May 1 issue of Genes and Development, provide a new understanding of how radiation impacts cellular and molecular processes, but perhaps more importantly, they suggest new possibilities for improving hematopoietic stem cell regeneration in the bone marrow following cancer radiation treatment.

red blood cells

The continuous, necessary production of blood cells, including these red blood cells captured in a scanning micrograph by
Thomas Deerinck, is the responsibility of hematopoietic stem cells found in bone marrow.

Ionizing radiation exposure – accidental or deliberate – can be fatal due to widespread destruction of hematopoietic stem cells, the cells in the bone marrow that give rise to all blood cells. A number of cancer treatments involve irradiating malignancies, essentially destroying all exposed blood cells, followed by transplantation of replacement stem cells to rebuild blood stores. The effectiveness of these treatments depends upon how well the replacement hematopoietic stem cells do their job.

In their new paper, principal investigator Tannishtha Reya, PhD, professor in the department of pharmacology, and colleagues used mouse models to show that radiation exposure triggers activation of a fundamental cellular signaling pathway called Wnt in hematopoietic stem and progenitor cells.

“The Wnt pathway and its key mediator, beta catenin, are critical for embryonic development and establishment of the body plan,” said Reya, who also works at the Sanford Consortium for Regenerative Medicine. “In addition, the Wnt pathway is activated in stem cells from many tissues and is needed for their continued maintenance.”

The researchers found that mice deficient in beta-catenin lacked the ability to activate canonical Wnt signaling and suffered from impaired hematopoietic stem cell regeneration and bone marrow recovery after radiation. Specifically, mouse hematopoietic stem cells without beta-catenin could not suppress the production of oxidative stress molecules that damage cell structures. As a result, they could not recover effectively after radiation or chemotherapy.

“Our work shows that Wnt signaling is important in the mammalian hematopoietic system, and is critical for recovery from chemotherapy and radiation,” Reya said. “While these therapies can be life-saving, they take a heavy toll on the hematopoietic system from which the patient may not always recover.”

The findings have significant clinical implications.

“There are two major reasons why accelerating regeneration is important clinically,” said Reya. “One is that after cancer patients are irradiated and transplanted with stem cells, the rate and extent of recovery is often not sufficient to protect the patient from anemia or infections, which can be difficult to treat and sometimes deadly. Identifying signals that can boost regeneration after the bone marrow is severely damaged may help improve outcomes after transplantation.

“Second, doses of chemotherapy and radiation used to treat cancer are often limited by the collateral damage they cause to normal tissues. Although higher doses might kill more cancer cells more effectively, they can’t be used because they kill normal cells too. If we can improve and accelerate recovery, we might be able to use higher doses of radiation or chemotherapy and reduce the risk of cancer relapse.”

Reya said post-therapy hematopoietic stem cell regeneration could be accelerated by modulating the Wnt pathway, either by delivering additional Wnt proteins directly to patients or through drugs that activate the pathway.  Further studies will be needed to determine if these approaches may be clinically useful to mitigate the damage caused by radiation and chemotherapy.

Co-authors include William Lento, UCSD Department of Pharmacology, Sanford Consortium for Regenerative Medicine (SCRM) and Duke University departments of Pharmacology and Medicine; Takahiro Ito, UCSD Department of Pharmacology and SCRM; Chen Zhao, Duke University Department of Pharmacology; Jeffrey R. Harris, Wei Huang, Sadhna Piryani and Nelson Chao, Duke University Department of Medicine; Chen Jiang and Kouros Owzar, Duke University Department of Biostatistics and Bioinformatics; Luigi Racioppi, University of Naples Federico II.

Funding for this research came, in part, from National Institutes of Health grants T32CA059365, U19AI067798, DK63031, HL097767 and DP1CA174422, the California Institute for Regenerative Medicine and the Leukemia and Lymphoma Society.

# # #

Media contact: Scott LaFee, 619-543-6163, slafee@ucsd.edu


Related Specialties

Cancer

Radiation Therapy



Media Contact

Scott LaFee
858-249-0431
slafee@health.ucsd.edu

Heather Buschman, PhD
858-249-0456
hbuschman@health.ucsd.edu

Share This Article


Related News

2/28/2019
Pharmaceutical leader Cam Garner and his wife Wanda, a cancer workshop facilitator and philanthropic fundraiser, recently gave $2 million to establish the Garner Family Chancellor’s Endowed Chair in B ...
10/27/2016
Acute myeloid leukemia (AML) is an aggressive cancer known for drug resistance and relapse. In an effort to uncover new treatment strategies, researchers at University of California San Diego School o ...
3/7/2016
UC San Diego Health and Vantage Oncology are collaborating to provide comprehensive cancer care services to patients in Imperial Valley. Through a joint venture, UC San Diego Health and Vantage will o ...
2/23/2016
Cancer immunology is based upon boosting the body’s own immune system to vanquish malignancies. It is among the fastest growing areas of oncology research. Researchers at UC San Diego Moores Cancer Ce ...



Follow Us