in the bone marrow
The protein beta-catenin plays a critical role in promoting the recovery of hematopoietic stem cells (HSCs) after exposure to radiation or chemotherapy, according to preclinical research published in Genes & Development.
The study provides new insight into the impact of radiation and chemotherapy on cellular and molecular processes.
And it points to possibilities for improving HSC regeneration in cancer patients who have undergone these treatments.
Study investigators first used mouse models to show that exposure to radiation triggers activation of the Wnt signaling pathway 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,” explained Tannishtha Reya, PhD, of the University of California, San Diego.
“In addition, the Wnt pathway is activated in stem cells from many tissues and is needed for their continued maintenance.”
Dr Reya and her colleagues then found that mice deficient in beta-catenin lacked the ability to activate canonical Wnt signaling. They also suffered from impaired HSC regeneration and bone marrow recovery after radiation or chemotherapy.
Mouse HSCs without beta-catenin could not suppress the production of reactive oxygen species or resolve DNA double-strand breaks. As a result, they could not recover effectively after radiation exposure or treatment with the chemotherapeutic agent fluorouracil.
“Our work shows that Wnt signaling is important in the mammalian hematopoietic system and is critical for recovery from chemotherapy and radiation,” Dr Reya said. “There are 2 major reasons why accelerating regeneration is important clinically.”
“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 . . . . 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. 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.”
Dr Reya added that this research suggests HSC 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.
