More than half of cancer patients undergo radiotherapy, in which high doses of radiation are aimed at diseased tissue to kill cancer cells. But due to a phenomenon known as radiation-induced bystander effect (RIBE), in which irradiated cells leak chemical signals that can travel some distance to damage unexposed healthy cells, many suffer side-effects such as hair loss, fatigue and skin problems. This bystander effect may also make targeted cells resistant to radiation treatment, research suggests.
Researchers at the University of Colorado Boulder published a study (“Cysteine Protease Cathepsin B Mediates Radiation-Induced Bystander Effects”) in Nature that sheds new light on the precise mechanism behind the RIBE. The team identified both a protein released by irradiated cells and the pathway it takes to influence healthy ones. Ultimately, researchers hope it could lead to a medication patients could take before radiation treatment.
“Although RIBEs have important implications for radioprotection, radiation safety and radiotherapy, the molecular identities of RIBE factors and their mechanisms of action remain poorly understood. Here we use Caenorhabditis elegans as a model in which to study RIBEs, and identify the cysteine protease CPR-4, a homologue of human cathepsin B, as the first RIBE factor in nematodes, to our knowledge,” write the investigators. “Our study provides crucial insights into RIBEs, and will facilitate the identification of additional RIBE factors and their mechanisms of action.”
“Inhibiting RIBE would allow doctors to kill two birds with one stone,” said lead author Ding Xue, Ph.D., a professor of molecular, cellular, and developmental biology at CU Boulder who collaborated with colleagues in China, Taiwan, and Japan for the study. “We could minimize the bad effects of radiotherapy on healthy bystander cells, and at the same time, enhance cancer cell killing by radiotherapy.”
To be sure RIBE occurred in C. elegans, researchers exposed a population of the worms to radiation, then took a medium secreted by the C. elegans cells and bathed healthy C. elegans in it. The once-healthy animals began to show increased embryo deaths and other signs of RIBE.
The researchers then systematically treated the medium with agents designed to destroy proteins, DNA, and RNA, in order to determine which might be a key compound at play in RIBE. When the medium was treated with a protease, C. elegans exposed to it did not show signs of RIBE.
Once the scientists discovered that the agent causing RIBE was a protein, they used mass spectrometry to establish which proteins present in the medium were at play. CPR-4 emerged as the prime candidate, and cathepsin B is known to be a biomarker in several types of cancer.
Next the group studied which biological pathway enabled CPR-4 to signal changes in healthy cells that were never exposed to radiation. They identified a pathway mediated by the insulin-like growth factor receptor DAF-2. To confirm these findings, they irradiated the heads of C. elegans who either lacked the gene that codes for CPR-4 or lacked the gene that codes for the insulin-like growth factor receptor DAF-2. The bystander effect was blunted, with cells elsewhere in the body remaining healthy.
The study also found that tumor suppressor gene P53 may be at play in RIBE, prompting cells to produce more of the damaging CPR-4 protein when a cell is exposed to radiation.
“This is basically the first comprehensive study to identify the factor and mechanisms behind this radiation-induced bystander effect in animals,” said Dr. Xue, who hopes to work with other researchers in the future to identify other RIBE factors and mechanisms and help develop drugs that inhibit them.