Low doses of radiation give cancer-capable cells a competitive advantage over normal cells

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Low doses of radiation equivalent to three CT scans, which are considered safe, give cancer-capable cells a competitive advantage over normal cells in healthy tissue, scientists have discovered.

Researchers at the Wellcome Sanger Institute and the University of Cambridge studied the effects of low doses of radiation in the esophagus of mice.

The team found that low doses of radiation increase the number of cells with mutations in p53, a well-known genetic change associated with cancer.

However, giving the mice an antioxidant before radiation promoted the growth of healthy cells, which outcompeted and replaced the p53 mutant cells.

The results, published today (18 July) in Cell Stem Cell show that low doses of radiation promote the spread of cancer-capable cells in healthy tissue.

Researchers recommend that this risk should be considered in assessing radiation safety.

The study also offers the possibility of developing non-toxic preventative measures to cut the risk of developing cancer by bolstering our healthy cells to outcompete and eradicate cancer-capable cells.

Every day we are exposed to various sources of ionising radiation, including natural radiation in soil and rock, and important medical procedures like CT scans and x-rays.

Low doses of radiation, such as the exposure from medical imaging, are considered safe as they cause little DNA damage and apparently minimal effect on long-term health.

Until now, other effects of exposure to low levels of radiation have remained hidden, meaning understanding the true risk associated with low doses of radiation has been difficult.

Researchers have previously shown that our normal tissues, like skin, are battlefields where mutant cells compete for space against healthy cells.

We all have cancer-capable mutant cells in healthy tissues, including those with p53 mutations, which increase in number as we age, yet very few eventually go on to form cancer.

In this new study, researchers show that low doses of radiation weigh the odds in favour of cancer-capable mutant cells in the esophagus.

The Sanger Institute researchers and their collaborators gave mice a 50 milligray dose of radiation, equivalent to three or four CT scans.

As a result, the p53 mutant cells spread and outcompeted healthy cells.

Dr David Fernandez-Antoran, first author from the Wellcome Sanger Institute, said: “Our bodies are the set of ‘Game of Clones’ — a continuous battle for space between normal and mutant cells.

We show that even low doses of radiation, similar to three CT scans’ worth, can weigh the odds in favour of cancer-capable mutant cells. We’ve uncovered an additional potential cancer risk as a result of radiation that needs to be recognised.”

Researchers then gave the mice an over-the-counter antioxidant — N-Acetyl Cysteine (NAC) — before exposure to the same level of radiation.

The team discovered that the antioxidant gave normal cells the boost needed to outcompete and eradicate the p53 mutant cells.

However, the antioxidant alone without exposure to radiation did not help normal cells battle the mutant clones.

Dr Kasumi Murai, an author from the Wellcome Sanger Institute, said: “Giving mice an antioxidant before exposing them to low doses of radiation gave healthy cells the extra boost needed to fight against the mutant cells in the esophagus and make them disappear.

However, we don’t know the effect this therapy would have in other tissues — it could help cancer-capable cells elsewhere become stronger.

What we do know is that long term use of antioxidants alone is not effective in preventing cancer in people, according to other studies.”

Professor Phil Jones, lead author from the Wellcome Sanger Institute and MRC Cancer Unit, University of Cambridge, said: “Medical imaging procedures using radiation, such as CT scans and x-rays, have a very low level of risk — so low that it’s hard to measure.

This research is helping us understand more about the effects of low doses of radiation and the risks it may carry. More research is needed to understand the effects in people.”

The team suggests this research also highlights the possibility of developing therapies to prevent cancer. By making healthy cells fitter they naturally push out cancer-capable cells, without any toxic side effects for the patient.


The purpose of this study is to determine the effects of low-dose radiation on fibroblast cells irradiated by spectrally and dosimetrically well-characterized soft x-rays. To achieve this, a new cell culture x-ray irradiation system was designed.

This system generates characteristic fluorescent x-rays to irradiate the cell culture with x-rays of well-defined energies and doses.

3T3 fibroblast cells were cultured in cups with Mylar® surfaces and were irradiated for one hour with characteristic iron (Fe) K x-ray radiation at a dose rate of approximately 550 μGy/hr.

Cell proliferation, total protein analysis, flow cytometry, and cell staining were performed on fibroblast cells to determine the various effects caused by the radiation. Irradiated cells demonstrated increased proliferation and protein production compared to control samples.

Flow cytometry revealed that a higher percentage of irradiated cells were in the G0/G1 phase of the cell cycle compared to control counterparts, which is consistent with other low-dose studies.

Cell staining results suggest that irradiated cells maintained normal cell functions after radiation exposure, as there were no qualitative differences between the images of the control and irradiated samples.

The result of this study suggest that low-dose soft x-ray radiation might cause an initial pause, followed by a significant increase, in proliferation. An initial “pause” in cell proliferation could be a protective mechanism of the cells to minimize DNA damage caused by radiation exposure.

The new cell irradiation system developed here allows for unprecedented control over the properties of the x-rays given to the cell cultures.

This will allow for further studies on various cell types with known spectral distribution and carefully measured doses of radiation, which may help to elucidate the mechanisms behind varied cell responses to low-dose x-rays reported in the literature.

Introduction

Ionizing x-ray radiation exposure can cause DNA damage and the development of cancer, yet people are constantly exposed to x-rays and other forms of radiation from many different sources [1].

These sources include naturally occurring background radiation, cosmic radiation during space travel, diagnostic medical imaging such as x-rays and CT scans, radiation therapy for cancer treatment, and even from disaster areas like Fukushima [17].

Since the 1980’s, medical imaging has become an integral part of healthcare diagnostics, exposing patients to radiation at ever-increasing frequencies [38].

Recent in vitro experiments support the hypothesis that the radiation environment of space could also contribute to the long-term physiological changes astronauts experience after missions [910].

Because radiation exposure is so ubiquitous and can vary greatly across populations, it is important to fully understand the effects of low and high dose radiation on all human tissue and cell types to recognize and prevent detrimental effects.

Exposure from different sources has various total doses, exposure rates, linear energy transfer, and spectral features, which make certain aspects more harmful or more beneficial than others [11].

Medical radiation sources such as linear accelerators used for cancer treatment are designed to destroy cancerous tissue by the use of focused high doses [several 10s of Gy over the course of a treatment) of high-energy radiation (in the MeV photon range) while sparing healthy tissue in the regions of low dose [12].

Diagnostic x-ray sources operate with lower-energy (around 100 keV) radiation which has higher linear energy transfer (LET) than therapeutic devices, but these x-ray sources are considered to have acceptable risk of damage due to low-dose (on the order of 0.1 mGy to 400 mGy) employed [28].

In order to minimize the unwanted damage that ionizing radiation sources produce, the physical and biological processes involved need to be understood with properly characterized systematic measurements, especially in the low-dose region [41314].

Research on the effect of low-dose radiation on cells has shown wide ranges of results due to the variation in cell types, radiation source, and doses [1418].

Some studies have shown no effect of low-dose (<0.1 Gy) radiation on cells [1920], but others have suggested that low-dose x-ray radiation has positive effects on the proliferation of cell types such as fibroblasts and osteoblasts, as well as in animal models [161821].

Our study aimed to determine the effect of low dose (here approximately 550 μGy) x-ray radiation on fibroblast cells in vitro using characteristic fluorescent x-rays with well-defined energies and doses. Well-defined characteristic x-rays produced by a novel x-ray fluorescence irradiation device were utilized to aid the physical characterization of the radiation, as standard x-ray tube sources produce a mix of Bremsstrahlung and characteristic emissions [22].

Characteristic x-rays have a narrow wavelength band; therefore, the type and dose of x-rays given to the cells in this study are more controlled than previous studies using standard x-ray tubes or electron beam based sources [16182326].

Fibroblasts were chosen for this study due to their presence in connective tissues and critical role in secreting wound-healing proteins in the presence of tissue damage [27].

 In vitro, the NIH 3T3 fibroblast cell line is well studied and experiences proliferation at a very high rate, which facilitates observation of the effects of irradiation on proliferation and serves as an ideal subject for testing the well characterized x-rays produced by the novel irradiation device in this study.

Since low-dose radiation is known to affect the cell cycle of some cell types [16], we hypothesized that the exposure will accelerate the fibroblast cell cycle leading to increased proliferation of cells over time.

Conclusions

The new tunable monochromatic low-dose x-ray cell irradiation system presented here reduces the complexity and cost of cell radiation experiments, which opens new avenues of study.

For instance, this system can allow researchers to investigate the effect of x-ray wavelength on cells.

The results of low dose, well-characterized irradiation studies could help develop new ways of utilizing low dose radiation in clinical settings, as well as fully determine specific dose and dose rate thresholds for certain outcomes. Further studies will help determine the full breadth of benefit and harm that monochromatic, low-dose, soft x-rays can have.

We have employed a novel, well-characterized x-ray fluorescence setup to irradiate 3T3 fibroblast cells with a low-dose of soft x-ray radiation.

The total dose of radiation consisted of 6.5 keV and 7.05 keV monochromatic photons fully depositing their energy within the volume of the cell culture and the surrounding media. Although x-rays have a much lower LET in comparison to charged particle sources, the low energy x-rays used in this study have a higher LET than many of those used for diagnostic imaging and therapeutic devices.

Thus, the amount of ionizations and potentially damaging events within the cell are higher than those typically used in many medical applications. However, because clinical x-ray sources produce a broad spectrum of x-rays, the energies used here are within the spectrum of the x-ray energies that are emitted from some clinical sources (i.e. Molybdenum sources used for mammography [40]).

Most radiation sources used in biological experiments are not fully characterized. In most studies, the only properties reported about the source are the method of generating the radiation (linear accelerator, x-ray tube, elemental decay, etc) and the total dose applied. In some studies, the dose rate is also reported. Our system has opened up the possibility of more fully characterizing the applied radiation, and in turn being able to determine if different wavelengths and energies, or methods of generating radiation have significantly different effects on their biological targets.

The dose used in this study is similar to the x-ray dose received by tissues during standard clinical x-ray imaging at higher x-ray energies [4142] and astronauts in low-earth orbit [7].

The organ dose limit recommended by the National Council on Radiation Protection and Measurements for air flight personnel and low-earth orbit astronauts is 250 mSv- 1.5 Sv over 30 days. If this dose is reached through continuous exposure, this translates to an exposure rate of 0.35–2 mSv/hr.

The dose rate from the irradiation system described here was set to 0.55 mGy/hr to be within this range but it should be noted that the dose rate can easily be varied by changing the power to the x-ray source (Fig 2). By allowing for independent control of parameters, this novel x-ray irradiation system useful for further studies studying the effect of total dose, dose rate, and x-ray wavelength on cell cultures [43].

The increased proliferation rate and protein concentration for the irradiated 3T3 fibroblast cells at this dose rate suggests that very low dose soft x-ray radiation might cause an initial pause in cell proliferation followed by a significant increase cell proliferation, which is consistent with prior studies using similar x-ray total doses on other cell types [25].

While the exact mechanism for this phenomenon is currently unknown, it can now be further studied systematically as a function of the properties and characteristics of x-rays using the new system described here [26]. These tests further prompt the investigation of more specific responses that cause proliferation change by using various doses and various spectral distributions of radiation on several cell types.


Materials provided by Wellcome Trust Sanger Institute

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