ANNETTE LEXA
PhD Toxicology, EUROTOX
MAY 26, 2021
Adjuvant radiotherapy plays an important role in the treatment of breast cancer and its effectiveness has been demonstrated. However, we also know that for every 2,000 women screened for breast cancer after age 50, 10 will be over-diagnosed and one of them will have her life shortened by treatment (surgery, radiation, chemotherapy), a risk not taken by unscreened women. This over-treated woman will die either from chemotoxicity, or from radiotoxicity resulting in fibrosis of supporting tissues 6 to 30 months later (lungs, heart, coronary arteries...), or from radiation-induced cancer 3 to 20 years or more after the initial treatment.
What do we know today about these radiation-induced cancers (RIC)?
The Chernobyl accident showed significant excesses in the incidence of papillary thyroid cancer as well as sarcomas for which it has not been possible to find a specific genomic and transcriptomic signature (see box). Today, one of the main causes of radiation-induced cancers seems to be exposure to medical radiation, either in the form of radiotherapy for a malignant tumor or diagnostic radiography.
These tumors occur after a latency period that can extend over decades and the survival rate - in the cohort study of KIROVA et al, 2006 - was 36%. These are not recurrences of the original cancer but a cancer that affects the peripheral tissues in the irradiated area.
Generally speaking, the patients most at risk of IR cancer are those who were irradiated at a young age. In addition to secondary cancers of the lung, skin and hematological malignancies, sarcomas - rare tumors - representing 1% of cancers but overrepresented in IR cancers, have been the most studied. The latter are on the increase due to the lengthening of the survival time of patients.
Susceptibility is multifactorial: genetic predisposition, chemotherapy and radiotherapy are known to be risk factors for cancer.
More than 90% of angiosarcomas[1] occurring after radiotherapy for primary breast cancer are attributable to radiotherapy. One in a thousand women receiving such radiotherapy will develop angiosarcoma, with a latency of several years, a severe prognosis and a high recurrence rate. This figure may seem low, especially when, a priori, the benefit outweighs the risk.
Many uncertainties remain concerning the role of ionizing radiation in this type of carcinogenesis. The initial hypothesis evoked that cancers result from irreversible lesions of the DNA (mutations, deletions of genes), but they do not seem to be correlated with the level of energy sent.
Could such a risk be avoided by early detection? Do we have the tools to detect them earlier to improve survival?
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*A genomic signature of early hormone-dependent (HR+), HER2-negative (HER2-) tumors avoids adjuvant chemotherapy in postmenopausal breast cancer (https://www.lequotidiendumedecin.fr/specialites/cancerologie/une-signature-genomique-permet-deviter-la-chimiotherapie-adjuvante-dans-le-cancer-du-sein-post )
Chronic oxidative stress, an epigenetic signature of radiation-induced cancers
The scientific community has been investigating whether there is a genetic or epigenetic signature of IR cancers.
It has been shown[2] that radiation-induced sarcoma shows an increase in mutations in certain genes known to play a role in the development of cancer:
- TP53 gene of the p53 protein: it is the most important for the protection of the cell against cancerization. It is involved in the regulation of the cell cycle, autophagy and apoptosis. More than 50% of human cancers have an inactivated TP53 gene and if it is mutated, the cell becomes much more at risk of malignant transformation (this explains why in these cases of inactivated p53, chemotherapy may not work)
- RB retinoblastoma protein gene, a tumor suppressor gene that controls the cell cycle; a mutation in the pRB gene can lead to a tumor.
- PIK3CA gene and its associated oncogenic protein present in HER2 metastatic breast cancer, observed in breast cancer associated to radiation
But these signatures are not specific to radiotoxicity.
Although it has not been possible to identify a genomic signature (DNA), a transcriptomic signature has been demonstrated and suggests that one of the characteristics of IR cancers is a mitochondrial dysfunction (see box) associated with a sign of chronic oxidative stress (see box) linked to an overproduction of reactive oxygen species (ROS) by these same mitochondria [3]. Moreover, a known direct effect of ionizing radiation, visible under the electron microscope, is the alteration of the structure of mitochondria which "shrivel".
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These discoveries of the last decade evoke the old work of Otto Warburg (Nobel Prize in Physiology and Medicine, 1931) who demonstrated that cancer cells produce energy mainly by anaerobic glycolysis (see mitochondria box), followed by lactic acid fermentation, even if there is enough oxygen, with the consequence of producing H+ ions, which causes an acidification disrupting the metabolism of the cell.
According to Warburg, the development of cancer is due to a dysfunction of the mitochondria of cancer cells, which, instead of consuming glucose normally through the Krebs cycle, ferment this glucose. However, at present, the question remains whether this is the cause or the consequence of cell carcinogenesis and the scientific community is still debating the complex relation between the mitochondria and the nucleus.
The body often kills damaged cells by apoptosis - a self-destruct mechanism that involves the mitochondria - but this mechanism fails in cancer cells where the mitochondria malfunction and can no longer properly produce the energy necessary for the metabolic functioning of the cells, with a build-up of lactic acid, making the cellular environment unsuitable for certain enzymatic reactions.
Oxidative stress (see box) is an essential function of cells. It plays a major role in the elimination of pathogenic microbes and is essential for the functioning of mitochondria. However, like Janus, it has a negative side because it is involved in inflammation, cancer, autoimmune diseases, neuronal degeneration such as Parkinson's disease and aging. Oxidative stress has been maintained throughout evolution because it allows macrophages to eliminate pathogens, mitochondria to communicate with the nucleus, to initiate apoptosis and to send signals to other cells in the body to stimulate the influx of calcium (which blocks the functioning of mitochondria leading to an accumulation of ROS/NRS).
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Several other genes involved in detoxification and antioxidant functions are also deregulated in this type of IR cancers. However, genes encoding enzymes important in ROS detoxification (catalase, glutathione reductase..) are not expressed differently in IR sarcomas or in primary non-IR sarcomas. These genes are known to be involved in the response to acute oxidative stress. It is therefore not the acute oxidative stress that is dysfunctional but the chronic oxidative stress that ultimately impairs the turnover and removal of oxidized proteins and lipids from the cell as well as DNA repair.
Ionizing radiation generates reactive oxygen species and oxidative stress promoting genotoxicity. An international team [4] has demonstrated the involvement of ROS/NRS in metastatic human breast cancer cells. In IR sarcomas, cells have been selected and adapted to survive chronic oxidative stress. The progeny of surviving cells after irradiation are characterized by genomic instability - acquisitions of genetic alterations promoting genotoxicity, mutagenesis and carcinogenesis - induced by chronic oxidative stress due to mitochondrial dysfunction. However, it is not yet known whether this signature is that of radiation-induced cancerogenesis in general (Chernobyl-type) or whether it is specific to radiation-induced sarcomas in radiotherapy.
Antioxidants have an anti-carcinogenic role
The reduction of oxidative stress is an approach to limit the development of radio-induced cancers, even if we do not know if this chronic oxidative stress is the cause or the consequence. In vitro studies (on cancer cell cultures) are studying this avenue but they are rather rare.
In the meantime, and considering the important role of oxidative stress in cellular communication processes, it may be useful to recall that a balanced intake of micronutrients is a path that should not be neglected, even if the epidemiological evidence is not yet indisputable: B vitamins but also antioxidants such as ß-carotene (provitamins A), ascorbic acid (vitamin C), tocopherol (vitamin E), polyphenols and lycopene from tomatoes, and the large family of polyphenols among which flavonoids[5] very widespread among plants (especially flavonols such as kaempferol, quercetin, myricetol, rutin, rutoside... ), tannins (cocoa, coffee, tea, grapes, nuts, etc.. ), anthocyanins (red fruits) and phenolic acids (in cereals, fruits, vegetables). As these substances are naturally found in plants, a healthy and balanced diet remains the best source of natural antioxidants.
At present, as with any dietary supplementation, and particularly in the case of people with cancer, it is important to not practice self-supplementation but to seek advice from a professional specialized in nutrition.
Conclusion
Radiation-induced cancer is a rare, serious and often fatal cancer. The main therapy is surgery when possible. However, these cancers are often detected too late and we do not know precisely the process of their development even if we have succeeded in highlighting some very interesting cellular mechanisms.
In the meantime, any unnecessary radiotherapy would need to be avoided or at least weighed up, especially in the case of in situ cancer, in order to avoid the risk of over-treatment with the admittedly rare but extremely dangerous consequences of radiation-induced secondary cancer, especially as there is no means of early detection to date.
In the meantime, and as a principle of caution, it is useful to ask for a predictive test of radiosusceptibility on which two articles have been written on the Cancer Rose website:
Predictive testing for radiation reactions: women at great risk
Radiotoxicity and breast cancer screening: caution, caution, caution...
Additional bibliography used
Angiosarcoma associated with radiation therapy after treatment of breast cancer. Retrospective study on ten years, Verdin V et al, Cancer Radiother. 2021 Apr;25(2):114-118.
Radiation-induced sarcomas after breast cancer:experience of Institute Curie and review of literature, KIROVA Y. et al., Cancer/Radiothérapie 10 (2006) 83–90
A little vocabulary ....
Autophagy: mechanism by which unwanted or damaged organelles are collected and transported for degradation. This process allows the recycling of proteins and is essential for the homeostasis of the cell. This natural process malfunctions in cancer cells
Deletion : Loss of a DNA fragment by a chromosome.
Homesotasia: process of maintaining the equilibrium of the internal environment (cells, organisms), whatever the external constraints. Thus cells and organisms maintain the concentration of glucose, sodium or potassium within a narrow range.
Hypoxia: lack of oxygen in the cells and tissues of the organism
Mutation: a rare change, accidental or provoked, of the genetic information (DNA or RNA sequence) in the genome (chemical agents, radiation, virus....)
References
1] Some sarcomas are specific such as angiosarcoma, osteosarcoma, fibrosarcoma, myosarcoma.... Angiosarcoma is a soft tissue sarcoma. A very rare cancer, it originates in an artery. It is characterized by the proliferation of abnormal cells in the vascular endothelium. It can be located in veins, arteries, but is usually found below the surface of the skin and in lymph nodes. This type of cancer can be due to exposure to toxic products such as thorium, arsenic, pesticides and vinyl chloride or to previous irradiations (radiotherapy for another cancer...).
[2] Behjati, S., Gundem, G., Wedge, D. et al. Mutational signatures of ionizing radiation in second malignancies. Nat Commun 7, 12605 (2016).
3] Reactive oxygen species ROS (superoxide anion, H2O2,...) often in synergy with reactive nitrogen species ERA (peroxynitrile..) produced by the cells attack the essential components of the cells (lipids, proteins, DNA, amino acids..)
Of exogenous origin (solar UV, IR) but also endogenous (nitrogen metabolites in immune reactions to kill microorganisms)
[4] Y. Li, K. Hu, Y. Yu, S.A. Rotenberg, C. Amatore, M.V. Mirkin., Direct Electrochemical Measurements of Reactive Oxygen and Nitrogen Species in Nontransformed and Metastatic Human Breast Cells, J. Am. Chem. Soc. 139, 2017, 13055-13062,& address correction in J. Am. Chem. Soc. 140, 2018, 3170−3170.