|Year : 2017 | Volume
| Issue : 2 | Page : 114-117
Radiation carcinogenesis: Mechanisms and experimental models - A meeting report
Nagarajan Rajendra Prasad
Department of Biochemistry and Biotechnology, Annamalai University, Chidambaram, Tamil Nadu, India
|Date of Web Publication||14-Jun-2017|
Nagarajan Rajendra Prasad
Department of Biochemistry and Biotechnology, Annamalai University, Chidambaram, Tamil Nadu
Source of Support: None, Conflict of Interest: None
The first International School on Radiation Research (2017) of Society for Radiation Research on the theme of “Radiation Carcinogenesis: Mechanisms and Experimental Models” was held in the Department of Biochemistry and Biotechnology, Annamalai University, Chidambaram, Tamil Nadu, India, during February 2–4, 2017. The school gathered basic/translational scientists and young researchers interested in recent developments in molecular and clinical aspects of cancer and radiation carcinogenesis. The objective of the School was to educate and train the young researchers about the theoretical and practical aspects of radiation carcinogenesis. The renowned faculties from India and aboard delivered expert lectures and conducted practical sessions during the school. The topics ranged from the basics of cancer and carcinogenesis; role of DNA damage and genomic instability in the mechanism of carcinogenesis; heavy metal radionuclides induced carcinogenesis; low-dose radiobiology and risk of cancer; ultraviolet (UV)-induced carcinogenesis; experimental models for carcinogenesis studies, and cancer incidence during cancer radiotherapy. During the practical session, demonstrations were arranged of techniques such as DNA damage, apoptosis, measurement of reactive oxygen species, mitochondrial membrane potential, fluorescence in situ hybridization, animal model of UV carcinogenesis, and histopathological observations of various stages of oral cancer. This report presents a brief overview of the scientific and practical sessions of the school.
Keywords: Carcinogenesis, DNA damage and repair, experimental models, radiation
|How to cite this article:|
Prasad NR. Radiation carcinogenesis: Mechanisms and experimental models - A meeting report. J Radiat Cancer Res 2017;8:114-7
| Introduction|| |
Radiation is considered to be a physical agent that may induce cancer. Ionizing radiation-induced carcinogenesis is a multistage complex cellular phenomenon involving several cellular and molecular events. Radiation carcinogenesis is an important area of research, which addresses the processes of cancer incidence under various radiation exposure scenarios such as environmental, occupational, medical, accidental, and therapeutic exposures. In the recent past, significant advancement has been made to understand the cellular and molecular basis of radiation-induced cancer incidence. Moreover, a range of in vitro and in vivo experimental models have been developed for better simulation of human radiation exposure conditions and the associated cancer risk. In view of the increasing use of radiation and its technologies in research, medicine and nuclear energy, the concern of health effects of radiation has received growing attention. A better understanding of radiation carcinogenesis would assist in optimizing the safe and effective application of diagnostic and therapeutic radiation technologies. Moreover, advancement in knowledge in this area would help to develop better strategies to prevent and minimize cancer incidence in case of undesired radiation exposure.
| Basics Of Carcinogenesis|| |
There were number of physical, chemical, and environmental agents possess carcinogenic potential and may induce cancer in the exposed populations. G. B. Maru (ACTREC, Tata Memorial Centre, Navi Mumbai, Maharashtra, India) delivered a lecture on the basic aspects of carcinogenesis. He stated that carcinogenesis is a multistage process and characterized by changes at the cellular, genetic, and epigenetic levels. Initiation is considered as the first step in carcinogenesis, and during this process, one or more stable mutations occur in a targeted cell. Successive accumulation of mutations and chromosomal aberrations support the transformed cells to grow into malignant, and the process of increasing malignant subpopulation is known as tumor progression. The occurrence of mutations provides major cause of cancer than hereditary or environmental mutagens. The majority of cancer incidence (60%–80%) environmental/lifestyle associated while inheritable cancer is only 5%–10%. In case of smoking-associated cancer, leaving of smoking decreases the risk of cancer but still higher than cancer incidence rate of nonsmokers.
Histopathological features of carcinogenesis, including potentially malignant changes, the international classification of tumors, the tumor invasion front and tumor biomarkers as well as the tumor microenvironment and function of cancer-associated fibroblasts in the most common type of oral cancer that is encountered by oral pathologists were presented by Madhavan R. Nirmal (Department of Oral Pathology, Annamalai University, Chidambaram, Tamil Nadu, India). Further, he has mentioned the associations between the proliferation, basal lamina degradation, and connective tissue modulation. He emphasized histopathological observations are vital during different stages of carcinogenesis as these variations are directly associated with the survival time of cancer patients.
| DNA Damage Response After Radiation Exposure and Carcinogenesis|| |
Detrimental effects of ionizing radiation are correlated to their varying efficiency to induce complex DNA damage. DNA damages can consist of double-strand breaks (DSBs), single-strand breaks, and/or non-DSB lesions such as base damages and apurinic/apyrimidinic (abasic) sites in different combinations. In higher eukaryotes, DSBs are repaired by homologous recombination repair (HRR) or nonhomologous end joining (NHEJ). In addition to these, cells employ a backup pathway NHEJ (B-NHEJ). Cellular response of DNA damage occurs through an integrated sensing and signaling network that maintains genomic stability. In higher eukaryotic cells with defect in the repair of DSBs contributes to genomic instability and possibly to carcinogenesis. During the inaugural session, George Iliakis (Institute of Medical Radiobiology, Germany) delivered a keynote lecture on DNA damage and repair with implications in cancer radiotherapy. He gave detailed account of multiple repair processes for damaged DNA. The DNA repair processes have sensitive signaling mechanism, which becomes operational depending on the magnitude and nature of damage. He mentioned that total protein sequencing of major tumor types showed single-base substitutions (~70% in colorectal and ~10% in medulloblastoma). Cells take DSBs very seriously and use the different types of repair pathways depending on the requirement. At high dose of radiation, HRR pathways get saturated. In general, the order of preference for the use of DSB pathways is HRR, NHEJ, and B-NHEJ. He highlighted the need of greater understanding about the molecular mechanism of radiation damage and repair in relevance to radiation carcinogenesis.
Sathees C. Ragavan (Indian Institute of Science, Bengaluru, Karnataka, India) gave a lecture on DNA damage and genomic instability in the mechanism of carcinogenesis. Repair of DNA breaks is critical for maintenance of genomic integrity. He illustrated that NHEJ is the predominant DNA DSB repair pathway in higher eukaryotes. Inhibition of DSB repair pathway proteins can be used as a novel strategy to induce apoptosis in the cancer cells. Several inhibitors of NHEJ serves as an effective chemotherapeutic agent against multiple cancer types and on coadministration can bring down the effective dose of radiotherapy.
Further, the treatment of cancers relies heavily on DNA damaging agents to eliminate cancer cells and decrease the tumor burden. Dindial Ramotar (University of Montreal, Canada) talked about novel drug uptake transporters that induce mutagenesis by environmental genotoxic compounds. He demonstrated the uptake of these DNA-damaging anticancer drugs are mainly depends on the membrane bound organic cation transporters (OCTs). Caenorhabditis elegans OCT-2 is a novel drug uptake transporter that could mediate chemosensitivity to DNA-damaging anticancer drugs. He also mentioned that it is possible to engineer a set of supersensitive C. elegans strains that can serve as the most powerful living sensors to test the cyto- and geno-toxicities of a battery of old and new drugs developed by pharmaceuticals.
| Tobacco-associated Carcinogenesis and Prevention of Carcinogenesis by Natural Compounds|| |
The lifestyle-associated tobacco carcinogens (such as N-nitrosodiethylamine [NDEA], benzo[a] pyrene, polyaromatic hydrocarbons, and N-nitrosamine) steadily increases cancer incidence, and these chemicals are widely used for carcinogenesis studies in experimental animal models. C. K. Panda (Chittaranjan National Cancer Institute, Kolkata, West Bengal, India) mentioned tobacco habit is one of the main etiological factors responsible for multiple organs cancer incidence. He demonstrated that active metabolites of tobacco carcinogen NDEA could induce cellular reactive oxygen species (ROS), binds to DNA, thereby transforming the stem cells of the specific organs toward neoplasm. Involvement of Wnt and Hedgehog signaling in tobacco carcinogenesis in addition to chemopreventive ability of agents (like epigallocatechin-3-gallate [EGCG], plumbagin, resveratrol) was highlighted. Irrespective of the route of administration of carcinogen, EGCG could prevent cancer incidence in mice model.
Different epidemiological studies showed natural compounds might reduce the risk of carcinogenesis. Chemopreventive role of several crude extracts and active compounds against radiation carcinogenesis, and chemical carcinogenesis were well established. K. Suresh (Annamalai University, Chidambaram, Tamil Nadu, India) mentioned the antioxidant, anti-inflammatory, and anticarcinogenic potential of natural dietary phytochemicals against chemical carcinogenesis studied in experimental animals. Particularly, he emphasized the role of dietary nutrients on chemoprevention in 7,12-dimethylbenz[a] anthracene (DMBA)-induced buccal pouch carcinogenesis. He demonstrated the chemopreventive potential of -shogaol, a dietary phytochemical, on DMBA-induced tumor incidence in hamster models.
| Carcinogenic Risk from Low-dose Radiation Exposure|| |
During an evening lecture of the school, K. P. Mishra (Ex-BARC, Mumbai, Maharashtra, India) stated that life has evolved in the high-radiation background and living organism including human have developed capacity to adapt the radiation environment. The living cells have armed themselves with many strategies to counter the effects of ionizing radiation. He pointed out that there is variation of background natural radiation dose in the various parts of the world. However, there is no reported document showing any adverse effect of radiation on human health at these doses. Research on biological effects of ionizing radiation has enabled to understand the mechanism of action on living systems and broadly characterize the low-dose radiation effect for cancer incidence as stochastic (random). He mentioned that the scientific curiosity of low-dose radiation biology continues. He argued that the diagnostic radiation is useful to public health is not likely to cause any cancer. However, future studies are needed for deeper understanding about the risk associated with low dose of radiation exposure. Estimation of cancer risk from radiation is of interest in all situations. Carcinogenic risk from low-dose radiation exposure is a matter of discussion. A number of recent publications question cancer risk estimation from low-dose radiation exposures, which is mainly based on the linear no threshold model. It would be of better rationale to consider the existence of a threshold dose, below which organisms show beneficial effects than predicted harmful effects.
| Radiation Carcinogenesis After Heavy Metal Radionuclides Exposure|| |
The carcinogenic potential of internalized radioisotopes is another important aspect of radiation carcinogenesis. B. N. Pandey (BARC, Mumbai, Maharashtra, India) stated that actidine radionuclides are of great importance in nuclear industry. Further, he mentioned that workers and public may get exposed with alpha/beta-emitting radionuclides through inhalation, ingestion, and wounds while occupational or accidental exposure. On accumulation in the target organs, these radionucleotides elicit energy deposition and induce continuous radiation damage. Compared to external radiation, in case of internal exposure of actinide radionuclides results in both chemical as well as radiological toxicity. Due to highly complex DNA strand breaks or clustered DNA damage and inefficient repair, there is a high probability for incorrect DNA repair and accumulation of neoplastic mutations, which may contribute for the development of organ-specific cancer after high linear energy transfer (LET) radiation exposure. Mechanism of carcinogenesis involves mostly direct effects, but some involve indirect/abscopal effects at distant cells/organs. For high-LET radiation exposure, cancer incidence generally rises more steeply as a function of dose and less dependent on dose rate. At low to intermediate dose levels, carcinogenic effects of radiation often remain unexpressed unless promoted by other agents. At high-dose levels, expression of carcinogenic effects tends to be suppressed by the sterilization of potentially transformed cells.
| Carcinogenic Potential of Nonionizing Radiations|| |
The carcinogenic potential of nonionizing radiations should not be underestimated as nonionizing ultraviolet (UV) wavebands is classified as Group I carcinogen. Rajendra Prasad Nagarajan (Annamalai University, Chidambaram, Tamil Nadu, India) mentioned UV radiation is a very prominent environmental carcinogen and has been implicated in the initiation and progression of carcinogenesis. Further, he emphasized the potential of UV radiation exposure on numerous cellular and molecular events which include epigenetic modifications, cyclobutane pyrimidine formation, generation of ROS, inflammatory and immunosuppression, photoaging and carcinogenesis. UV radiation-induced DNA damage and defect in nucleotide excision repair mechanism are recently proved to be involved in tumor promotion effects. He mentioned experimental models suitable for UV-carcinogenesis studies. Human skin-derived dermal fibroblasts, epidermal keratinocytes, and melanocytes serve as excellent cellular model systems for the understanding of UV-mediated carcinogenic events. Scientists have recently developed reconstituted three-dimensional normal human skin equivalent models for the study of UV-radiation induced carcinogenic experiments.
| Perspectives and Risk of Secondary Malignancy in Cancer Radiotherapy|| |
Nagraj Huilgol (Nanavati Hospital, Mumbai, Maharashtra, India) explained the possible risk and mechanism of second cancer incidence after cancer radiotherapy. He reviewed the effects of radiation therapy on normal tissues, which is the basis for radiation-induced malignancies. Radiation-induced malignancies are late complications, which may arise after radiotherapy in the survivors of pediatric and adult cancer patients. Genetic background harboring germline mutation in tumor suppressor genes are recognized risk factors for cancer incidence after radiotherapy.
The role of bystander response and genomic instability in late effects of cancer radiotherapy is emerging areas of research. Bystander response is defined as the manifestation of radiation on the unexposed cells which are in the closer vicinity of the directly exposed; on the other hand, genomic instability is defined as the expression of radiation signatures in the progeny of exposed cells. Venkatachalam Perumal (Sri Ramachandra Medical University, Chennai, Tamil Nadu, India) revealed that the bystander effects are variable and depend on dose, type of radiation, and type of recipient cells. He has been explained the possible role of radiation-induced bystander effect and genomic instability in the development of secondary malignancy.
| Application Of Genomics In Radiation Oncology|| |
Indranil Chatopadhyay (Central University of Tamil Nadu, Thiruvarur, Tamil Nadu, India) reviewed possible genetic markers for personalized radiotherapy. He has also talked about possible associations between germline genetic variation and normal tissue toxicity after radiotherapy. Ionizing radiation changes the expression of at least 23 microRNAs (miRNAs) (for example let-7, miR-21, miR-34s, miR-181a, and miR-449a), many of which affect radiosensitivity, DNA repair, and apoptosis. Further, he stated that combinatorial approaches to radiation-induced gene expression studies and genome-wide single-nucleotide polymorphism genotype studies may discover candidate biomarkers for personalized radiotherapy treatment and to identify genetic alterations that may affect normal tissue toxicity.
| Practical Sessions|| |
Radiation exposure induces ROS generation, mitochondrial membrane potentials (MMPs) alteration, oxidative DNA damages, DSBs, chromosomal translocations, and apoptosis in the exposed cells. Demonstrations were carried out on γ-H2AX foci for DSBs analysis by P. Venkatachalam (Sri Ramachandra University, Chennai, Tamil Nadu, India); fluorescence in situ hybridization techniques by Sathees C. Raghavan (Indian Institute of Science, Bengaluru, Karnataka, India); ROS, MMP, apoptosis, and oxidative DNA damage by Rajendra Prasad Nagarajan (Department of Biochemistry and Biotechnology, Annamalai University, Chidambaram, Tamil Nadu, India); and histopathological observations in oral tumor samples by Madhavan R. Nirmal (Department of Oral Pathology, Annamalai University, Chidambaram, Tamil Nadu, India).
| Conclusion|| |
Enthusiastic feedback from the participants showed the school as very useful and inspiring. Participants of the school opined that such school brings together eminent radiation scientists from various radiobiological disciplines to young researchers who are perusing research in radiation biology. Pertaining to International School on Radiation Research, a special issue of Journal of Radiation and Cancer Research on “Radiation Carcinogenesis and Cancer Prevention” was published, which can be viewed at http://www.journalrcr.org/currentissue.asp?sabs=n (ISSN 0973-0168).
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Conflicts off interest
There are no conflicts of interest.
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