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Event: 1556

Key Event Title

The KE title should describe a discrete biological change that can be measured. It should generally define the biological object or process being measured and whether it is increased, decreased, or otherwise definably altered relative to a control state. For example “enzyme activity, decreased”, “hormone concentration, increased”, or “growth rate, decreased”, where the specific enzyme or hormone being measured is defined. More help

Increase, lung cancer

Short name
The KE short name should be a reasonable abbreviation of the KE title and is used in labelling this object throughout the AOP-Wiki. The short name should be less than 80 characters in length. More help
Increase, lung cancer

Biological Context

Structured terms, selected from a drop-down menu, are used to identify the level of biological organization for each KE. Note, KEs should be defined within a particular level of biological organization. Only KERs should be used to transition from one level of organization to another. Selection of the level of biological organization defines which structured terms will be available to select when defining the Event Components (below). More help
Level of Biological Organization

Organ term

Further information on Event Components and Biological Context may be viewed on the attached pdf.The biological context describes the location/biological environment in which the event takes place.  For molecular/cellular events this would include the cellular context (if known), organ context, and species/life stage/sex for which the event is relevant. For tissue/organ events cellular context is not applicable.  For individual/population events, the organ context is not applicable. More help

Key Event Components

Further information on Event Components and Biological Context may be viewed on the attached pdf.Because one of the aims of the AOP-KB is to facilitate de facto construction of AOP networks through the use of shared KE and KER elements, authors are also asked to define their KEs using a set of structured ontology terms (Event Components). In the absence of structured terms, the same KE can readily be defined using a number of synonymous titles (read by a computer as character strings). In order to make these synonymous KEs more machine-readable, KEs should also be defined by one or more “event components” consisting of a biological process, object, and action with each term originating from one of 22 biological ontologies (Ives, et al., 2017; See List). Biological process describes dynamics of the underlying biological system (e.g., receptor signalling). The biological object is the subject of the perturbation (e.g., a specific biological receptor that is activated or inhibited). Action represents the direction of perturbation of this system (generally increased or decreased; e.g., ‘decreased’ in the case of a receptor that is inhibited to indicate a decrease in the signalling by that receptor).Note that when editing Event Components, clicking an existing Event Component from the Suggestions menu will autopopulate these fields, along with their source ID and description. To clear any fields before submitting the event component, use the 'Clear process,' 'Clear object,' or 'Clear action' buttons. If a desired term does not exist, a new term request may be made via Term Requests. Event components may not be edited; to edit an event component, remove the existing event component and create a new one using the terms that you wish to add. More help

Key Event Overview

AOPs Including This Key Event

All of the AOPs that are linked to this KE will automatically be listed in this subsection. This table can be particularly useful for derivation of AOP networks including the KE. Clicking on the name of the AOP will bring you to the individual page for that AOP. More help
AOP Name Role of event in AOP Point of Contact Author Status OECD Status
Deposition of energy leading to lung cancer AdverseOutcome Brendan Ferreri-Hanberry (send email) Under development: Not open for comment. Do not cite EAGMST Approved


This is a structured field used to identify specific agents (generally chemicals) that can trigger the KE. Stressors identified in this field will be linked to the KE in a machine-readable manner, such that, for example, a stressor search would identify this as an event the stressor can trigger. NOTE: intermediate or downstream KEs in one AOP may function as MIEs in other AOPs, meaning that stressor information may be added to the KE description, even if it is a downstream KE in the pathway currently under development.Information concerning the stressors that may trigger an MIE can be defined using a combination of structured and unstructured (free-text) fields. For example, structured fields may be used to indicate specific chemicals for which there is evidence of an interaction relevant to this MIE. By linking the KE description to a structured chemical name, it will be increasingly possible to link the MIE to other sources of chemical data and information, enhancing searchability and inter-operability among different data-sources and knowledgebases. The free-text section “Evidence for perturbation of this MIE by stressor” can be used both to identify the supporting evidence for specific stressors triggering the MIE as well as to define broad chemical categories or other properties that classify the stressors able to trigger the MIE for which specific structured terms may not exist. More help

Taxonomic Applicability

Latin or common names of a species or broader taxonomic grouping (e.g., class, order, family) can be selected from an ontology. In many cases, individual species identified in these structured fields will be those for which the strongest evidence used in constructing the AOP was available in relation to this KE. More help
Term Scientific Term Evidence Link
human Homo sapiens High NCBI
rat Rattus norvegicus High NCBI
mouse Mus musculus High NCBI

Life Stages

The structured ontology terms for life-stage are more comprehensive than those for taxa, but may still require further description/development and explanation in the free text section. More help
Life stage Evidence
All life stages High

Sex Applicability

The authors must select from one of the following: Male, female, mixed, asexual, third gender, hermaphrodite, or unspecific. More help
Term Evidence
Unspecific High

Key Event Description

A description of the biological state being observed or measured, the biological compartment in which it is measured, and its general role in the biology should be provided. For example, the biological state being measured could be the activity of an enzyme, the expression of a gene or abundance of an mRNA transcript, the concentration of a hormone or protein, neuronal activity, heart rate, etc. The biological compartment may be a particular cell type, tissue, organ, fluid (e.g., plasma, cerebrospinal fluid), etc. The role in the biology could describe the reaction that an enzyme catalyses and the role of that reaction within a given metabolic pathway; the protein that a gene or mRNA transcript codes for and the function of that protein; the function of a hormone in a given target tissue, physiological function of an organ, etc. Careful attention should be taken to avoid reference to other KEs, KERs or AOPs. Only describe this KE as a single isolated measurable event/state. This will ensure that the KE is modular and can be used by other AOPs, thereby facilitating construction of AOP networks. More help

Abnormally high levels of cell proliferation in the lungs may eventually culminate in the formation of malignant tumours and thus lung cancer. The term lung cancer refers to all malignant neoplasms arising from the bronchial, bronchiolar, and alveolar epithelium (Keshamouni et al., 2009). The cellular origin(s) of lung cancer remains largely unknown. It has been speculated that different tumour histopathological subtypes arise from distinct cells of origin localized in defined microenvironments. Histological characteristics of lung cancers, as defined by light microscopy, have led to the categorization of lung cancers into four main subtypes: small cell carcinoma, adenocarcinoma, squamous cell carcinoma, and large cell carcinoma (Beasly et al., 2005). These histological subtypes are grouped under one of the two umbrella terms used to describe lung cancers:  small cell lung cancer (SCLC) and non-small cell lung cancer (NSCLC). The term SCLC refers to small cell carcinoma. The term NSCLC, which represents approximately 85% of all lung cancers (Molina et al., 2008), encompasses squamous cell carcinoma, adenocarcinoma, and large cell carcinoma. These three tumour types are grouped together due to similarities in their prognosis and management (Keshamouni et al., 2009); patients with NSCLC often have poor prognoses and low 5-year survival rates due to the high metastatic potential of the tumours (Spira and Ettinger, 2004; Herbst et al., 2008). Some of the most common sites for lung cancer metastasis are the other lobe of the lungs, skeleton, adrenal glands, liver, and brain (Simon et al., 2015).

How It Is Measured or Detected

One of the primary considerations in evaluating AOPs is the relevance and reliability of the methods with which the KEs can be measured. The aim of this section of the KE description is not to provide detailed protocols, but rather to capture, in a sentence or two, per method, the type(s) of measurements that can be employed to evaluate the KE and the relative level of scientific confidence in those measurements. Methods that can be used to detect or measure the biological state represented in the KE should be briefly described and/or cited. These can range from citation of specific validated test guidelines, citation of specific methods published in the peer reviewed literature, or outlines of a general protocol or approach (e.g., a protein may be measured by ELISA).Key considerations regarding scientific confidence in the measurement approach include whether the assay is fit for purpose, whether it provides a direct or indirect measure of the biological state in question, whether it is repeatable and reproducible, and the extent to which it is accepted in the scientific and/or regulatory community. Information can be obtained from the OECD Test Guidelines website and the EURL ECVAM Database Service on Alternative Methods to Animal Experimentation (DB-ALM). ?
Assay Name Reference Description OECD Approved Assay
Computed Tomography (CT) Scans: CT, High-Resolution CT (HRCT), and   Positron Emission Tomography-CT (PET-CT) Bach et al., 2012; Ollier et al., 2014 CT scans are described as a 3D X-ray; They provide cross-sections of organs/tissues/bones, and can thus be used to detect tumours N/A
Magnetic Resonance Imaging (MRI) Khalil et al., 2016; Wu et al., 2011 This technique uses magnetic fields and radio waves (NOT ionizing radiation) to generate a picture of organs, and can thus be used to detect tumours N/A
Sputum Analysis Hubers et al., 2013 Sputum is collected and analyzed for a variety of markers, including mutations in KRAS and TP53, specific RNA/protein biomarkers, and chromosomal aberrations N/A
Bronchoscopy: Conventional White Light Bronchoscopy, Autofluorescence Bronchoscopy (AFB), and Endobronchial Ultrasonography (EBUS) Ikeda et al., 2007 Bronchoscope (usually with a camera) is passed down through the throat to the lungs to provide a visual of the respiratory tract; Traditionally, visualization has been performed using conventional white light, but new technologies have also allowed for visualization using fluorescence and ultrasound technologies N/A
Transbronchial Needle Aspiration Navani et al., 2015; Aziz, 2012 A needle is used to aspirate a tissue sample from a lesion of suspected lung cancer  for analysis N/A
Analysis of Volatile Organic Compounds in the Breath Zhou et al., 2017 Volatile organic compounds, which may act as lung cancer biomarkers, are  collected from the breath and quantified (mostly using mass spectrometry) N/A
Cell Transformation Assays Redpath et al., 1987 Measurement of the tumourigenicity of a tumour/biopsy sample by analyzing changes in cell physiology and morphology in response to tumour-inducing radiation or chemicals Yes (No. 231)

Rodent Two-Year Cancer Bioassays

(Carcinogenicity Studies)

Matsumo, 2012; Nambiar, 2014; Maronpot, 2015 Animals are exposed to a possible carcinogen for a long period of time (often two years), allowing for long-term cancer-related studies Yes (No. 451)
Window Chamber Models Moeller, 2004; Schafer, 2014; Chen, 2016 Window chambers are implanted into the animal to observe tumour progression in living animals using imaging techniques such as in vivo microscopy, MRI or nuclear imaging N/A
Xenograft Assays Wang, 2018; Shi, 2017; Jin, 2018; Wang, 2017; Zhou, 2012 Tumour cells (usually human) are grown in vitro and injected into animals to induce tumour growth and/or to test the tumourigenicity of the injected cells N/A

Domain of Applicability

This free text section should be used to elaborate on the scientific basis for the indicated domains of applicability and the WoE calls (if provided). While structured terms may be selected to define the taxonomic, life stage and sex applicability (see structured applicability terms, above) of the KE, the structured terms may not adequately reflect or capture the overall biological applicability domain (particularly with regard to taxa). Likewise, the structured terms do not provide an explanation or rationale for the selection. The free-text section on evidence for taxonomic, life stage, and sex applicability can be used to elaborate on why the specific structured terms were selected, and provide supporting references and background information.  More help

Lung cancer and subsequent metastasis occurs in multicellular eukaryotic vertebrate organisms that have lungs.

Evidence for Perturbation by Stressor

Regulatory Significance of the Adverse Outcome

An AO is a specialised KE that represents the end (an adverse outcome of regulatory significance) of an AOP. For KEs that are designated as an AO, one additional field of information (regulatory significance of the AO) should be completed, to the extent feasible. If the KE is being described is not an AO, simply indicate “not an AO” in this section.A key criterion for defining an AO is its relevance for regulatory decision-making (i.e., it corresponds to an accepted protection goal or common apical endpoint in an established regulatory guideline study). For example, in humans this may constitute increased risk of disease-related pathology in a particular organ or organ system in an individual or in either the entire or a specified subset of the population. In wildlife, this will most often be an outcome of demographic significance that has meaning in terms of estimates of population sustainability. Given this consideration, in addition to describing the biological state associated with the AO, how it can be measured, and its taxonomic, life stage, and sex applicability, it is useful to describe regulatory examples using this AO. More help

At present the AOP framework is not readily used to support regulatory decision-making in radiation protection practices.The goal of developing this AOP is to bring attention to the framework as an effective means to organize knowledge and identify gaps associated with the mechanistic understanding of low dose radiation exposures. We have used lung cancer as the case example due to its relevance to both radiation and chemical risk assessment. This AOP will help build the concept of an “all hazards” approach to risk assessment, as it will be the first  with a molecular initiating event that is specific to a radiation insult. This in turn could serve to identify networks that are critical to both radiation and chemical exposure scenarios and contribute to prioritizing co-exposures of relevance to risk assessment. By developing this AOP, we will support the necessary efforts highlighted by the international and national radiation protection agencies such as, the United Nations Scientific Committee on the Effects of Atomic Radiation, International Commission of Radiological Protection, International Dose Effect Alliance and the Electric Power Research Institute Radiation Program to consolidate and enhance the knowledge in understanding the mechanisms of low dose radiation exposures from the cellular to organelle levels within the system.


List of the literature that was cited for this KE description. Ideally, the list of references, should conform, to the extent possible, with the OECD Style Guide ( (OECD, 2015). More help

Aziz, F. (2012), “Endobronchial ultrasound-guided transbronchial needle aspiration for staging of lung cancer: a concise review”, Transl Lung Cancer Res, 1(3), 208-213. doi:10.3978/j.issn.2218-6751.2012.09.08.

Bach, P. B. et al. (2012), “Benefits and harms of CT screening for lung cancer: a systematic review”, JAMA, 307(22), 2418-2429. doi:10.1001/jama.2012.5521

Beasley, M. B., Brambilla, E., & Travis, W. D. (2005), “The 2004 World Health Organization classification of lung tumors”, Seminars in Roentgenology, 40(2), 90-97. doi:10.1053/

Chen Y, Maeda A, Bu J, DaCosta R. (2016), “Femur Window Chamber Model for In Vivo Cell Tracking in the Murine Bone Marrow”, J Vis Exp. (113). doi: 10.3791/54205.

Herbst, R. S., Heymach, J. V., & Lippman, S. M. (2008), “Lung cancer”, N Engl J Med. 359, 1367– 80.

Hubers, A. J. et al. (2013), “Molecular sputum analysis for the diagnosis of lung cancer”, Br J Cancer. 109(3), 530-537. doi:10.1038/bjc.2013.393

Ikeda, N. et al. (2007), “Comprehensive diagnostic bronchoscopy of central type early stage lung cancer”, Lung Cancer, 56(3), 295-302. doi:10.1016/j.lungcan.2007.01.009

Jin, Y. et al. (2018), “Simvastatin inhibits the development of radioresistant esophageal cancer cells by increasing the radiosensitivity and reversing EMT process via the PTEN-PI3K/AKT pathway”, Exp Cell Res.362(2):362-369. Doi: 10.1016/j.yexcr.2017.11.037.

Keshamouni, V., Arenberg, D., & Kalemkerian, G. (2009), “Lung Cancer Metastasis: Novel Biological Mechanisms and Impact on Clinical Practice”, Springer Science + Business Media. Doi: 10.1007/978-1-4419-0772-1.

Khalil, al. (2016), “Contribution of magnetic resonance imaging in lung cancer imaging”, Diagnostic and Interventional Imaging, 97(10), 991-1002. doi:10.1016/j.diii.2016.08.015

Maronpot RR, Thoolen RJ, Hansen B. (2015), “Two-year carcinogenicity study of acrylamide in Wistar Han rats with in utero exposure”,Exp Toxicol Pathol. 67(2):189-95. doi: 10.1016/j.etp.2014.11.009.

Matsumoto, M. et al. (2012), “Carcinogenicity of ortho-phenylenediamine dihydrochloride in rats and mice by two-year drinking water treatment”,  Arch Toxicol. 86(5):791-804. doi: 10.1007/s00204-012-0800-z.

Moeller, BJ. et al.(2004), “Radiation activates HIF-1 to regulate vascular radiosensitivity in tumors: role of reoxygenation, free radicals, and stress granules”, Cancer Cell. 5(5):429-41.

Molina JR. et al. (2008), “Non-small cell lung cancer: epidemiology, risk factors, treatment, and survivorship”, Mayo Clin Proc. 83(5):584-94. doi: 10.4065/83.5.584.

Nambiar PR. et al. (2015), “Two-year carcinogenicity study in rats with a nonnucleoside reverse transcriptase inhibitor”, Toxicol Pathol. 43(3):354-65. doi: 10.1177/0192623314544381.

Navani, N. et al. (2015), “Lung cancer diagnosis and staging with endobronchial ultrasound-guided transbronchial needle aspiration compared with conventional approaches: an open-label, pragmatic, randomised controlled trial”, Lancet Respir Med. 3(4), 282-9. doi: 10.1016/S2213-2600(15)00029-6

Ollier, M. et al. (2014), “Chest CT scan screening for lung cancer in asbestos occupational exposure: a systematic review and meta-analysis”, Chest. 145(6), 1339-1346. doi:10.1378/chest.13-2181

Redpath, J. L. et al. (1987), “Neoplastic Transformation of Human Hybrid Cells by y Radiation: A Quantitative Assay”, Radiat.Res. 110, 468-472.

Schafer R, Leung HM, Gmitro AF. (2014), “Multi-modality imaging of a murine mammary window chamber for breast cancer research”, Biotechniques. 57(1):45-50. Doi: 10.2144/000114191.

Sher, T., Dy, G. K., & Adjei, A. A. (2008), “Small cell lung cancer”, MayoClin Proc. 83(3), 335-367. doi: 10.4065/83.3.355

Shi ZM. Et al.(2017), “Downregulation of miR-218 contributes to epithelial-mesenchymal transition and tumor metastasis in lung cancer by targeting Slug/ZEB2 signaling”, Oncogene. 36(18):2577-2588. Doi: 0.1038/onc.2016.414.

Simon,  G.R., & Brustugun, O.T. (2015), “Metastatic Patterns of Lung Cancer”, Oncolex Oncology Encyclopedia.

Spira, A., & Ettinger, D. S. (2004), “Multidisciplinary management of lung cancer”,Engl J Med. 350(4), 379–92. doi: 10.1056/NEJMra035536

Wang T. et al. (2017), “Role of Nrf2 signaling pathway in the radiation tolerance of patients with head and neck squamous cell carcinoma: an in vivo and in vitro study”, Onco Targets Ther. 2017 Mar 23;10:1809-1819.

Wang L. et al. (2018), “K-ras mutation promotes ionizing radiation-induced invasion and migration of lung cancer in part via the Cathepsin L/CUX1 pathway”, Exp Cell Res. 362(2):424-435. Doi: 10.1016/j.yexcr.2017.12.006.

Wu, N. Y. et al. (2011), “Magnetic resonance imaging for lung cancer detection: experience in a population of more than 10,000 healthy individuals”, BMC Cancer, 11, 242. doi:10.1186/1471-2407-11-242.

Zhou, J. et al. (2012), “Antitumor activity of Endostar combined with radiation against human nasopharyngeal carcinoma in mouse xenograft models”, Oncol Lett. 4(5):976-980. Doi: 10.3892/ol.2012.856.

Zhou, J. et al. (2017), “Review of recent developments in determining volatile organic compounds in exhaled breath as biomarkers for lung cancer diagnosis”, Anal Chim Acta, 996, 1-9. doi:10.1016/j.aca.2017.09.021