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Key Event Title
|Level of Biological Organization|
Key Event Components
Key Event Overview
AOPs Including This Key Event
|AOP Name||Role of event in AOP||Point of Contact||Author Status||OECD Status|
|DNA alkylation -> cancer 2||AdverseOutcome||Carole Yauk (send email)||Not under active development|
|DNA alkylation -> cancer 1||AdverseOutcome||Carole Yauk (send email)||Open for adoption|
|ROS formation leads to cancer via inflammation pathway||AdverseOutcome||John Frisch (send email)||Under development: Not open for comment. Do not cite|
|ROS formation leads to cancer via PPAR pathway||AdverseOutcome||John Frisch (send email)||Under development: Not open for comment. Do not cite|
|All life stages||High|
Key Event Description
Cancer is a general key event for related diseases each exhibiting uncontrolled proliferation of abnormal cells (for review see Hanahan and Weinberg 2011). A cancer often is initially associated with a specific organ, with malignant tumors developing ability to metastasize, or travel to other areas of the body. Most cancers develop from genetic mutations in normal cells, although a minority of cancers are hereditary. Exposure to chemical stressors, radiation, tobacco smoke, or viruses can increase the likelihood that cancer will develop.
Cancer cells proliferate due to capabilities summarized by Hanahan and Weinberg (2011):
- Sustained proliferation signaling – by deregulating normal cell signals, cancer cells can sustain chronic proliferation.
- Evading growth suppressors – by evading activities of tumor suppressor genes, cancer cells continue to proliferate.
- Activating invasion and metastasis – by altering shape and attachment to cells in the extracellular matrix, cancer cells gain ability to move to other locations.
- Enabling replicative immortality – by disabling senescence pathways, cancer cells have extended lifespans.
- Inducing angiogenesis – by enabling neovasculature, cancer cells receive nutrients and oxygen and get rid of waste products.
- Resisting cell death – by evading apotosis and necrosis defense pathways, cancer cells avoid elimination.
How It Is Measured or Detected
Most carcinogenicity studies are conducted with rodents (see OECD 2018; Zhou et al. 2023 for methods) or in-vitro with mammalian cell lines (see OECD 2023 for methods). Cancer is usually detected by biopsy or histopathological examination of tissue. Gene expression levels can also be assessed, as increased transcription of known genes have been associated with specific cancers (ex. Tumor Necrosis Factor (Pavet et al. 2014); Heat Shock Factors (Vihervaara and Sistonen 2014; Androgen Receptor (Heinlein and Chang 2004)).
Domain of Applicability
Life Stage: All life stages. Older individuals are more likely to manifest this key event (adults > juveniles > embryos).
Sex: Applies to both males and females.
Taxonomic: Appears to be present broadly, with representative studies including mammals (humans, lab mice, lab rats), teleost fish, and invertebrates (cladocerans, mussels).
Regulatory Significance of the Adverse Outcome
Cancer is a critical endpoint in human health risk assessment. It is embedded in regulatory frameworks for human health protection in many countries (see OSHA 2023 for examples of US regulations and European Parliament 2022 for examples of regulations in Europe).
Abraha, A.M. and Ketema, E.B. 2016. Apoptotic pathways as a therapeutic target for colorectal cancer treatment. World Journal of Gastrointestinal Oncology 8 (8): 583-491
European Parliament. 2022. Directive 2004/37/EC of the European Parliament on the protection of workers from the risks related to exposure to carcinogens, mutagens or reprotoxic substances at work. Retrieved 3 August 2023 from http://data.europa.eu/eli/dir/2004/37/2022-04-05
Hanahan, D. and Weinberg, R.A. 2011. Hallmarks of cancer: the next generation. Cell 144(5): 646-674.
Heinlein, C.A. and Chang, C. 2004. Androgen receptor in prostate cancer. Endocrine Reviews 25: 276-308.
OECD. 2018. Test no. 451: OECD Guideline for the Testing of Chemicals: Carcinogenicity Studies. OECD Publishing, Paris. Retrieved 3 August 2023 from https://www.oecd.org/env/test-no-451-carcinogenicity-studies-9789264071186-en.htm
OECD. 2023. Test No. 487: In Vitro Mammalian Cell Micronucleus Test, OECD Guidelines for the Testing of Chemicals, Section 4, OECD Publishing, Paris. Retrieved 3 August 2023 from https://doi.org/10.1787/9789264264861-en.htm
OSHA. 2023. Carcinogens. Retrieved 3 August 2023 from https://www.osha.gov/carcinogens/standards
Pavet, V., Shlyakhtina, Y., He, T., Ceschin, D.G., Kohonen, P., Perala, M., Kallioniemi, O., and Gronemeyer, H. 2014. Plasminogen activator urokinase expression reveals TRAIL responsiveness and support fractional survival of cancer cells. Cell Death and Disease 5: e1043.
Vihervaara, A. and Sistonen, L. 2014. HSF1 at a glance. Journal of Cell Scientce 127: 261-266.
Zhou, Y., Xia, J., Xu, S., She, T., Zhang, Y., Sun, Y., Wen, M., Jiang, T., Xiong, Y., and Lei, J. 2023. Experimental mouse models for translational human cancer research. Frontiers in Immunology 14: 1095388.