This Key Event Relationship is licensed under the Creative Commons BY-SA license. This license allows reusers to distribute, remix, adapt, and build upon the material in any medium or format, so long as attribution is given to the creator. The license allows for commercial use. If you remix, adapt, or build upon the material, you must license the modified material under identical terms.

Relationship: 2977

Title

A descriptive phrase which clearly defines the two KEs being considered and the sequential relationship between them (i.e., which is upstream, and which is downstream). More help

General Apoptosis leads to Increase, Cancer

Upstream event
The causing Key Event (KE) in a Key Event Relationship (KER). More help
Downstream event
The responding Key Event (KE) in a Key Event Relationship (KER). More help

Key Event Relationship Overview

The utility of AOPs for regulatory application is defined, to a large extent, by the confidence and precision with which they facilitate extrapolation of data measured at low levels of biological organisation to predicted outcomes at higher levels of organisation and the extent to which they can link biological effect measurements to their specific causes.Within the AOP framework, the predictive relationships that facilitate extrapolation are represented by the KERs. Consequently, the overall WoE for an AOP is a reflection in part, of the level of confidence in the underlying series of KERs it encompasses. Therefore, describing the KERs in an AOP involves assembling and organising the types of information and evidence that defines the scientific basis for inferring the probable change in, or state of, a downstream KE from the known or measured state of an upstream KE. More help

AOPs Referencing Relationship

AOP Name Adjacency Weight of Evidence Quantitative Understanding Point of Contact Author Status OECD Status
Reactive Oxygen Species (ROS) formation leads to cancer via inflammation pathway adjacent High Not Specified John Frisch (send email) Under development: Not open for comment. Do not cite
Reactive Oxygen (ROS) formation leads to cancer via Peroxisome proliferation-activated receptor (PPAR) pathway adjacent High Not Specified John Frisch (send email) Under development: Not open for comment. Do not cite

Taxonomic Applicability

Latin or common names of a species or broader taxonomic grouping (e.g., class, order, family) that help to define the biological applicability domain of the KER.In general, this will be dictated by the more restrictive of the two KEs being linked together by the KER.  More help
Term Scientific Term Evidence Link
human Homo sapiens High NCBI
mouse Mus musculus High NCBI
rat Rattus norvegicus High NCBI

Sex Applicability

An indication of the the relevant sex for this KER. More help
Sex Evidence
Unspecific High

Life Stage Applicability

An indication of the the relevant life stage(s) for this KER.  More help
Term Evidence
All life stages High

Key Event Relationship Description

Provides a concise overview of the information given below as well as addressing details that aren’t inherent in the description of the KEs themselves. More help

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; in this key event relationship we are focusing on disruption of apoptosis and necrosis pathways, leading to cancer.   Exposure to chemical stressors, radiation, tobacco smoke, or viruses can increase the likelihood that cancer will develop.  Pathways leading to apoptosis, or single cell death, have traditionally been studied as both independent and simultaneous from pathways leading to necrosis, or tissue-wide cell death, with both overlap and distinct mechanisms (Elmore 2007). For the purposes of this key event relationship, we are characterizing cancer due to widespread cell-death.

Cancer cells proliferate due to capabilities summarized by Hanahan and Weinberg (2011):

  1. Sustained proliferation signaling – by deregulating normal cell signals, cancer cells can sustain chronic proliferation.
  2. Evading growth suppressors – by evading activities of tumor suppressor genes, cancer cells continue to proliferate.
  3. Activating invasion and metastasis – by altering shape and attachment to cells in the extracellular matrix, cancer cells gain ability to move to other locations.
  4. Enabling replicative immortality – by disabling senescence pathways, cancer cells have extended lifespans.
  5. Inducing angiogenesis – by enabling neovasculature, cancer cells receive nutrients and oxygen and get rid of waste products.
  6. Resisting cell death – by evading apotosis and necrosis defense pathways, cancer cells avoid elimination.

Evidence Collection Strategy

Include a description of the approach for identification and assembly of the evidence base for the KER. For evidence identification, include, for example, a description of the sources and dates of information consulted including expert knowledge, databases searched and associated search terms/strings.  Include also a description of study screening criteria and methodology, study quality assessment considerations, the data extraction strategy and links to any repositories/databases of relevant references.Tabular summaries and links to relevant supporting documentation are encouraged, wherever possible. More help

This KER was identified as part of an Environmental Protection Agency effort to represent putative AOPs from peer-reviewed literature which were heretofore unrepresented in the AOP-Wiki. Support for this KER is referenced in publications cited in the originating work of Jeong and Choi (2020).

Evidence Supporting this KER

Addresses the scientific evidence supporting KERs in an AOP setting the stage for overall assessment of the AOP. More help
Biological Plausibility
Addresses the biological rationale for a connection between KEupstream and KEdownstream.  This field can also incorporate additional mechanistic details that help inform the relationship between KEs, this is useful when it is not practical/pragmatic to represent these details as separate KEs due to the difficulty or relative infrequency with which it is likely to be measured.   More help

The biological plausibility linking cancer to avoidance of apoptosis is strong.  Apoptosis is a series of related pathways that eliminate abnormal cells.  Cancer cells proliferate due to evasion of cellular defenses (apoptosis pathways) and tissue-level defenses (necrosis pathways).   Specific modifications to cancer cells that enable proliferation rather than elimination are listed under the Key Event Relationship Description. For review see:

1. Heinlein and Chang (2004): Role of androgen receptor in apoptosis, loss of androgen pathway function resulting in increases in mammalian prostate cancer.

2. Hanahan and Weinberg (2011): Biological capabilities gained by cancer cell to enable proliferation of tumor cells and evasion of normal regulating mechanisms of apoptosis and necrosis pathways in mammals.

3. Pavet et al. (2014): Role of tumor necrosis factor-related apoptosis-inducing ligandin to induce apoptosis in mammalian cells and reduce incidence of cancer.

4. Vihervaara and Sistonen (2014): Role of increased rate of transcription of heat shock factor 1 in mammalian cancer cells enhancing survival and metastasis, as well as evasion of cellular defenses.

Uncertainties and Inconsistencies
Addresses inconsistencies or uncertainties in the relationship including the identification of experimental details that may explain apparent deviations from the expected patterns of concordance. More help

Known modulating factors

This table captures specific information on the MF, its properties, how it affects the KER and respective references.1.) What is the modulating factor? Name the factor for which solid evidence exists that it influences this KER. Examples: age, sex, genotype, diet 2.) Details of this modulating factor. Specify which features of this MF are relevant for this KER. Examples: a specific age range or a specific biological age (defined by...); a specific gene mutation or variant, a specific nutrient (deficit or surplus); a sex-specific homone; a certain threshold value (e.g. serum levels of a chemical above...) 3.) Description of how this modulating factor affects this KER. Describe the provable modification of the KER (also quantitatively, if known). Examples: increase or decrease of the magnitude of effect (by a factor of...); change of the time-course of the effect (onset delay by...); alteration of the probability of the effect; increase or decrease of the sensitivity of the downstream effect (by a factor of...) 4.) Provision of supporting scientific evidence for an effect of this MF on this KER. Give a list of references.  More help
Response-response Relationship
Provides sources of data that define the response-response relationships between the KEs.  More help
Time-scale
Information regarding the approximate time-scale of the changes in KEdownstream relative to changes in KEupstream (i.e., do effects on KEdownstream lag those on KEupstream by seconds, minutes, hours, or days?). More help
Known Feedforward/Feedback loops influencing this KER
Define whether there are known positive or negative feedback mechanisms involved and what is understood about their time-course and homeostatic limits. More help

Domain of Applicability

A free-text section of the KER description that the developers can use to explain their rationale for the taxonomic, life stage, or sex applicability structured terms. More help

Life Stage: The life stage applicable to this key event relationship is all life stages. 

Sex: This key event relationship applies to both males and females.

Taxonomic: This key event relationship appears to be present broadly, with representative studies focused in mammals (humans, lab mice, lab rats).

References

List of the literature that was cited for this KER description. More help

Elmore, S.  2007.  Apoptosis: A Review of Programmed Cell Death.  Toxicologic pathology 35 (4): 495-516.

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.

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.