To the extent possible under law, AOP-Wiki has waived all copyright and related or neighboring rights to KE:1182

Event: 1182

Key Event Title

A descriptive phrase which defines a discrete biological change that can be measured. More help

Increase, Cell Proliferation (Epithelial Cells)

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. More help
Increase, Cell Proliferation (Epithelial Cells)
Explore in a Third Party Tool

Biological Context

Structured terms, selected from a drop-down menu, are used to identify the level of biological organization for each KE. More help
Level of Biological Organization
Cellular

Cell term

The location/biological environment in which the event takes place.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.  Further information on Event Components and Biological Context may be viewed on the attached pdf. More help
Cell term
epithelial cell

Organ term

The location/biological environment in which the event takes place.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.  Further information on Event Components and Biological Context may be viewed on the attached pdf. More help

Key Event Components

The KE, as defined by a set structured ontology terms consisting of a biological process, object, and action with each term originating from one of 14 biological ontologies (Ives, et al., 2017; https://aopwiki.org/info_pages/2/info_linked_pages/7#List). Biological process describes dynamics of the underlying biological system (e.g., receptor signalling).Biological process describes dynamics of the underlying biological system (e.g., receptor signaling).  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 signaling 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.  Further information on Event Components and Biological Context may be viewed on the attached pdf. More help
Process Object Action
cell proliferation increased

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
ER activation to breast cancer KeyEvent Brendan Ferreri-Hanberry (send email) Open for adoption
RONS leading to breast cancer KeyEvent Evgeniia Kazymova (send email) Under development: Not open for comment. Do not cite Under Development
Increased DNA damage leading to breast cancer KeyEvent Allie Always (send email) Under development: Not open for comment. Do not cite Under Development

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 KE.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

Life Stages

An indication of the the relevant life stage(s) for this KE. More help

Sex Applicability

An indication of the the relevant sex for this KE. More help

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. More help

Proliferation occurs when changes in external signals release inhibitory controls limiting entry into the cell cycle, and oncogenic mutations act via these same pathways to generate abnormal proliferation (Hanahan and Weinberg 2011; Weber, Desai et al. 2017). Inhibitory signals such as contact inhibition or TGF-β (Polyak, Kato et al. 1994; Francis, Bergsied et al. 2009) stabilize the mechanisms limiting entry into the cell cycle. Proliferative signals such as those following progesterone or estrogen (Croce 2008; Weber, Desai et al. 2017) or compensatory proliferation after apoptosis (Fogarty and Bergmann 2017) relieve inhibition and enable cells to enter the cell cycle. Mutations that inactivate inhibitory signals (tumor suppressors) or activate proliferative signals (oncogenes) promote proliferation outside of the normal biological context (Gustin, Karakas et al. 2009; Francis, Chakrabarti et al. 2011; Hanahan and Weinberg 2011; Weber, Desai et al. 2017). Abnormal proliferation is typically met with apoptosis or senescence, so additional mutations or other mechanisms are required to escape these additional levels of control for proliferation to continue indefinitely (Garbe, Bhattacharya et al. 2009; Shay and Wright 2011; Fernald and Kurokawa 2013).

Proliferation increases mutations as DNA damage and replication errors become integrated into the genome (Kiraly, Gong et al. 2015). Proliferation can also promote the expansion of existing cells with proliferative mutations. Genomic mutations favoring further proliferation are positively selected from among the expanded cells, resulting in the accumulation of mutational errors and moving the organism further towards cancer. Different clonal populations can also collaborate to promote growth (Marusyk, Tabassum et al. 2014; Franco, Tyson et al. 2016).

How It Is Measured or Detected

A description of the type(s) of measurements that can be employed to evaluate the KE and the relative level of scientific confidence in those measurements.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). Do not provide detailed protocols. More help

Past cellular proliferation can be measured directly using labels that are incorporated into cells upon cell division (BRDU or cytoplasmic proliferation dyes) or indirectly by measuring a change in population size. Ongoing current proliferation can be quantified by labeling a protein associated with the cell cycle (e.g. Ki67). Methods for measuring proliferation were reviewed in (Romar, Kupper et al. 2016) and summarized in Table 1.

Table 1. Common methods for detecting proliferation

Target

Name

Method

Strengths/Weaknesses

Past proliferation

Nucleoside analog incorporation (BRDU)

Microscopy

Stable, so can see proliferation from a specific time point onward. Can be used in vivo. BRDU must be labeled with a secondary fluorescent or other label for visualization, so it cannot be measured in living cells.

Past proliferation

Cytoplasmic proliferation dyes:  carboxyfluorescein diacetate succinimidyl ester (CFSE).

Microscopy

Enables quantification of successive cell divisions and differentiation between slowly and rapidly cycling cells. Cells survive analysis, so these dyes can be used as part of ongoing experiments. The dyes are better suited to in vitro experiments.

Past proliferation

Cell counting

Microscopy

An increase in cell numbers over time could represent proliferation or a decrease in apoptosis. Better suited to in vitro experiments, unless a label can be used to uniquely label a population of cells.

Ongoing proliferation rate

Ki67 probe

Microscopy

Labels all non-G0 phase proliferating cells. Labeling requires permeabilization so examination terminates the experiment.

Domain of Applicability

A description of the scientific basis for the indicated domains of applicability and the WoE calls (if provided).  More help

References

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

Croce, C. M. (2008). "Oncogenes and cancer." The New England journal of medicine 358(5): 502-511.

Fernald, K. and M. Kurokawa (2013). "Evading apoptosis in cancer." Trends in cell biology 23(12): 620-633.

Fogarty, C. E. and A. Bergmann (2017). "Killers creating new life: caspases drive apoptosis-induced proliferation in tissue repair and disease." Cell death and differentiation 24(8): 1390-1400.

Francis, S. M., J. Bergsied, et al. (2009). "A functional connection between pRB and transforming growth factor beta in growth inhibition and mammary gland development." Molecular and cellular biology 29(16): 4455-4466.

Francis, S. M., S. Chakrabarti, et al. (2011). "A context-specific role for retinoblastoma protein-dependent negative growth control in suppressing mammary tumorigenesis." PLoS One 6(2): e16434.

Franco, O. E., D. R. Tyson, et al. (2016). "Altered TGF-alpha/beta signaling drives cooperation between breast cancer cell populations." FASEB journal : official publication of the Federation of American Societies for Experimental Biology 30(10): 3441-3452.

Garbe, J. C., S. Bhattacharya, et al. (2009). "Molecular distinctions between stasis and telomere attrition senescence barriers shown by long-term culture of normal human mammary epithelial cells." Cancer research 69(19): 7557-7568.

Gustin, J. P., B. Karakas, et al. (2009). "Knockin of mutant PIK3CA activates multiple oncogenic pathways." Proceedings of the National Academy of Sciences of the United States of America 106(8): 2835-2840.

Hanahan, D. and R. A. Weinberg (2011). "Hallmarks of cancer: the next generation." Cell 144(5): 646-674.

Kiraly, O., G. Gong, et al. (2015). "Inflammation-induced cell proliferation potentiates DNA damage-induced mutations in vivo." PLoS Genet 11(2): e1004901.

Marusyk, A., D. P. Tabassum, et al. (2014). "Non-cell-autonomous driving of tumour growth supports sub-clonal heterogeneity." Nature 514(7520): 54-58.

Polyak, K., J. Y. Kato, et al. (1994). "p27Kip1, a cyclin-Cdk inhibitor, links transforming growth factor-beta and contact inhibition to cell cycle arrest." Genes & development 8(1): 9-22.

Romar, G. A., T. S. Kupper, et al. (2016). "Research Techniques Made Simple: Techniques to Assess Cell Proliferation." The Journal of investigative dermatology 136(1): e1-7.

Shay, J. W. and W. E. Wright (2011). "Role of telomeres and telomerase in cancer." Seminars in cancer biology 21(6): 349-353.

Weber, R. J., T. A. Desai, et al. (2017). "Non-autonomous cell proliferation in the mammary gland and cancer." Current opinion in cell biology 45: 55-61.