API

Event: 1182

Key Event Title

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Increase, Cell Proliferation (Epithelial Cells)

Short name

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Increase, Cell Proliferation (Epithelial Cells)

Biological Context

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Level of Biological Organization
Cellular

Cell term

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Cell term
epithelial cell


Organ term

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Key Event Components

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Process Object Action
cell proliferation increased

Key Event Overview


AOPs Including This Key Event

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Stressors

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Taxonomic Applicability

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Life Stages

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Sex Applicability

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Key Event Description

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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

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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

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Evidence for Perturbation by Stressor



Ionizing Radiation

While higher doses of ionizing radiation cause cell death in the short term (especially of dividing cells), IR is associated with delayed proliferation in vitro and in vivo. In vitro, IR can promote the proliferation/expansion in p16-suppressed and immortal epithelial populations as well as in bystander CHO cells co-cultured with IR-exposed cells (Han, Chen et al. 2010; Mukhopadhyay, Costes et al. 2010; Tang, Fernandez-Garcia et al. 2014). In vivo, IR increases apoptosis and compensatory proliferation in adult rats (Loree, Koturbash et al. 2006), and long term expression of proliferation in adolescent but not adult mammary gland (Datta, Hyduke et al. 2012; Snijders, Marchetti et al. 2012; Suman, Johnson et al. 2012), possibly via the expansion of a population of stem-like cells in vivo (Nguyen, Oketch-Rabah et al. 2011; Tang, Fernandez-Garcia et al. 2014). This proliferation appears to be associated with TGF-β/Notch activity (Tang, Fernandez-Garcia et al. 2014) and nitric oxide (Han, Chen et al. 2010). IR also increases mammary hyperplasia (Faulkin, Shellabarger et al. 1967; Imaoka, Nishimura et al. 2006). While IR can induce senescence in epithelial cells, IR selects for a post-senescent variant of epithelial cell which would be more conducive to tumorigenesis (Mukhopadhyay, Costes et al. 2010).

Datta, K., D. R. Hyduke, et al. (2012). "Exposure to ionizing radiation induced persistent gene expression changes in mouse mammary gland." Radiat Oncol 7: 205.

Faulkin, J. L. J., C. J. Shellabarger, et al. (1967). "Hyperplastic Lesions of Sprague-Dawley Rat Mammary Glands After X Irradiation2." JNCI: Journal of the National Cancer Institute 39(3): 449-459.

Han, W., S. Chen, et al. (2010). "Nitric oxide mediated DNA double strand breaks induced in proliferating bystander cells after alpha-particle irradiation." Mutation research 684(1-2): 81-89.

Imaoka, T., M. Nishimura, et al. (2006). "Persistent cell proliferation of terminal end buds precedes radiation-induced rat mammary carcinogenesis." In Vivo 20(3): 353-358.

Loree, J., I. Koturbash, et al. (2006). "Radiation-induced molecular changes in rat mammary tissue: possible implications for radiation-induced carcinogenesis." International journal of radiation biology 82(11): 805-815.

Mukhopadhyay, R., S. V. Costes, et al. (2010). "Promotion of variant human mammary epithelial cell outgrowth by ionizing radiation: an agent-based model supported by in vitro studies." Breast cancer research : BCR 12(1): R11.

Nguyen, D. H., H. A. Oketch-Rabah, et al. (2011). "Radiation acts on the microenvironment to affect breast carcinogenesis by distinct mechanisms that decrease cancer latency and affect tumor type." Cancer Cell 19(5): 640-651.

Snijders, A. M., F. Marchetti, et al. (2012). "Genetic differences in transcript responses to low-dose ionizing radiation identify tissue functions associated with breast cancer susceptibility." PLoS One 7(10): e45394.

Suman, S., M. D. Johnson, et al. (2012). "Exposure to ionizing radiation causes long-term increase in serum estradiol and activation of PI3K-Akt signaling pathway in mouse mammary gland." International journal of radiation oncology, biology, physics 84(2): 500-507.

Tang, J., I. Fernandez-Garcia, et al. (2014). "Irradiation of juvenile, but not adult, mammary gland increases stem cell self-renewal and estrogen receptor negative tumors." Stem Cells 32(3): 649-661.


References

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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.