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Relationship: 2577
Title
Apoptosis leads to tumor growth
Upstream event
Downstream event
Key Event Relationship Overview
AOPs Referencing Relationship
AOP Name | Adjacency | Weight of Evidence | Quantitative Understanding | Point of Contact | Author Status | OECD Status |
---|---|---|---|---|---|---|
Activation of the AhR leading to metastatic breast cancer | adjacent | High | Louise Benoit (send email) | Under Development: Contributions and Comments Welcome | Under Development |
Taxonomic Applicability
Term | Scientific Term | Evidence | Link |
---|---|---|---|
Homo sapiens | Homo sapiens | High | NCBI |
Sex Applicability
Sex | Evidence |
---|---|
Mixed | High |
Life Stage Applicability
Term | Evidence |
---|---|
Adult | High |
Key Event Relationship Description
Apoptosis, also known as programmed cell death, is a natural and tightly regulated process that plays a crucial role in maintaining tissue homeostasis by eliminating damaged, aged, or unnecessary cells. When apoptosis is impaired or decreased, it can contribute to tumor growth and the progression of cancer. It is one of the hallmarks of cancer (Hanahan) :
- Accumulation of Mutated or Damaged Cells: Apoptosis is a mechanism for eliminating cells with DNA damage or mutations. When apoptosis is reduced, cells with genetic abnormalities or mutations that might have led to their destruction can persist and accumulate. The accumulation of these abnormal cells provides a foundation for the development of tumors, as they may carry oncogenic mutations that promote uncontrolled cell proliferation (Schmitt)
- Resistance to Cell Death Signals: Cancer cells often develop resistance to signals that would normally induce apoptosis. This resistance can be acquired through various mechanisms, including mutations in apoptotic pathway components or the overexpression of anti-apoptotic proteins. Decreased sensitivity to apoptotic signals allows cancer cells to evade elimination, contributing to their survival and uncontrolled proliferation. Some cancers overexpress proteins like Bcl-2 and FLIP, which inhibit the apoptotic machinery and promote cell survival. This allows cancer cells to evade cell death signals and continue proliferating (Fulda).
- Enhanced Survival of Cancer Cells: Apoptosis acts as a natural mechanism to eliminate cells that are no longer needed or pose a threat to the organism. When apoptosis is suppressed, cancer cells gain a survival advantage, allowing them to resist death signals and persist in the tissue. This enhanced survival capability contributes to the prolonged existence and growth of cancer cells within the tumor microenvironment. p53 plays a critical role in triggering apoptosis in response to DNA damage or other stresses. Mutations inactivating p53 are common in many cancers and contribute to uncontrolled cell proliferation and resistance to apoptosis.
- Uncontrolled Cell Proliferation: Apoptosis and cell proliferation are intricately linked processes that help maintain tissue homeostasis. A decrease in apoptosis disrupts the balance between cell death and cell division. Cancer cells, with reduced susceptibility to apoptosis, can undergo uncontrolled and sustained proliferation, leading to the formation of a tumor mass. Many cancers harbor mutations that activate pro-proliferative signaling pathways like Ras or PI3K/Akt (Fulda, Luo). These pathways normally promote cell growth and division, but when dysregulated, they can contribute to uncontrolled proliferation even in the absence of proper growth signals.
Evidence Collection Strategy
Evidence Supporting this KER
Biological Plausibility
- Unchecked Cell Proliferation: Healthy tissues maintain homeostasis through a finely tuned balance between cell proliferation and apoptosis. When apoptosis is compromised, cells that would normally undergo programmed cell death survive and continue to divide, leading to an uncontrolled increase in cell number and contributing to the initial mass of a tumor.
- Sustained Proliferative Signaling: Many cancers harbor mutations that activate pro-proliferative signaling pathways like Ras or PI3K/Akt. These pathways normally promote cell growth and division, but when dysregulated due to mutations, they can continue to signal proliferation even in the absence of proper growth signals or when apoptosis should occur. Additionally, a decrease in apoptosis can prevent the activation of pro-apoptotic pathways that would normally act as brakes on cell division.
- Evasion of Growth-Inhibitory Signals: Healthy cells respond to various cues, including density-dependent inhibition and nutrient limitations, by activating apoptosis. When apoptosis is compromised, cells can evade these growth-inhibitory signals and continue dividing even when resources are limited or cell density is high. This allows the tumor to expand beyond its normal boundaries and invade surrounding tissues.
- Selection for Favorable Traits: Tumor development is often described as a process of clonal selection. Cells harboring mutations that grant them a growth advantage, including those that escape apoptosis, will have a higher chance of surviving and proliferating. This selection pressure over time can lead to a tumor population with a decreased overall apoptotic response, further accelerating tumor growth.
Empirical Evidence
- Observational Studies:These studies have observed correlations between increased cancer risk and factors associated with decreased apoptosis, such as chronic inflammation or exposure to certain carcinogens (Schottenfeld) While correlation doesn't prove causation, it provides an initial link for further investigation.
- Animal Models: Studies with mice engineered to have dysfunctional apoptotic pathways often develop tumors at higher rates compared to control animals (Zhang). This suggests that a decrease in apoptosis can directly contribute to tumor formation.
- Cellular Studies:Experiments using cancer cell lines have shown that manipulating apoptotic pathways can influence their proliferation and survival. For example, inducing apoptosis using specific drugs can lead to a decrease in cell growth (Fulda).
- Clinical Trials: Some cancer therapies, like Bcl-2 inhibitors, aim to restore apoptosis in cancer cells by targeting proteins that block the cell death machinery. These therapies have shown promising results in clinical trials, demonstrating the potential of targeting apoptosis for cancer treatment (Adams).
- Tumor analysis: Researchers have identified changes in gene expression and protein levels associated with apoptosis in tumor biopsies compared to healthy tissues. These changes can serve as biomarkers and potentially predict tumor development or response to therapy (Hanahan)
Uncertainties and Inconsistencies
- Establishing Direct Causation: While various studies support the association, proving a direct and definitive cause-and-effect relationship between decreased apoptosis and tumor development in vivo remains challenging. Tumorigenesis is a complex process with multiple contributing factors, making it difficult to isolate the sole effect of reduced apoptosis in a living organism.
- Heterogeneity of Cancers: Different types of cancers may have varying levels of dependence on reduced apoptosis for their growth and progression. This heterogeneity presents a challenge in understanding the universal impact of apoptosis across all cancers.
- Role of Other Cell Death Mechanisms: Apoptosis is not the only form of cell death. Other mechanisms like necrosis and autophagy also play roles in tumor development and can interact with apoptosis in complex ways. The relative contribution of each type of cell death to tumorigenesis in different contexts remains an active area of research.
- Limitations of Experimental Models: In vitro studies using isolated cells provide valuable insights on specific aspects of apoptosis, but they often lack the complex cellular and environmental context present in vivo. This can limit the generalizability of findings to real-world scenarios.
- Challenges in Therapeutic Targeting: While targeting the apoptotic pathway holds promise for cancer treatment, effectively manipulating these processes in vivo without unintended consequences remains a significant challenge. Additionally, tumors may develop resistance mechanisms to therapies targeting apoptosis, hindering their long-term effectiveness.
Known modulating factors
Quantitative Understanding of the Linkage
Response-response Relationship
Time-scale
Known Feedforward/Feedback loops influencing this KER
Domain of Applicability
Human
Mice
References
Schmitt, C. A., et al. (2000). Senescence and apoptosis. Oncogene, 19(56), 6207-6210. https://pubmed.ncbi.nlm.nih.gov/11101894/
Schottenfeld, D., & Beebe-Wood, L. (2012). Chronic inflammation and cancer prevention: A bird's-eye view. Nature Reviews Cancer, 12(3), 189-201. https://pubmed.ncbi.nlm.nih.gov/22273994/
Zhang, J., et al. (2008). The role of the BCL-2 family in the development of transgenic mouse models of cancer. Current Molecular Medicine, 8(1), 70-82. https://pubmed.ncbi.nlm.nih.gov/18275977/
Hanahan, D., & Weinberg, R. A. (2011). Hallmarks of cancer: The next generation. Cell, 144(5), 646-674. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5446472/
Fulda, S., & Debatin, K. M. (2007). Apoptosis signaling in cancer. Experimental Cell Research, 313(9), 1503-1515. https://pubmed.ncbi.nlm.nih.gov/17296041/
Luo, X., & Heng, H. H. (2003). Apoptosis and cancer therapy: lessons from the past and new directions. Current Pharmaceutical Design, 9(21), 1803-1816. https://pubmed.ncbi.nlm.nih.gov/14574468/
Schmitt, C. A., et al. (2000. Senescence and apoptosis. Oncogene, 19(56), 6207-6210. https://pubmed.ncbi.nlm.nih.gov/11101894/