Cancer is a disease characterized by uncontrolled cell growth. Cancer cells differ from normal cells by accumulating genetic mutations that allow them to grow and divide uncontrollably, spread to other parts of the body, and evade the body’s natural defense mechanisms. Understanding what triggers cancer cell growth is an important area of cancer research that can lead to new prevention strategies and treatments.
What causes genetic mutations in cells?
Genetic mutations occur frequently in normal cells during cell division. Cells have mechanisms in place to detect and repair these mutations. Cancer develops when cells acquire certain types of mutations that override the normal cell regulatory processes. There are several factors that can increase the risk of developing mutations that trigger cancer cell growth:
- Carcinogens – Exposure to chemicals, radiation, or infectious agents that damage DNA
- Inherited genetic defects – Inherited mutations or deficiencies in DNA repair genes
- Random mistakes – Replication errors and mismatches during cell division
- Chronic inflammation – Long-lasting inflammation which produces DNA-damaging chemicals
How do mutations lead to cancer?
Cancer is caused by mutations that lead to growth signal autonomy and evasion of growth suppressors. Normal cells only grow and divide in response to certain signals. Cancer cells develop mutations that allow them to grow independent of these signals. Additionally, mutations in tumor suppressor genes that normally restrain cell division and growth allow cancer cells to evade these suppression mechanisms.
There are several key types of cancer-promoting mutations:
- Oncogene activation – Mutations that hyperactivate proteins involved in growth factor signaling and cell proliferation pathways.
- Tumor suppressor inactivation – Mutations that inactivate proteins that inhibit cell cycle progression and cell growth.
- Defects in programmed cell death – Mutations that inhibit apoptosis and allow prolonged cancer cell survival.
- Genome instability – Mutations in DNA repair genes lead to an unstable genome and additional mutations.
As mutations accumulate, cells gain more cancer-associated capabilities including resisting cell death, inducing angiogenesis, activating invasion and metastasis, evading the immune system, and sustaining proliferative signaling – all hallmarks of cancer.
Common mutation types in cancer
Cancer cells have thousands of genetic mutations. Here are some common mutation types:
- Point mutations – Single base pair substitutions that can activate oncogenes or inactivate tumor suppressors.
- Chromosomal translocations – Genetic rearrangements that create abnormal gene fusions like the BCR-ABL fusion in chronic myeloid leukemia.
- Gene amplifications – Increased copies of genes like HER2/neu in breast cancer.
- Deletions – Loss of tumor suppressor genes through mutations, chromosomal loss, or epigenetic silencing.
External factors that promote mutations
In addition to random mutations that occur during cell division, there are external factors that can increase mutation rates and promote cancer development:
- Tobacco – Smoking introduces carcinogens like polycyclic aromatic hydrocarbons that cause DNA damage.
- Chemical carcinogens – Asbestos, arsenic, radon, pesticides, and other industrial chemicals are carcinogenic.
- Ionizing radiation – X-rays, gamma rays, radon, and other ionizing radiation damage DNA.
- UV radiation – Ultraviolet light causes pyrimidine dimer formation and DNA breaks.
- Viruses – Viruses like HPV, hepatitis B, and EBV promote cell proliferation and inhibit apoptosis.
- Bacteria – H. pylori infection produces inflammation and DNA damage.
- Inflammation – Chronic inflammatory conditions lead to reactive oxygen species that are mutagenic.
- Age – Advancing age increases random DNA replication errors and mutations.
DNA repair defects promote mutations
The DNA damage response network detects and repairs errors and damage to prevent potentially cancer-causing mutations. Inherited or acquired defects in DNA repair mechanisms increase mutation risk:
| DNA Repair Mechanism | Associated Cancer Predisposition Syndromes |
|---|---|
| Nucleotide excision repair | Xeroderma pigmentosum |
| Base excision repair | MUTYH-associated polyposis |
| Mismatch repair | Hereditary nonpolyposis colorectal cancer (Lynch syndrome) |
| Homologous recombination | BRCA1/2 mutation – Breast/ovarian cancer |
Patients with these DNA repair defects have high mutation rates and increased susceptibility to certain cancers due to an inability to fix damaged or mismatched DNA.
Epigenetic alterations can activate oncogenes
In addition to genetic mutations, epigenetic changes in cells can contribute to cancer development. Epigenetic alterations are heritable changes that affect gene expression without altering the DNA sequence. Common epigenetic mechanisms in cancer include:
- DNA methylation – Hypermethylation silences tumor suppressor genes.
- Histone modification – Changes in histone tails repress transcription of genes.
- Non-coding RNAs – MicroRNAs regulate oncogenes and tumor suppressors.
These allow cancer cells to activate oncogenes or silence tumor suppressor genes by regulating their expression through epigenetic mechanisms instead of by direct mutation.
Genomic instability enables continuing mutation
As cancers develop, they exhibit increasing genomic instability which accelerates the rate of mutation accumulation:
- Chromosomal instability – Errors in mitosis and chromosomal segregation.
- Microsatellite instability – Defects in DNA mismatch repair lead to replication errors.
- Nucleotide instability – Defects in DNA replication proofreading cause substitution mutations.
- Chromothripsis – Massive DNA rearrangements and fragmentation.
This instability allows cancer cells to continuously evolve through new mutations, promoting tumor heterogeneity and drug resistance. Genomic instability also enables mutations in genes that orchestrate the hallmarks of cancer.
Non-genetic factors that enable cancer growth
While mutations underlie cancer formation, other non-genetic factors in the tumor microenvironment support the growth of cancer cells:
- Inflammation – Chronic inflammatory conditions provide growth factors, survival factors, and pro-angiogenic factors.
- Hypoxia – Low oxygen levels lead to the activation of hypoxia-inducible factors that promote angiogenesis, metastasis, and glycolysis.
- Metabolic changes – Alterations in metabolism induced by cancer cells create an acidic, nutrient depleted environment.
- Immune evasion – Cancer cells avoid immune destruction through strategies like downregulating tumor antigens and producing immunosuppressive factors.
- Extracellular matrix – Interactions between cancer cells and extracellular matrix proteins promote proliferation, survival, and migration.
These non-genetic elements create a permissive microenvironment that allows cancer cells to thrive.
Oncogene addiction of cancer cells
Despite the complex genetic changes in cancer cells, they often become dependent on single oncogenes for their continued proliferation and survival – a phenomenon known as “oncogene addiction”:
- HER2/neu – HER2-amplified breast cancer cells require constant HER2 signaling.
- BCR-ABL – Chronic myeloid leukemia cells need this fusion protein for growth.
- KIT – Gastrointestinal stromal tumor cells rely on activated KIT signaling.
- EGFR – Lung cancer cells with EGFR mutations depend on EGFR activation.
Targeting these critical oncogenes with drugs like imatinib, trastuzumab, or erlotinib leads to cancer cell death and tumor shrinkage. However, secondary mutations can confer resistance by reducing oncogene addiction.
Cancer stem cells may evade treatment
Evidence suggests that a small population of cancer stem cells exist within tumors that are capable of self-renewal and differentiation into heterogeneous cancer cell types. Cancer stem cells may promote metastasis and recurrence due to:
- Relative resistance to chemotherapy and radiation.
- Increased DNA repair capacity.
- Quiescence – Entering non-proliferative state allows avoidance of anti-proliferative drugs.
- Multidrug resistance transporters – Efflux pumps expel drugs from cells.
Targeting cancer stem cells may be critical for preventing relapse and metastasis.
Conclusion
Cancer growth is enabled by diverse molecular mechanisms including mutations that activate oncogenes, inactivate tumor suppressors, and confer biological capabilities. Carcinogens, inflammation, DNA repair defects, and genomic instability promote mutations. Non-genetic factors in the tumor microenvironment support cancer progression. Identifying and targeting key oncogenic dependencies may lead to more effective cancer treatments.