Chemical Contaminants: A Trigger For Cancerous Cell Transformation?

Cancer is caused by changes to certain genes that alter the way our cells function. Some of these genetic changes occur naturally when DNA is replicated during the process of cell division. But others are the result of environmental exposures that damage DNA. These exposures may include substances, such as the chemicals in tobacco smoke, or radiation, such as ultraviolet rays from the sun.

The National Toxicology Program (NTP) has identified the chemical substances listed below as known human carcinogens in the NTP's 15th Report on Carcinogens. Simply because a substance has been designated as a carcinogen, however, does not mean that the substance will necessarily cause cancer. Many factors influence whether a person exposed to a carcinogen will develop cancer, including the amount and duration of the exposure and the individual’s genetic background.

The following are some examples of chemical pollutants that can cause a cell to become cancerous:

- Arsenic

- Benzene

- Chromium

- Nickel

- Lead

- Vinyl chloride

- Formaldehyde

- Benzopyrene

- Toluene

- Methylene chloride

- Trichloroethylene

- Tetrachloroethylene

- Ethylene oxide

- Nickel chloride

- Bisphenol A

- Butyltins

- Methylmercury

- Paraquat

Carcinogens can cause direct DNA damage or have indirect effects on cellular or physiological processes

Direct DNA damage

Carcinogens can directly damage DNA, causing genetic mutations or genomic damage. This can be caused by exposure to chemicals, radiation, or viruses. For example, asbestos fibres can cause DNA damage by generating reactive oxygen species (ROS) and triggering the Haber-Weiss reaction, which produces highly oxidising hydroxyl radicals.

Indirect effects on cellular or physiological processes

Carcinogens can also have indirect effects on cellular or physiological processes, such as:

• Preneoplastic changes in the microenvironment: Carcinogens can cause field cancerisation, leading to widespread premalignant changes in the microenvironment of an organ or tissue. This can include increased inflammatory cytokine production and aberrant cell-to-cell signalling, creating a pro-tumour microenvironment.
• Matrix metalloproteinases (MMPs): Carcinogens can deregulate MMPs, which are involved in tissue remodelling and the breakdown of the extracellular matrix (ECM).
• Vascular cells and angiogenesis: Carcinogens can affect vascular cells and angiogenesis, the formation of new blood vessels. For example, exposure to carcinogens can increase levels of vascular endothelial growth factor (VEGF), which is critical for angiogenesis.
• Fibroblasts: Carcinogens can influence fibroblasts, a type of cell that produces and maintains the ECM. Carcinogens can induce fibroblasts to transform into myofibroblasts, which can promote tumour growth.
• Immune effectors: Carcinogens can modulate immune cells such as macrophages, natural killer (NK) cells, and T cells. For example, exposure to urethane, a known carcinogen, has been linked to increased levels of immunosuppressive myeloid-derived suppressor cells and regulatory T cells (Tregs) in the tumour microenvironment.
• Soluble factors: Carcinogens can deregulate soluble factors such as cytokines, leading to local inflammation. For instance, exposure to carcinogens can increase levels of interleukin-6 (IL-6) and transforming growth factor-beta (TGF-beta), which are associated with tumour progression.
• Metabolic perturbators: Carcinogens can disrupt metabolic processes, such as insulin and insulin-like growth factor-1 (IGF-1) signalling, which are linked to an increased risk of certain cancers.
• Ionising radiation: Ionising radiation is a known carcinogen that can both initiate and promote cancer. It can induce genomic instability and have systemic and microenvironmental effects, such as chronic inflammation, that contribute to tumour development and progression.
• Disrupting chemicals in the aquatic environment: Carcinogens can contaminate the aquatic environment, leading to the bioaccumulation of toxic compounds in marine organisms and seafood. This can result in exposure to potential carcinogens through the food chain.

Carcinogens can affect the tumour microenvironment, which consists of blood vessels, the extracellular matrix, and signalling molecules

Carcinogens can cause inflammation, which is associated with an increased risk of cancer formation. Inflammation attracts activated immune cells that produce cytokines with pro-tumourigenic properties, such as interleukin-6 (IL-6) and transforming growth factor-beta (TGF-beta). These signalling molecules activate intracellular pathways in the pre-tumour cells, such as nuclear factor-kappaB (NF-kB) and Wnt, that promote proliferation and decrease susceptibility to apoptosis.

Carcinogens can also cause DNA damage, which can lead to genetic mutations and genomic instability. This can be caused by direct DNA damage or through indirect cellular or physiological effects. Ionising radiation is one of the few environmental exposures unequivocally associated with increased cancer risk.

Carcinogens can also affect the tumour vasculature. Tumour cells undergo a process called epithelial-mesenchymal transition (EMT), where they become invasive and favour cell-ECM (extracellular matrix) rather than cell-cell adhesions. Matrix metalloproteinases (MMPs) are involved in EMT, and their expression and activity can be regulated by carcinogens.

The tumour microenvironment is also influenced by infiltrating immune effectors, such as regulatory T cells, antigen-presenting cells, and natural killer (NK) cells. Carcinogens can modulate the activity of these immune cells, which can affect the antitumour immune response.

In addition to these direct effects on the tumour microenvironment, carcinogens can also have indirect effects by disrupting the tissue homeostasis. This can lead to alterations in tissue architecture and function, which can create an environment conducive to tumour growth and progression.

Overall, carcinogens can affect the tumour microenvironment through a variety of mechanisms, including inflammation, DNA damage, EMT, immune modulation, and disruption of tissue homeostasis. These effects can promote tumour growth, invasion, and progression.

Carcinogens can cause field cancerisation, which refers to widespread premalignant changes in the microenvironment of an organ or tissue

The microenvironment is integral to the process by which known and possible carcinogens contribute to tumourigenesis. Tumour initiation is associated with the recruitment and activation of multipotent stromal cells/mesenchymal stem cells, fibroblasts, endothelial cell precursors, antigen-presenting cells, and other hematopoietic cells. These non-tumour host cells recruit stroma and immune cells and produce cytokines that collectively contribute to the tumour microenvironment.

Carcinogens can influence the tumour microenvironment through effects on epithelial cells, the most common origin of cancer, as well as on stromal cells, extracellular matrix components, and immune cells.

Field cancerisation can be seen in the progression from benign adenomatous polyps preceding colorectal cancer, intraepithelial neoplasia progressing to cervical carcinoma, and benign monoclonal plasma cell proliferation in individuals who later develop multiple myeloma.

Carcinogens can cause genetic, epigenetic, or transcriptomic changes within a cell

Genetic Changes

Cancer is a genetic disease caused by changes in genes that control the way cells grow and multiply. Genes are sections of DNA that carry instructions to make a protein or several proteins. Carcinogens can cause genetic changes by altering the DNA sequence, for example, through random mistakes in our DNA as our cells multiply, or by directly altering our DNA. These genetic changes can happen throughout our lives and even in the womb. While most genetic changes aren't harmful on their own, an accumulation of genetic changes over many years can turn healthy cells into cancerous cells.

Epigenetic Changes

Epigenetic changes refer to changes in gene expression that occur independently of changes in the primary DNA sequence. Carcinogens can cause epigenetic changes, such as DNA methylation and histone modifications, that affect how DNA is packaged in the nucleus and alter how much protein a gene makes. For example, DNA methylation can lead to gene silencing by preventing or promoting the recruitment of regulatory proteins to DNA. Carcinogens that cause epigenetic changes include tobacco smoke, heavy metals like cadmium, and viruses like the Epstein-Barr virus.

Transcriptomic Changes

Transcriptomic changes refer to changes in the expression of genes and their products, such as RNA and proteins. Carcinogens can cause transcriptomic changes by altering the expression of specific genes or pathways. For example, carcinogens may activate oncogenes or silence tumor suppressor genes, leading to aberrant cell signaling and uncontrolled cell proliferation.

Carcinogens can induce chronic inflammation, which is associated with an increased risk of cancer formation

Carcinogens are cancer-causing agents that can be found in the environment, such as asbestos, benzene, nickel, and vinyl chloride. They can also be found in tobacco smoke, radiation, and certain medications. These substances can cause genetic changes in cells, leading to uncontrolled cell growth and division, resulting in the formation of tumors.

Chronic inflammation is a prolonged inflammatory response that can be triggered by exposure to carcinogens. It is associated with an increased risk of cancer formation in many tissues, including the colon, lung, and pancreas. The mechanisms by which chronic inflammation promotes carcinogenesis are multifaceted and involve the activation of various signaling pathways and the production of inflammatory cytokines.

One example of a carcinogen that induces chronic inflammation is asbestos. When inhaled, asbestos fibers can be ingested by macrophages, leading to the production of inflammatory cytokines such as IL-1β. This, in combination with other growth factors, triggers a fibrotic response in the lung, resulting in the development of asbestosis, a chronic inflammatory condition. The presence of asbestos bodies, which are asbestos fibers covered in collagen deposits, is directly linked to an increased risk of lung cancer.

Another carcinogen that induces chronic inflammation is methylmercury (MeHg), a ubiquitous pollutant that can induce oxidative stress and mitochondrial dysfunction. Oxidative stress is a key mechanism through which carcinogens induce cellular damage and promote carcinogenesis. MeHg exposure has been associated with an increased risk of cancer, particularly in individuals with high exposure levels.

In addition to direct DNA damage, carcinogens can also act indirectly by perturbing the tumor microenvironment. This includes effects on epithelial cells, stromal cells, the extracellular matrix, and immune cells. Carcinogens can influence the production of cytokines, growth factors, and other signaling molecules, creating a pro-tumorigenic microenvironment that facilitates tumor progression.

Overall, carcinogens can induce chronic inflammation by activating inflammatory pathways, producing inflammatory cytokines, and causing oxidative stress. This, in turn, creates a favorable environment for cancer formation and progression.

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