6. Chemical carcinogenesis

What is cancer?

• Uncontrolled growth of cells (cell division beyond the normal limits)

• Invasion (intrusion on and destruction of adjacent tissues)

• Metastasis (spread to other locations in body via lymph or blood)

Benign vs malignant tumors

Benign

• Well differentiated cells

• No infiltration, capsule

• Slow growth

• Absence of necrosis

Malignant

• Poorly differentiated cells

• Infiltration, no capsule

• Fast growth

• Necrotic tissue

Cancer risk factors

• Tobacco

• Diet

• Alcohol

• Infection

• Geophysical factors

Why is cancer a multi-step process?

• Initial mutation inactivates a negative cell cycle regulator

• Next mutation over-activates a positive cell cycle regulator

• Third mutation inactivates a genome stability factor

• Additional mutations accumulate rapidly

• Cancer cells are formed

This shows that not one mutation causes cancer, accumulation of damage to a number of genes across time leads to cancer

Additionally depending on how relevant the segment of DNA is that is mutated, will also affect the chances of cancer being formed.

Which cell cycle regulators promote development of cancer when mutated?

• Overactivation of positive regulators (oncogenic)

• Inactivation of negative regulators

Overactivation of positive regulators

Proto-oncogenes: genes with a normal function in regulating cell division

• Different effects of mutations:

  • “always on” protein

  • amplification (more protein)

  • “combo” unregulated

Oncogenes: transformed genes causing uncontrolled cell division

Proto-oncogenes → oncogenes

Overactivation of negative regulators

Inhibition of tumor suppressors

• Tumor suppressor: a gene that normally blocks cell cycle progression (in response to DNA damage)

• Active tumor suppressor gene → inactive tumor suppressor genes

  • Inactivation occurs through mutation

  • Inactive tumor suppressor genes causes no control of cell division of cells

Genotoxic vs non-genotoxic carcinogens

• Genotoxic: every molecule increases cancer risk

• Non-genotoxic: a threshold/safe level of exposure can be defined

PAHs

• Chemical carcinogenesis

• Genotoxic carcinogens

Aflatoxin B1

• Chemical carcinogenesis

• Pro-carcinogen is activated when it gains an epoxide group.

• This makes the ultimate carcinogen very reactive and it attaches itself to the DNA

• Happens on P53 gene which is a gene coding for a DNA repair.

• Causes liver cancer

P53 tumor protein

• Normal p53:

  • p53 activated binds DNA

  • This stops cell division, activates DNA repair enzymes and triggers apoptosis if repair is impossible.

  • As a result cells do not pass on damaged DNA

• non-functional p53:

  • p53 cannot bind DNA

  • hence the effects mentioned above do not occur

  • As a result damaged DNA is passed on

Non-genotoxic chemicals

• no direct binding of chemical to DNA

• no direct damage

• no interaction of chemical or metabolite with DNA

• yet, some chemicals can cause cancer

how can non-genotoxic chemicals cause cancer?

• Chemicals that:

  • Cause cell death and aberrant repair

  • Affect metabolism of chemicals

  • Affect cell growth

  • induce DNA synthesis → gene expression

  • Affect hormonal system

  • Induce production of reactive oxygen species

Dioxins

• non-genotoxic chemicals

• can be found in milk or eggs

• activate aryl hydrocarbon receptor

• results in uncontrolled cell division

Asbestos fibers

• Non-genotoxic

• Activates macrophages, however they cannot do this and therefore keep releasing cytokines which causes inflammation

• Causes malignant mesothelioma

Classes of carcinogenicity

• Group 1: carcinogenic to man; should be forbidden

• Group 2A: probably carcinogenic to man; should be forbidden

• Group 2B: possibly carcinogenic

• Group 3: Compound cannot be classified because of lack of sufficient data

• Group 4: proven to be non-carcinogenic

How is carcinogenicity data collected for risk assesment?

• Epidemiology studies in humans

  • Preferred but absent in most ases

  • Can define group 1 carcinogens

• Avoidable chemicals: when positive in genotoxicity studies, no testing

• Non avoidable chemicals: carcinogenicity studies still needed