28 Carcinogenesis, Oncogenesis, Tumorigenesis

What is carcinogenesis? Oncogenesis Tumorigenesis?

All 3 terms, carcinogenesis, oncogenesis, and tumorigenesis are defined as the process of normal cells transforming into cancerous cells, which typically involves multi-steps.  Each of the 3 terms is constructed using the suffix -genesis which is the Greek word for “creation’. The prefix ‘carcino’ is the Greek word for crab, and was originally used to describe a crab-shaped sore or ulcer.  The prefix ‘onco’ comes from the Greek word ‘onkos’ for mass, and tumor is a Latin word meaning ‘a swelling’.  Each of these terms is used to describe the process by which a cell becomes cancerous.

There are several steps involved in the transformation of a normal cell into first a dysplastic (pre-cancerous) state and then into an anaplastic (cancerous) state, characterized by excess cell division of immature, atypical cells that accumulate inappropriately forming a tumor and then spreading through the body.  Usually only one or two cell types are affected, becoming cancerous, so the terms monoclonal- or polyclonal-expansion of cells are sometimes used.

In order to become cancerous, a fully mature cell typically becomes undifferentiated, re-enters the cell cycle, and starts inappropriately going through cell division continuously.  In doing so the cell reverts to an immature-like cell that is no longer capable of performing the functions of a mature cell.  In this immature state, it becomes similar to a stem cell, though has many abnormalities that set itself apart from a normal stem cell.  The first is that the cellular changes have taken place that have affected the negatively affected the regulatory ability of enzymes involved in cell cycle checkpoints, DNA repair, cell differentiation, and apoptosis.

Cancer is thought to be a multifactorial disease because typically a combination of many factors is involved in creating DNA damage, mutations, or epigenetic changes that affect gene expression.  Factors that cause DNA damage (e.g. UV radiation, smoking), or DNA repair errors, or epigenetic changes (e.g. DNA methylation) can affect the genes responsible for proper regulation of cell cycling, cell differentiation and apoptosis.

Cancerous cells often have mutations or epigenetic changes in regulatory genes that result in stimulating too much cell cycling, and not enough cell differentiation or apoptosis.  Factors that caused DNA mutation that lead to a cell becoming cancerous are called carcinogens.

Carcinogenic factors can include any of the following:

1. Environmental cancer-causing agents and carcinogens = factors that are capable of causing DNA mutations (e.g. smoking, asbestos, formaldehyde, industrial pollutants)
2. Spontaneous (or Sporadic) Change in gene mutation which are not inherited if mutations occur in somatic cells, but can be inherited if sex cells are affected and remain viable.
3. Infections = some pathogens are capable of causing DNA mutations, especially if prolonged infections occur as these viruses can alter the host cell’s DNA, for example:
   1. HPV (Human Papilloma Virus) =frisk factor for cancer of the cervix, anus, penis, vagina, and oropharynx
   2. HBV and HCV (Hepatitis B and C Viruses) = risk factors for hepatic cancers
   3. EBV (Epstein-Barr Virus) = risk factor for lymphomas

It is important to know that not all DNA mutations or damage will result in cancer.   DNA damage that affects most regions of DNA, specifically DNA that is not involved in reguating cell cycling, cell differentiation or the rate of apoptosis will typically not result in the creation of a cancerous cell.

Mutations in non-coding or non-transcribed regions of a cell may have no effect on the cell at all.  Whereas mutations of genes that are transcribed and required for that cell to function may cause cellular dysfunction, cell death or induce apoptosis.  Depending on the mutation, the effects can range from mild to serious and can depend on whether the cell produces other proteins or enzymes that can compensate for any lost function.

If a cell’s DNA is mutated during cellular division in S phase, there are many cell cycle checkpoint kinases and inhibitors in place that can ensure DNA repair is completed prior to cell division.  Additionally, these checkpoint regulators will trigger the cell to induce apoptosis if DNA repairs are not completed.  This safety net prevents cells from passing on genomes that may lead to dysfunction, death or cancer. However, with 3 billion pairs of nucleotides in the human genome, occasionally sequencing mistakes are made and passed on to daughter cells.

Both age and the number of mitotic events a cell experiences are risk factors for cancer.  The reason for this is because the more times the cell’s DNA is duplicated, the more chance that DNA polymerase will cause an error that goes unnoticed.  Therefore, frequent mitosis and cell division events can be seen as a risk factor for cancer.  Thus, severe injuries and chronic disease can be considered risk factors due to the large number of mitotic events required for repair.  Additionally, cell types (e.g. epithelial cells) that have a naturally short lifespan and undergo more DNA duplication and mitotic events, are more likely to experience spontaneous errors by DNA polymerase.  Epithelial cells do experience more frequent turnover that other cell types, with new cells being produced to replace older cells.  In a previous section, it was noted that 90% of all cancers are epithelial cancers (carcinomas).

DNA mutations that are capable of giving rise to cancer specifically have to occur in one of three different categories of genes: proto-oncogenes, tumor suppressor genes, or stability genes.

1. >40 Proto-oncogenes have been identified: proto-oncogenes are translated into proteins that are required to stimulate cell division and inhibit both cell differentiation and apoptosis in healthy cells.  When these proto-oncogenes are mutated they are typically expressed as a dominant mutation and are then called oncogenes. Oncogenes are translated into dysfunction proteins that stimulate inappropriate increases in cell division rates, and decreases in the rates of cell differentiation and apoptosis.
2. Tumor Suppressor Genes (TSG): code for proteins that normally slow down cell division, and promote apoptosis; unfortunately when these genes mutate & are turned off; cells do not slow down cell division, and do not promote apoptosis, instead the cells become immortal, continuously dividing, giving rise to an accumulation of atypical immature cancerous cells that form tumors and spread → cancer
3. Stability Genes that normally repair DNA and other genes that control the rate of mutation. These genes do not have a direct impact on rate of mitosis or apoptosis.  However they are amongst the most important.  Without the ability to repair DNA and other genes, the mutation rate increases and likelihood of cell dysfunction or cancer increases.

Many of these regulatory genes (proto-oncogenes, TSGs and stability genes) play a role at cell cycle check-points to ensure that the appropriate progression and regulation of cell cycling, DNA duplication, cell differentiation and cell apoptosis are in place.  It has been found that either direct mutations or epigenetic changes disrupting levels of expression (protein production) of these regulatory genes can contribute to a cell becoming cancerous.

For example 30-50% cancers are thought to have TP53 mutation.  TP53 is a TSG, that codes for p53 which plays a crucial role in ensuring that cell cycling stops between G1/S and G2/M until the DNA is checked for errors and repaired.  DNA is duplicated in S phase of cell cycling and any acquired mutations (e.g. from environmental toxins) or spontaneous errors made by DNA polymerase must be fixed prior to moving past G2 phase and into the mitosis phase.  p53 is therefore often called “guardian of the genome” and is a potent tumor suppressor.  If DNA errors are detected between G1 and G2, p53 can trigger DNA repair, or cell cycle arrest (cellular senescence) or apoptosis.  If the p53-regulated checkpoint is no longer functional due to p53 mutations, more spontaneous mutations in the DNA are likely to occur which can further lead towards a cell becoming dysfunctional or cancerous.

It has been found that cells do not often become cancerous, unless more than one regulatory gene (proto-oncogene, TSG, or stability gene) is altered or mutated due to the number of safety check-points in place.  The exact number of mutations required for a cell to become cancerous is not known, and it is also likely that some people have more genetic susceptibilities than others to cancer.

Oncogenesis Risk Factors:

Risk factors for the development of mutations in proto-oncogenes, tumor suppressor genes and stability genes that can lead to cancer fall into many categories, including those that are modifiable and those that are non-modifiable.  Here is a list of the most common known risk factors:

Non-modifiable Risk Factors:

• Age
• Biological Sex (depending on the cancer type)
• Geographical location due to environmental factors
• Genetic risk factors
  • Inherited BRCA1/2 mutations
  • Genetic susceptibility: e.g., fewer DNA checker enzymes
• Hormone Levels
  • Longer exposure to elevated estrogen (e.g., early menarche and late menopause, or nulliparity) increases risk of developing breast, mammary tissue, and ovarian cancers
  • Changes in testosterone/estrogen levels are a risk factor for prostate cancer
• Disease or Injury
  • Chronic disease or repetitive injury (e.g. chronic gastric ulcers caused by H. pylori bacteria infection is a risk factor for stomach cancer)

Modifiable Risk Factors:

• Nutrition and Lifestyle Factors
  • Smoking
  • High-fat diet
  • Food additives, smoked foods (nitrites)
  • Alcohol
• Environmental Factors, work-place or residential exposure to:
  • asbestos, nickel, radon, lead, solvents (e.g. benzene)
  • smoke
  • gasoline, diesel exhaust, industrial pollution
  • viruses (HPV, HBV, HCV, HIV, EBV)
  • UV radiation, including tanning beds
  • ionizing radiation (x-rays, gamma rays=nuclear radiation)

Oncoviruses and p53

Unfortunately, there has been a strong evolutionary push for dsDNA viruses and ssRNA retroviruses to replicate by taking hostage the host cell’s DNA transcription machinery.  It allows for the virus to have a smaller genome itself, however can create deadly problems for the host cell.

Some DNA viruses insert themselves into the host’s genome and then to ensure that their genome is replicated, the virus produces proteins that inactivate the host cell’s TSG, p53.  By inactivating p53, their DNA presence in the genome goes unchecked and also DNA duplication continues without stopping.  This allows for viral DNA particles to be constantly created and virions to be packaged. 

Additionally, viruses overcome two problems that their host cell may have for them.  Their host cell may be a fully differentiated cell (e.g. keratinocyte of the cervix) which has exited the cell cycle and therefore does not have a pool of nucleotides for the viruses to make viral genomes for packaging into virions.  By inactivating p53, and restarting the cell cycle, the host cell begins to accumulate the required nucleotides for the virus to make virions.   Specific strains of HPV (Human Papillomavirus) work in this manner and are key players in the development of cancers of the cervix, anus, penis, vagina and oropharynx.   For this reason, HPV is considered an oncovirus.  

Oncoviruses are viruses that alter the host cell’s proteins and DNA (proto-oncogenes, TSGs, and stability genes) causing a cell’s cycling and apoptotic regulatory mechanisms to become disrupted, leading to the cell becoming cancerous.  It is estimated that oncoviruses may account for 20% of cancers worldwide.

HIV, Immunosuppression, and Cancer Risk

HIV (Human Immunodeficiency Virus) also disrupts cell cycling, though instead of causing the cell to continually cycle, it causes cell cycle arrest, which aids the spread of this virus, as the host cells are key players in the immune response (Helper T cells).  Unfortunately, without Helper T cells, the ensuing immunosuppression that develops during AIDS becomes a risk-factor for cancer development, as with fewer active WBCs, cancerous cells are easily able to survive.  Frequent causes of death associated with HIV and AIDS are pneumonia, tuberculosis and cancer.  The development of Kaposi sarcomas, lymphomas and other cancers that are thought to be more often stopped by the immune system also are more prevalent in cases of HIV and AIDS.

Summary of Carcinogenesis

• Process:  Normal, often fully differentiated cells acquire DNA mutations or epigenetic alterations that cause them to loss the functions of a mature cell, and become atypical, immature, undifferentiated cells that continuously cell cycle producing atypical, immature cells that accumulate and spread.
• Steps:
  • Carcinogens cause initial irreversible DNA changes.
  • Further mutations to DNA occur, affecting regulatory genes for cell cycling and apoptosis.
  • Cells lose differentiation, mitosis rate increases, apoptosis decreases.
  • Continued exposure to carcinogens leads to malignancy.
  • Metastasis occurs when cancer cells are undetectable, evade Natural Killer cells and other WBCs, and spread locally, regionally and/or distantly.

Think about question:

Did you know that elephants have more copies of stability genes than humans?

Given the great cell number (size of an elephant) does this make elephants more likely or less likely to develop cancer?