Cell Cycle Control Breakdown And Cancer

How Cancer Forms

 

As shown in the diagram above, malignant tumor develops across time. The particular tumor on the diagram develops as a result of four mutations, but the number of mutations involved can vary from one type of tumor to the other. The exact number of mutations required for a normal cell to become a fully malignant cell remains unknown, but the number is probably less than ten.

The tumor begins to develop when a cell experiences a mutation that makes the cell more likely to divide than it normally would. The altered cell and its descendants grow and divide too often, a condition called hyperplasia. At some point, one of these cells experiences another mutation that further increases its tendency to divide. This cell’s descendants divide excessively and look abnormal, a condition called dysplasia. As time passes, one of the cells experiences yet another mutation. This cell and its descendants are very abnormal in both growth and appearance. If the tumor that has formed from these cells is still contained within its tissue of origin, it is called in situ cancer. In situ cancer may remain contained indefinitely. If some cells experience additional mutations that allow the tumor to invade neighboring tissues and shed cells into the blood or lymph, the tumor is said to be malignant. The escaped cells may establish new tumors (metastases) at other locations in the body.

When the cell cycle control system breaks down, a normal cell turns into a cancerous (tumor) cell.

Benign tumor cells are localized in a particular organ/tissue; malignant tumor cells can spread to nearby tissues.

The spread of cancer cells beyond their original site is called metastasis.

Genes that stimulate normal cell division, in their normal state, are called proto-oncogenes. When mutated, they are called oncogenes. Most oncogenes behave as dominant alleles (ex.: the ras proto-oncogene).

Genes that suppress normal cell growth and division are called tumor suppressor genes. Mutations in these genes release cells from their controlling functions, such as DNA repair, cell adhesion, or cell-cycle inhibition. Tumor-suppressor genes usually behave as recessive alleles (ex.: BRCA 1 an BRCA2).

An important class of tumor suppressor genes is the DNA repair genes. Mutations in these genes impair the ability of the cell to repair any further mutations, thus accelerating the progression of cancer.

All cancers are caused by the accumulation of genetic mutations that cause, or allow, a cell to grow out of control and become a tumor. Some mutations occur during somatic DNA replication when cells in the body copy their genetic material and an error is introduced into a gene (spontaneous mutations). Some mutations are caused by environmental factors. Some mutations occur in reproductive cells and then subsequently can be passed from parent to child, from one generation to the next. The latter type of mutation is said to be hereditary and may cause an inherited (familial) form of cancer.

Carcinogens and mutagens

Cancer is overwhelmingly a result of environmental factors. Ex- posure to mutagens in the environment increases mutation rate, thus increasing the chance of cancer. At least 50% of cancers are environmentally induced. Recent studies indicate that this can actually be up to 90%.

Carcinogens are mutagens that cause mutations which lead to cancer. Nearly 75% of the risk of colorectal cancer is due to diet. 75% of chance of developing head and neck cancers is because of tobacco and alcohol. 86% of cases of skin cancer are due to sun exposure. Direct continuous exposure to UV light (a carcinogen) leads to formation of thymine dimers (abnormally paired thymines), which interfere with the fidelity of DNA replication. Xeroderma pigmentosum is a form of skin cancer that results from mutations in DNA repair enzymes responsible for the removal of thymine dimers.

Two classes of genes appear to play major role in triggering cancer. Oncogenes can transform a normal cell into a cancerous cell by continuously inducing the cell to divide. Tumor suppressor genes are genes that normally suppress cell growth, but, when affected by a mutation, permit the cell to grow without restraint.

DNA repair genes ensure that each DNA strand is replicated (during the S phase of the cell cycle) without mistakes. DNA repair genes are classified as tumor suppressor genes.

Genes Involved In Human Cancer

Oncogenes

Oncogenes are mutated forms of proto-oncogenes. Normally, proto-oncogenes function as growth factors, growth factor receptors, relay molecules and transcription factors. Proto-oncogenes regulate cell cycle by promoting cell division in response to an extracellular signal (hormones and other growth factors etc.) via the signal transduction pathway. Gain-of- function mutations in proto-oncogenes may lead a proto- oncogene to be permanently turned on. Such mutations in proto-oncogenes are usually dominant in nature (the product of an oncogene must be PRESENT in order to override the normal regulation of cell division). Mutations that permanently switch proto-oncogenes “on” result in abnormally accelerated cell division, which may lead to cancer.

Major mutational events that lead to proto-oncogenes changing to oncogenes are chromosomal translocations (in this case, proto-oncogene would be in the vicinity of the breakpoint) and amplifications of chromosomal regions harboring proto- oncogenes.

To date, more than 50 proto-oncogenes have been discovered. Examples of proto-oncogenes:

Examples of proto-oncogenes

PDGF

•  encodes a protein called platelet-derived growth factor (involved in some forms of brain cancer).

Ki-ras

• encodes a protein involved in a stimulatory signaling pathway (involved in lung, ovarian, colon, and pancreatic cancer).

MDM2

• codes for a protein that is an antagonist of the p53 tumor-suppressor protein (involved in certain connective tissue cancers)

Tumor-Suppressor Genes

Tumor suppressor genes (TSGs) tell the cell to stop dividing. TSGs normally function in the cell by suppressing cell division. Loss-of-function mutations in TSGs may lead to an unregulated cell division (TSG gene products must be ABSENT in order for cell division to take place) and to cancer. Mutations in TSGs are usually recessive, but can show dominant pattern of inheritance, ex., p53. Most familial (inherited) cancers are related to defects in TSGs.

Examples of TSGs

NF-1

• codes for a protein that inhibits a stimulatory protein (involved in myeloid leukemia).

RB

• codes for the pRB protein, a key inhibitor of the cell cycle (involved in retinoblastoma and bone, bladder, and breast cancer).

BRCA1

• codes for a DNA repair protein associated with the breast and ovarian cancers).

 

BRCA Gene, Should You Be Worried?

By Tianna McCormick | August 22, 2018

https://raisevegan.com/brca-gene-should-you-be-worried/

The repost of the article adheres to the Fair Use application of 17 U.S. Code § 107, https://www.copyright.gov/title17/92chap1.html#107).

Everyone has a BRCA gene, and for most people, they function just fine. Without reading this or other articles, you probably wouldn’t even be aware of them, or have any reason to be aware of them. These two BRCA genes do have a specific and important function though, since they produce a type of protein called Tumor Suppressor Protein. Sounds important right? Yes, we definitely want a lot of tumor-suppressing going on.

What is the BRCA Gene?

BRCA1, a gene on our 17th chromosome and BRCA2, a gene on our 13th chromosome, are both tumor suppressor genes that produce a tumor suppressor protein called Breast Cancer Type 1 Susceptibility Protein and Breast Cancer Type 2 Susceptibility Protein, respectively. Mutations in these genes can be inherited from either parent with a 50/50 chance of inheritance. So what happens when there is a mutation in one of these genes and what do people need to do about it? Let’s understand the cell division process a little.

Human cells are always dividing through a process called mitosis. During the cell division process and the time before a cell dies, there are many different biochemical reactions taking place that direct the cell on DNA replication, performance, and even its death. The direction of these processes comes from the many of other proteins living inside the cell. One such protein, called a tumor suppressor protein, has a few goals, with the main purpose of controlling cell growth. They are able to do this by helping to repair damaged DNA.

When a cell divides, it replicates its own DNA. During replication, the double strand of DNA often breaks or has mistakes in the coding, leading to DNA mismatching. The role of the tumor suppressor is to repair these breaks and/or mismatches. If a mismatch or break is unable to be repaired, the tumor suppressor works with other cell proteins to induce programmed cell death, a process called apoptosis. This is a biochemical mechanism that occurs in our body on a regular basis. And generally speaking, it works very well…until our tumor suppressor proteins don’t work.

When a BRCA gene is mutated, the protein that is produced is non-functional. So not only is damaged DNA unable to be corrected, but also, the ability to induce apoptosis can also be inhibited, meaning that the cell can replicate with broken and mismatched DNA. As more of these damaged cells replicate, they will begin to form unhealthy tissue, leading to malignant tumors.

People with mutations still have one healthy functioning gene (because we are born with two of each gene) so there isn’t a 100% chance that malignancy will occur. However, studies show that people with specific BRCA1 and BRCA2 mutations have a 69% and 72% chance of developing breast cancer by the age of 80, respectively, and the risk of developing ovarian cancer is 44% and 17%, respectively. Considering that the general population has a 12% chance of developing breast cancer and a 1.3% chance for ovarian cancer, those numbers are considerable. So what does one do?

Enhanced screening through various scans and exams can catch cancers in the very early stages however there are limitations, especially with ovarian cancer, which has no proven effective screening tool. Chemoprevention and oral contraceptives are also options to lower breast and ovarian cancer respectively. People are also advised to have prophylactic or risk-reducing surgery. This includes bilateral salpingo–oopherectomy, removal of both ovaries and fallopian tubes, and mastectomy, the removal of one or both breasts. However, the decision to have such invasive surgery is very personal and definitely not a choice all people are willing to make.

So what happens when you learn that you have a mutation in one of a BRCA gene? Learn everything you possibly can about your mutation and what your personal risks are. It is important to note that not all mutations are bad, so be sure to work closely with a medical care team who understands not only your mutation, but also your risk based on family history as well.

p53 tumor suppressor gene

p53 is “the guardian of the genome” because it causes cells that have DNA breaks and other DNA damage (“genotoxic injury”) to arrest in the G1 interval of the cell cycle or undergo programmed cell death, thereby preventing replication of the DNA breaks, which could result in broken chromosomes and progressive genetic instability that leads to cancer.

Inactivation of the p53 tumor suppressor is a frequent event in tumorigenesis. In most cases, the p53 gene is mutated, giving rise to a stable mutant protein whose accumulation is regarded as a hallmark of cancer cells. Mutant p53 proteins not only lose their tumor suppressive activities, but often gain additional oncogenic functions that endow cells with growth and survival advantages.

The p53 tumor suppressor protein binds to DNA as a dimer or tetramer to regulate transcription of genes that mediate re- sponses to cellular stress. Mutant p53 protein, which takes on an abnormal conformation, is more stable than the wild-type (half-life of several hours compared to 20 minutes for the wild type p53). Furthermore, it appears that the mutant p53 protein can dimerize with the wild-type p53 and inhibit its normal func- tion. This loss of a function of a product form the “good” copy of the p53 gene in the presence of the product from a defective p53 is referred to as the loss of heterozygosity (LOH). LOH refers to a loss of the function of the wild type allele in a cell line of an individual who carries a mutation in a gene associated with cancer formation. Thus, the cell becomes essentially homo- zygous for the defective allele due to LOH, loosing the ability to control (restrict) its cell division.

In familial p53-related cancers, such as the Li-Fraumeni syndrome, one defective copy of a gene is inherited. Sometimes a mutation in one the p53 alleles can occur spontaneously in somatic cells (sporadic cancers).

Genetic Pathways To Cancer

The Two-Hit hypothesis (A.G. Knudson, 1971)

Both alleles of a tumor suppressor gene must be inactivated to get cancer (one active allele is enough to provide cell cycle regulation). One copy of defective gene is inherited and the other one is inactivated somatically (through LOH or chromo- some loss). This hypothesis explains inherited predisposition to cancer.

Example: retinoblastoma.

Children inherit one mutated pRB gene (one hit). Somatic mutation inactivates the second pRB gene (two hits) leading to retinoblastoma.

The Mutation Accumulation Hypothesis

No single event is enough to turn a cell into a cancerous cell. The accumulation of damage to a number of genes (“multiple hits”) across time leads to cancer.

Cancer results from an accumulation of somatic mutations in both TSGs and proto-oncogenes. Each new somatic mutation creates changes in the cell which contribute to the malignant phenotype.

Some mutations are common to many cancers, while others are specific.

Example: colorectal cancer.

Inactivation of APC tumor suppressor gene leads to benign tumors (polyps). Activation of k-ras oncogene and inactivation of 18q and TP53 tumor suppressor genes leads to intestinal carcinoma. Mutation of more oncogenes and tumor suppressor genes leads to metastatic colorectal cancer.

The Immune Surveillance Theory

This theory proposes that oncogenic transformation of normal cells is a frequent occurrence but the immune system clears them as they emerge.

Cancer cells “give themselves away” by displaying cell specific signals on their cell surface (ex., prostate-sensitive antigen, PSA) that are recognizable by the immune system. During prolonged periods of stress (chronic stress) the immune system is suppressed and, thus, is not functioning at its highest capacity and is unable to detect some of the tumor cells, which subsequently become cancerous. The suppression of the immune system function with advanced age lets cancer cells escape detection, resulting in an increased incidence of cancers in older people.

Recent studies on animal models as well as human cancer studies provide compelling evidence for the existence of tumor surveillance cells (Swann and Smyth, 2007).

 

Key Takeaways

• DNA replicates accurately and efficiently during the cell cycle.
• Cancer results from a breakdown in cell control regulation.
• The human immune system can remove cancer cells as they form.
• Cancer evolved to avoid the immune surveillance, particularly when the immune system is compromised, such as during chronic stress or at later stages of lifespan.