3.8.2.3 Gene Expression and Cancer

What do we need to know from the specification? 

1. Distinguish between benign and malignant tumours
2. Explain the role of oncogenes and tumour suppressor genes in the development of tumours
3. Explain the effects of abnormal methylation of tumour suppressor genes and oncogenes
4. Explain how increased oestrogen levels can cause breast cancer

Distinguish between benign and malignant tumours

What is a tumour? A tumour is a group of abnormal cells which experience unrestrained mistosis and as a result constantly grow and develop.

There are two main types of tumour; benign and malignant.

There are 10 characteristics of benign and malignant tumours which need to be known.

Size

Benign: Benign tumours can grow to a large size.

Malignant: Malignant tumours can grow to a large size.

Rate of Growth

Benign: Benign tumours grow at a very slow rate

Malignant: Malignant tumours grow at a very rapid rate

Differentiation of Cells

Benign: The cells in benign tumour are often highly differentiated (specialised)

Malignant: The cells in malignant tumours are often undifferentiated (unspecialised)

Metastasis?

Benign: Benign tumours produce molecules called adhesion molecules. These adhesion molecules make the tumour cells stick together and so they stay within the tissue they arise from. These are known as primary tumours.

Malignant: Malignant tumours do not produce adhesion molucules, therefore do not stick together. Therefore the tumour cells tend to spread to other regions of the body, through a process known as metastasis. These are known as secondary tumours.

Capsule?

Benign: Benign tumours are surrounded by a capsule of dense tissue, and so remain as a compact structure.

Malignant: Malignant tumours do not have any kind of capsule surrounding them. They grow finger like projections into other tissues.

Damage Level

Benign: Benign tumours are much less likely to be life threatening than malignant tumours, however they can disrupt the functioning of vital organs.

Malignant: Malignant tumours are much more likely to be life threatening than benign tumours.

Locality of effects

Benign: Benign tumours tend to have much more localised effects on the body.

Malignant:  Malignant tumours often have systemic (whole body) effects, e.g. weight loss & fatigue.

Removal

Benign: Benign tumours can usually be removed by surgery alone.

Malignant: Malignant tumour's removal usually involves surgery, radiotherapy and chemotherapy.

Rate of recurrence

Benign: Benign tumours very rarely recur after removal.

Malignant: Malignant tumours have a high rate of recurrence after removal.

The process of metastasis is illustrated below:

2. Explain the role of oncogenes and tumour suppressor genes in the development of tumours

In most cases, cancers are developed from a single mutant cell. The initial mutation will cause uncontrollable mitosis in a cell, and later on a second mutation of one of the resultant cells leads to another change where all subsequent cells are abnormal in growth and appearance. There are two main genes which are involved in the development of tumours:

• Oncogenes
• Tumour Suppressor Genes

Oncogenes

Oncogenes are mutations of a different type of gene called a proto-oncogene, Ordinarily, a proto-oncogene will stimuate a cell to divide by mitosis when a growth receptor is detected by a protein on the cell surface membrane. This attachment then activates the genes (proto-oncogenes) which cause DNA to replicate and cell division to occur. If a proto-oncogene mutates into a oncogene, it can become permenantly activated. This can occur for two reasons:

1. The receptor protein which detects growth factors on the cell surface membrane is permanently activated, so that cell division is  always switched on even in the absence of growth factors.
2. The oncogene may itself code for a growth factor which is then produced in excessive amounts, causing excessive cell division.

Either way, the result is that the cells divide too rapidly and out of control, and as a consequence, a tumour develops.  There are a few cancers which are caused by inherited proto-oncogene mutations, however most are acquired.

Tumour Suppressor Genes

Ordinarily, a tumour suppressor gene is active, and its roles include; slowing down cell mitosis, repairing mutated DNA, and apoptosis (programmed cell death) of cells it cannot repair. Therefore the function of the tumour suppressor gene is largely the opposite of that of the oncogenes. If  mutation occurs to a tumour suppressor gene,  it becomes inactive, and therefore stops inhibition of cell division, and thus cells can grow out of control. The mutated cells which are formed from these divisions are usually structurally and  functionally different from normal cells. While most die, those which survive can make cones of themselves and form tumours. There are a number of forms of the tumour supressor genes inculding TP53, BRCA1 and BRCA2l.

Some cancers are caused by inherited mutations of tumour suppressor genes, however most are acquired. For example, ore than half of human cancers display abnormalities of the TP53 gene, which codes for the protein p53, which is involved in causing cell apoptosis. Apoptosis is the programmed death of a cell, when its mutated DNA cannot be fixed. If  the protein p53 is not functioning properly due to a mutation in the TP53 gene, then it won't be able to suppress a tumour and the cells can divide in an unrestrained manner.

The key difference between oncogenes, and tumour suppressor genes is that oncogenes is that it is the activation of the oncogene which causes cancer, whereas it is the silencing off the tumour suppressor gene which causes cancer.

3. Explain the effects of abnormal methylation of tumour suppressor genes and oncogenes

It was learnt in the previous topic that the methylation of DNA induces the silencing of the localised gene (due to more coiling). 

It is now known that in the early stages of tumour development, there are abnormal levels of methylation in tAfthe tissue.

Two abnormalities known as hypermethylation and hypomethylation both have consequences which can bring about cancer.

Hypermethylation occurs at the promoter region of tumour suppressor genes. This leads to the silencing of the tumour suppressor gene by two metiods:

1. the methyl group attaches to a cytosine base, so that no transcription factors can bind to it. Therefore the transcription cannot begin.
2. the methyl group attracts proteins which make the chromatin more coiled (into homochromatin) by carrying out deacetylation of the associated histones, which makes the DNA more tightly coiled around the histones, thus making the base sequence inaccessible for the transcription factor.

The result of both of these is that the process of transcription, and therefore the production of mRNA cannot occur, and so the gene is silenced. Therefore, the proteins which inhibit cell division are not produced, allowing cells to divide by mitosis freely to form a tumour.

Hypomethylation also occurs at the promoter region, but this time on an oncogene. This is where there is reduced methylation, which leads to the expression of the oncogenes, thus stimulating the cell to divide, and a tumour to be formed.

4. Explain how increased oestrogen levels can cause breast cancer

After menopause, a woman's likelihood of developing breast cancer is reduced. At the point of menopause, the steroid hormone oestrogen ceases to be produced in the ovaries, and in the breasts the fat cells begin to produce increasing amounts. If a tumour were to develop in the breasts, the high levels of oestrogen would cause it grow, and in turn produce even more oestrogen.  In addition white blood cells are drawn to the tumour and increase oestrogen production, which leads to even greater tumour growth. 

But how does the oestrogen cause a tumour to grow?

The oestrogen is a steroid hormone, which means it's role is to activate transcription factors. In turn these transcription factors bind to a specific gene. If this gene is involved in cell mitosis, then it will stimulate increased cell division and lead to a tumour.  It is known that oestrogen in  the breasts causes proto-oncogenes to develop into oncogenes, which leads to the development of breast cancer.

Summary Questions

1. Describe a process by which oestrogen might cause breast cancer in post-menopausal women

Post-menopause, the ovaries produce less oestrogen and the fat cells of the breast produce more oestrogen. These locally produced oestrogen release an inhibitor molecule which prevents transcription, and causing proto-oncogenes of the breast tissue to develop into oncogenes. Thee oncogenes increase the rate at which cell division happens, hence the rate at which the tumour grows.

2. Explain why the activation of an proto-oncogene can cause cancer, while it requires the deactivation of a tumour suppressor gene. 

Proto-oncogenes increase the rate of cell division, and so their activation produces a mass of cells (i.e. a tumour). Contrastingly, a tumour suppressor decreases the rate of growth of tumours, so the deactivation of them will allow the cells in the tumour to divide freely

.

 3. Suggest two reasons why the surgical removal of a benign tumour is usually sufficient to prevent the tumour growing again. 

1. The benign tumour doesn't undergo metastasis due to the production of adhesive molecules. Therefore the tumour remains within the tissue of the cell in which it arises, so surgery will remove 100% of the tumour.
2. The benign tumour is enclosed in a dense tissue capsule, so that none of the tumour cells can escape into other tissues. Therefore, as long as the contents of the capsule are all removed, the tumour will totally removed.

4. Suggest why the surgical removal of a malignant tumour requires follow-up treatments such as chemotherapy and radiotherapy

The malignant tumour doesn't produce any adhesion molecules so the cells don't stay together and undergo the process of metastasis, which means secondary tumours can form around the body. Therefore surgical removal of the primary tumour means there's a chance not all of the tumour was removed and so some of it remains, which needs to be killed by chemotherapy/radiotherapy.

5. The enzyme histone deacetylase (HDAC) removes acetyl groups from the histones. Phenylbutyric acid is an inhibitor of the enzyme HDAC. Suggest how phenybutyric acid might be used to treat cancer. Explain your answer.

The removal of acetyl groups is a process which acts to silence certain genes. The act of removing an acetyl group from a histone results in an increase in charge on the histone, and so a greater attraction between the DNA and the histones, causing greater coiling, and meaning the gene is inaccessible for the transcription factor, therefore the transcription cannot occur. If phenylbutyric acid inhibits this process, then it prevents the process of silencing genes, and so will keep them active. A possible treatment using this is if the cancer is caused by the silencing of tumour suppressor genes, the phenylbutyric acid could be added to prevent their silencing and therefore stop the tumour growing. Tumour suppressor genes are used to slow down mitosis, repairing mutated DNA, and the apoptosis of irreparable cells. The reactivation of these genes would allow tumour growth to be stopped and thus cancer to be combated.

Students should be able to evaluate evidence showing correlations between environmental and genetic factors and various forms of cancer.

Students should be able to interpret information relating to the way in which an understanding of the roles of oncogenes and tumour suppressor genes could be used in the prevention, treatment and cure of cancer.