number Done by حسام أبو عوض Lara Abdallat Dr. Maha

Transcription

1 number 18 Done by حسام أبو عوض Lara Abdallat Dr. Maha

2 Continuing with the causes of cancer development In the previous lecture, the effect of chemicals on the development of cancer was discussed. In this sheet we will go into details of radiation and viruses relation to cancer (kinda difficult to be honest and I heard the doctor saying she ll make the exam challenging ) Radiation It can be easily shown that radiation has a direct effect on increasing the rate of cancer incidences for many examples prove this true and following are some: - Populations that got exposed to atomic bombs (i.e. Hiroshima and Nagasaki) showed increased incidence of developing several types of cancer like leukaemia. - Workers in mines where radioactive substances are present show an increased cancer incidence. - ALL pioneers dealing with radioactive materials also died due to different types of leukaemia. (I feel like something is wrong with this final example, but I literally wrote what the doctor said). We are exposed to several types of radiations in our daily lives and the following are the main ones: - Sun-rays (UV-light) - X-rays [here, the personnel affected the most are the radiologists not the patients. To minimise the chances of developing cancer, radiologists are obliged to wear a device which measures the total amount of radiation they got exposed to, if this amount exceeds a certain set value then the radiologist is given a forced-vacation till his body gets rid of some of that radiation]. - Nuclear fission (e.g. atomic bombs) - Radionuclides Ironically, radiation can be used as a treatment to certain conditions some of which are neoplastic. It can easily be predicted that using such treatments to non-neoplastic diseases (often in dermatology) increases the chance of development of cancer.

3 Other risk factors regarding radiation include: - Individual susceptibility [some individuals are more susceptible to developing cancer, e.g. white skinned people are at a higher risk of cancer due to the lack of the melanin layer present in darker skinned people. This melanin layer protects the skin from the effects of UV light. Indeed, skin tumours are considered to be classical tumours for fair skinned people and its incidences are quite high in western countries (were people are mostly fair skinned). Many skin cancers are also seen in the Middle East region but not as frequent as in the western world]. - Increasing exposure to sun. [This is a point doctor Malik also mentioned in pharmacology. Australia and New Zealand have the highest number of incidences of skin cancer due to the sun being closest to the Earth in those regions and therefore people are more exposed to the sun there and people there are also fair skinned (increasing the risk even more)]. - Efficiency of the repair enzymes. [These enzymes serve as a protective mechanism against skin cancer. UV-light can cause some DNA breakages which is repaired by these enzymes so lacking these enzymes means a higher chance of the DNA remaining damaged and therefore a higher chance of cancer. Digging deeper into the mechanism of this event, we notice that what the UV-light does is that it forms a pyrimidine-dimer (remember the thymine-dimer question in the microbiology mid-term exam? Here you ll find the answer) in the DNA, if this dimer was not removed then the growth of the cell is induced (and of course more growth=higher chances of mutation=higher chances of cancer), therefore,

4 there are specialised enzymes that excise (remove) this dimer from the DNA and repair the DNA structure. Skin cancer is usually seen in the elderly, however, if the DNA repair enzymes are missing (e.g. congenital genetic deficiency) then the patient becomes liable to get skin cancers and such patients are noted to develop cancer early in their lives]. Skin cancer development due to radiation can be in two forms: 1- Accumulative effect In this form, the cancer is usually induced by small doses of radiation to which the patient gets exposed continuously causing accumulative changes (like gene mutations or DNA breakages in cells). 2- Intense-intermittent exposure As the name suggests, the patient gets exposed to an intense (large dose) of radiation, even if intermittent,(متقطع) which causes cancer. A common type of cancer developed in this way is melanoma, which is a very serious malignant tumor. This often happens when a person takes a sun-bath or when using tanning devices (which are quite dangerous and risky to use). Viruses Viruses were very important regarding understanding the process of cancer development due to mutations (the genes to be discussed in the next lecture are actually derived from studies on the relationship between cancer and viruses). Viruses induce changes in the infected cell; they are obligatory intracellular organisms i.e. they need to enter into the cell to replicate. That s why viruses need to induce some changes in the cell (except parvo virus, just trying to help you link (and study) with other subjects as well). Both RNA and DNA viruses are involved in the development of cancer. RNA viruses were the first to be discovered to be causative agents of cancer. The RNA viruses that can cause cancer fall under the retrovirus family. Many DNA virus families can induce cancer. We ll first be giving a detailed example on an RNA virus and how it induces cancer. The human T-cell leukaemia virus type 1 (or HTLV for short) was the first virus to be studied in the virus-cancer relationship. In terms of function, this virus is pretty similar to the HIV (the virus that causes aids).

5 The HTLV is well known to infect the T-helper CD4+ lymphocytes. It was noticed that the incidences of T-cell lymphomas and leukaemia are quite high in certain areas (Japan and the Caribbean) compared to the rest of the world (most lymphomas and leukaemia have to do with the B-cells not the T-cells). It was quite puzzling, such rare types of leukaemia and lymphoma rise a lot in just specific areas The answer was then found to be the endemic HTLV infection. This viral infection occurs endemically in these areas (this means that a large number of the population show a positive result for being infected by this virus). This virus is transmitted sexually, through blood products and through breast feeding. Later on, infected patients go on to develop the tumour. The latent period here can be veeeeeeeeeeeeeery long (more than the number of e letters in my last very ), that is from YEARS. The reason behind that is the relationship between this viral infection and cancer development (the doctor gave no more details). The RNA viruses, like our HTLV, are considered to be defective because they contain no DNA. This means that they cannot synthesize their RNA (for replication) without the help of the host DNA. So, the retroviruses have a reverse transcriptase enzyme to be able to replicate their RNA using the host s DNA, that means that these viruses need to have some characteristic genes to be able to survive and proliferate, one of these important genes is called the TAX gene (found in the px region of the viral genome). The TAX gene is very strong in affecting the host s growth and division. In a normal cell, for growth and division to occur the cell should enter the cell cycle and certain genes need to be activated (to be discussed later) for the process to proceed. These genes control the movement of the cell from one phase of the cell cycle to the next phase (remember, for the virus to cause cancer it must INCREASE the rate of division of the cell to enhance the chances of mutation). One of the protein groups the TAX affects is the transcriptase proteins group. The transcriptase proteins are extremely important in DNA synthesis. In a normal situation, when the cell

6 enters the cell cycle, the transcriptase proteins should be produced for DNA synthesis to occur; the transcriptase proteins attach themselves to a site in the DNA and that site becomes the first point from which DNA replication begins, so these guys determine the site of DNA replication. After the cell (still in a normal situation) activates the transcriptase proteins it goes on to activate different types of cyclins; cyclins help other genes in replication. Both of these protein groups (cyclins and trascriptases) are activated by the viral TAX gene, so the TAX enhances cell division by activating these proteins. TAX can also interact with other genes needed in the cell cycle; the cell doesn t simply enter into the cell cycle and proceed to division, no no no, other genes are needed (besides cyclins and transcriptases) and they are also activated. TAX does not stop there, it INHIBITS genes responsible for producing inhibitory proteins for the cell cycle, so now nothing stops the cell from going on to its mitotic phase (normally, even when the cell is growing and dividing, the inhibitory signals are still there and are responded to, but according to the balance between them and the activating signals the cell either enters to the mitotic phase or stays away from it). Among the inhibitory factors that are inhibited by TAX are the p53 (remember the apoptosis lecture, lecture #4 I think) and p16. If p53 is active the cell can t enter the synthetic phase, so the TAX down-regulates this protein. The TAX goes on to play with the receptors of the interleukins; interleukins can activate T-cells, can activate genes for cell growth and can also induce the macrophages making them produce proteins (mitogens) which also stimulate the growth of T-cells. So, the process (TAX activity) ends with a large number of T-cells being produced. So far, these produced cells are called polyclonal as different types of cells are produced to overcome the virus, but what happens is that during this inflammatory reaction mutations can occur (a higher chance than normal) and the mutated cell can proliferate, this is a mono-cell now and monoclonal cells are seen. So, HTLV can induce T-cell leukaemia which is a very rare disease. After the HTLV, other viruses were studied; the viral genomes were traced in the DNA of malignant cells and indeed it was found that in certain types of lymphoma the genomes of some DNA viruses were present. There are 4 DNA viruses that induce cancer that we are interested in and these are: - Human Papilloma Virus (HPV)

7 - Epstein-Barr Virus (EBV) - Kaposi sarcoma herpes virus (KSHV) and herpes virus type 8 - Hepatitis C and B The importance of studying viruses comes from the insight it could give us on the pathogenesis of cancer. Taking things a step further, some scientists are trying to develop a genetic therapy to see which type of mutations are present and then produce certain drugs that target the mutation sites giving the patient a chance to recover. (the third one will not be discussed) Human Papilloma Virus It has many serotypes some of which cause malignant tumours and others cause benign tumours: Benign squamous papilloma (warts) (HPV serotypes 1,2,4 and 7) Genital warts (HPV serotypes 6 and 11) Cervical cancer (HPV serotypes 16 and 18) Oropharyngeal cancer (the above list is of great importance, there is a high chance that the doctor will include a question about these). In cervical cancer the tumour is malignant, but, fortunately, this type of cancer has been controlled and its incidence is getting reduced by controlling the infection. It can be sexually transmitted and now vaccines are present against this disease. In tracing the viral DNA in the malignant cells the PCR (polymerase-chainreaction) method is used making it quite an easy test to do these days. The ability of the HPV to produce malignancy is related to some viral genomes called E6 and E7. Both interact with tumour suppressor genes (they are several, not just one) (TSGs). The TSGs prevent the cell from entering into the S-phase of the cell cycle unless the DNA is completely normal, so repair mechanisms have to be done before entering into the S-phase, and by inhibiting these genes the virus is giving the cell the ability to move on to the S- phase with no restrictions, so defective TSGs mean that abnormal DNA can enter into the S-phase (the E7 gene produced by the virus binds to the

8 retinoblastoma in the DNA with those TSGs being within it). Now, cells with DNA abnormalities accumulate. One might wonder, why are there some serotypes that produce benign tumours usually and others that produce malignant ones? The answer is that this depends on the affinity of the viral genome to TSGs, the higher the affinity the more the chance of malignancy is. Keep in mind that TSGs are not working alone, these genes are themselves induced by other genes (e.g. p16 and p27, these are cyclin dependent kinase inhibitors, CDKIs, if mutated the control over the cell cycle decreases), but the TSGs remain the main genes here and the others are helping genes. The E6 gene produced by the virus interacts with one of the TSGs, the p53, which is known as the guardian of the genome as it is responsible for maintaining the normal genome, so if this gene is mutated almost no control at all is seen in entry to the S-phase. The changes above induced by viral proteins occur when the virus cooperates its genome into the DNA of the host and gets transcribed and translated producing the needed viral proteins. It is noteworthy that in serotypes causing malignant tumours the viral genome incorporates itself at important sites of the DNA of the host, these important sites are themselves the major sites (TSGs) described above. Other promoter genes are present in the DNA of the cell which work as regulators (like an on/off button) of the major sites, serotypes linked to benign tumours often affect these promoter regions rather than the major sites. Epstein-Barr Virus This virus is characterized by symptoms similar to those of other viral infections (fever, etc.) and by the enlargement of the left side of the throat (the infection caused by EBV is also known as the infective mononucleosis). The following tumours are caused by the EBV: Burkitt lymphoma (malignant) Lymphomas in immunosuppressed patients Hodgkin lymphoma T-cell lymphoma NK cell lymphoma

9 Gastric carcinoma Nasopharyngeal carcinoma In all the above diseases, except Burkitt lymphoma, the cause of the tumour could be non-viral (Burkitt lymphoma is always viral). EBV has a tropism to affect the B-cells. The EBV produces some viral cytokines, these are LMP₁, EBNA₂, vil-10 If the viral genome is seen in the cell this means that the cell proliferation has been activated and this can occur via several pathways, the most common one being the JAK/STAT pathway activated through the LMP₁, this occurs in B-cells, the pathways mimic the activation of the B-cells through the CD40 cell surface receptor. The progress of any leukaemia depends on the prevention of apoptosis, so the LMP₁ prevents apoptosis by activating the Bcl-2 protein (go back to lecture 4) which elongates the lifespan of the cell. EBNA₂ activates several genes including cyclin D and src family protooncogenes. vil-10 prevents the macrophages and monocytes from activating the T-cells so that they do not kill the virally infected cells. Burkitt Lymphoma has two types - African 100% of the children affected show a positive result for the viral genome. This results in the classical lymphoma around the jaw with a very big tumour. - Western Not all affected patients show the presence of the viral gene and this type usually results in an abdominal lymphoma. All patients, from both types, show a translocation in the MYC gene from chromosome 8 to chromosome 14 which results in a very aggressive type of lymphoma. This is because the MYC gene becomes very active as it is moved next to the gene that produces antibodies which is always active so the MYC gene becomes continuosly active as well. In a normal situation, the MYC gene would only get activated for a very short time in which it gives orders for the

10 cell to proliferate, but in this case it is constantly active so the proliferation becomes continuous. Whether the cause of Burkitt Lymphoma is viral (which is the usual case) or any other thing that we do not know of, the translocation of the MYC gene is clearly important in the process. In a similar way the EBV induces the nasopharyngeal carcinoma. Knowing if the cause is viral or not helps us in predicting the consequences. Hepatitis B and C Hepatitis infects the hepatocytes and this infection may become chronic (at the beginning it is acute) which may cause liver cirrhosis which is considered a pre-neoplastic condition which can produce hepatocellular carcinoma (which is usually induced by Hepatitis B or C). When the virus enters the hepatocyte it causes chronic damage. There were no viral oncogenes found in the hepatocytes of infected patients, but it is still believed to be due to the continuous degradation and regeneration that mutations can occur and that cancer can develop (induced virally). In recent researches, a gene related to the activation of transcription factors causing continuous genetic damage and cell division was found, some scientists say that apoptosis is also interfered with here, but all these are theories as of now and nothing has been proved. Helicobacter Pylori This bacteria causes gastric adenocarcinoma and MALT lymphoma. Unlike viruses, the bacteria are (usually) non-invasive, that is they do not enter into the cell and instead cause their infection from outside. This Helicobacter pylori for example stays in the mucosal surfaces. H. pylori is the most common cause of gastritis and chronic inflammations in mucosa (this may lead to atrophy which can then lead to metaplasia).

11 H. pylori is very common and many people get infected by it, but only a small percentage go on to develop cancers; curative drugs are present for this bacteria which led to these results. Note: I advise you to first study this sheet, then go on to read the slides (there are more details there, I included some of them in addition to what the doctor said in the lecture in this sheet, but due to the large amount of information written here it was difficult to include everything and apparently we are required to know those details in the slides ) and it would be a good idea to read the book after that as, for me, I can say that there is a high chance that questions from the book not mentioned in the slides/lecture will be included in the exam.