19th lecture (cancer, tumor)

Question 1

what are the percentages of cancer predispositions?

Answer 1

90% environmental

10% hereditary

Question 2

Classification/groups of cancer syndromes?

Answer 2

A/ autosomal dominant cancer syndrome
B/ Autosomal recessive:
C/ Familiar cancer: 2-3x more frequent in the family then in the general population.
1. usually has early age onset
2. arising in bilateral organs
3. multiple types of cancer can develop in the patients.

Question 3

Name the types of autosomal dominant cancer syndromes?

Answer 3

1. retinoblastoma (hereditary), retinal tumor cancers may develop in children, but they may also have osteosarcoma secondary cancer.
2. APC (adenomatous polyps cancer) intestinal polyps, could become cancer. (beta-catenine signal)
3. p53 (li fraumeni syndrome = p53 mutation) Multiple sites of cancer; breast, brain, stomach, bone, soft tissue.
4. MRG (mismatch repair genes) causes: hereditary non-polypus cancer syndrome (unlike p53 which was polypus)

Question 4

describe the autosomal dominant cancer syndrome?

Answer 4

A/ autosomal dominant cancer syndrome: (silencing both alleles of the tumor suppressor genes, one alleles is already inactivated in somatic cells and thus one mutation to the other allele causes cancer)

Question 5

describe the recessive cancer syndrome? And the 2 examples.

Answer 5

DNA repair system has a mutation.

• xeroderma pigmentosum: nucleotide excision repair is defective do to UV light; thus basal cell carcinoma of skin, or melanoma, skin cancer. (autosomal recessive)
• ataxia telangiectasia: homologue recombination repair system is defective thus DNA double breaks are not repaired. Thus the patient has breast, leukemia, lymphoma, hepatocellular cancers. (autosomal recessive)

Question 6

describe the different ways of carcinogenesis? and the different types and viruses.

Answer 6

during a mutation there will be an altered signaling of the cell. The mutation is generated by micro-biological agents, chemicals, radiation.

• Viral oncogenesis: RNA and DNA viruses. HTLV-1 virus is an RNA virus (human T-lymphocyte virus) causing leukemia and lymphoma.
• DNA viruses are: epstein barr virus, human papilloma virus, Heptatitis B and C virus, HHV-8 (human herpes virus 8)

Question 7

describe the different modalitites for oncogenesis.

Answer 7

A/ integrating and oncogenic modality: Virus integrates its own virus into the host gene causing its expression. An oncogeneic effect occurs due to its expression.
B/ integrating and regulatory: virus integrates its own virus, but the virus can upregulate a protooncogene that will become an oncogene. or downregulate a tumor suppressor gene.
C/ Episomal: the patient has an infection but the sequence does not integrate. The oncogene without integration can result in cell proliferation. It can affect the regulatory sequences of the coding regions; can overexpress genes or they can downregulation tumor suppressor genes.
D/ inflammation and proliferation. (characteristic for hepatitis C). EXAMPLE: liver cell is infected by a virus and the infected cells are recognized by the inflammatory cells and macrophages and they release inflammatory substrates and ROS. The ROS can generate mutations. The normal cell population wants to regenerate and proliferate to heal. So on one side there is damage and the other side there is high proliferation, this can lead to cancer.

Question 8

Describe how EBV (epstein barr virus) cause cancer.

Answer 8

This is transmitted by mosquitoes (malaria).
B-cells are infected (CD-21 receptor). They use this receptor to pickup the virus and integration into the B-cell genome occurs. There are 2 oncogenic areas called: LMP1, EBNA2.
LMP1; initiates B-cell proliferation by NF-kB or jak/stat
LMP1; block apoptosis via increased expresion of BCL-2
EBNA2 has a transgenic effect; they regulate the genes of the host; Sarc-gene and CDK inhibitors.
The aggressive push to proliferate causes mistakes to be made, and finally a translocation 8,14 occurs. 8 is the C-muc.
lymphoma develops (Cancer).

Question 9

Describe how HPV (human papillomavirus) cause cancer.

Answer 9

HPV causes cervical cancer and oral cancers. With HPV there are high and low risk serotypes.
Low risk is: 1,2,4,7. These case papilloma of the skin or mucus membrane (benign proliferation of the epithelium). NOTE; this virus infection is episomal (no DNA integration)
High risk is: HPV 16, 18, 31. There is an integration into the DNA, causing cervix carcinoma and nasopharyngeal carcinoma.
2 exomes: E7 and E6;
E7 makes a complex with the Rb (retinoblastoma) and thus nothing stops the E2F to push the cell to divide. They also form complexes with cyclin dependent kinase inhibitors causing cell proliferation.
E6 suspends p53 and via BAX they block apoptosis.

Question 10

Describe how HBV (hepatitis B virus) causes cancer

Answer 10

hepatocytes are infected by the virus and inflammation occurs and ROS increases. The normal cells attempt at regeneration and the DNA damage caused by the ROS leads to cancer.
HBV has an oncogene called HBX and this inactivates the p53 and thus blocks the chance for the DNA repair system.

Question 11

Describe bacterial oncogenesis.

Answer 11

the most well known is the helicobacter pylori which makes atrophic gastritis, and the patient may develop gastric cancer. They also initiate B-cell proliferation and generate gastric lymphoma; MALT lymphoma.

Question 12

Describe chemical oncogenesis.

Answer 12

chemicals are distributed into 2 groups:

1. direct affecting: the chemical causes damage directly without any modification. Used in chemotherapy, WWII chemical weapons. They are considered mild carcinogens as they rarely cause cancer.
2. indirect affecting: There chemicals have to be modified and then the substrate of the chemical is carcinogenic. They are metabolized by P450 that form carcinogenic chemicals. STRONG carcinogens (polycyclic carbon-hydrogens, found in burned things like cigarettes and animal fats being cooked, and smoking meat for preservation)

Question 13

Describe the multistep procedure that leads to cancer for indirect acting cancers.

Answer 13

-INITIATION: (dose and organ dependent)
In a population of cells, one cell acquires a mutation do to the carcinogen. (genotoxic effect)
-PROMOTION:
the number of the mutated cells increase but still mixed in with the normal cells. (humeral affect, causing neoplastic cells to overgrow) Example: breast cancer is mediated by Estrogen.
-PROGRESSION:
The neoplastic clone is selected and overgrown the normal cells.

Question 14

what are the most common chemicals causing carcinogenesis?

Answer 14

-polycyclic-aromatic-hydrogens, found in the tar in the cigarettes, meat preserved by smoking. They cause cancer in the: oropharyngeal, bronchial cancer, lung cancer. They can accumulate in the urine causing bladder cancer and kidney cancer.
-alkalating chemotherapeutical agents: cyclophosphamide, busulfan. (patients may develop a secondary cancer as a result of the chemotherapy)
-Radiation: 2 types;
1. ionizing radiation (X-ray, gamma, particular (alpha, beta). this causes double DNA break causing Tumor suppressor gene inactivity. 2 ways in which to damage the DNA:
DIRECT: directly break the DNA
INDIRECT: through the water, as the radiation causes the formation of ROS. Higher water content = more damage
2. non-ionizing radiation: UVB light: makes thymine dimers which are corrected by the excision repair system. The UV light can cause 2 different types of cancers; epidermal cancer (skin), basocellular, or planocellular carcinoma (this is done dependent). The other is the melanoma (this is related to the skin burn). Melanoma is high risk.

Question 15

based on the appearance of the cancer types we can classify them as:

• high risk
• medium risk
• low risk

Answer 15

• high risk: acute myloid leukemia (AML) Chronic myloid leukemia.
• medium risk: Breast, lung, salivatory cancer
• low risk: Skin, bone and GI tract.

Question 16

Describe the tumor immunity?

Answer 16

Tumor that has been infiltrated by immune cells have a better prognosis then on that has not been invaded. Immune suppressed person has high risk for cancer.
There are 2 groups of antigen that initiate the system of immune reaction;
A/ tumor specific antigens (TSA): This antigen exists only in neoplastic disease, they do not exist is normal population, mostly related to oncogeneic protein: BCR able, p53, K.RAS.
B/ Tumor associated antigens (TAA): genes that are expressed in normal cells but their expression is higher in the neoplastic tissue;

Question 17

Name the tumor associated antigens in the context of tumor immunity?

Answer 17

• overexpressed proteins: i.e. (PSA) prostatic specific antigen, expressed in the normal prostate but increases in prostate cancer. (this antigen is good for screening).
• Oncospermatogonal antigens: certain normal genes that are completely silent in all nonmalignant cells may be activated exclusively in malignant cells.
• oncogetal antigens: proteins which are typically present only during fetal development but are found in adults with certain kinds of cancer
• Virus specific antigens: there is a chance that neoplastic cells will express viral antignes (vaccine can be developed against this).
• Cell line specific antignes: i.e. B-cell has CD-20, its characteristic for the cell line and not an oncogene. but we can use this as targeted therapy to selectively kill cells.

Question 18

Describe what the immune system does to neoplastic cell.

Answer 18

The neoplastic cells have antigens which get into the circulation which are taken up APC. MHC2 molecules express them to the CD4 cells which generate interferon-gamma, which stimulate the macrophages which kill the cells, (delayed type hypersensitivity reaction).
The neoplastic cell has MHC1 molecules which presents the antigen to the CD8 tumor suppressor cells. which have cytotoxic affect on the infected cells.
- stress associated antigen that are activated upon DNA damage, and they activate Natural killer cells to kill them.

Question 19

How can neoplastic cells escape the immune system. (4 types)

Answer 19

• Clonal selection: A tumor cell population where most of them have the antigen but some of them do not. And the one that has antigen will be selected and overgrow the normal cells.
• Masking: neoplastic cells can get into the circulation and they could be covered by something, such as mucus to prevent the killing activity of the immune cells.
• T-cell regulation: neoplastic cells can produce factors which influence the T-regulatory cells to reduce the immune activity of the cells. They re-code the T-regulatory system
• The neoplastic cells can kill inflammatory cells by producing FasL because the T-cell has the FasR which is binds to. Then apoptosis occurs in the inflammatory cells.