Topics A63-66. Neoplasm 3: Viral/Microbial Oncogenesis, Chemical and Radiation Carcinogenesis, Tumor Antigens, Tumor Immunity

Question 1

What is the most frequent example of a bacteria involved in carcinogenesis?

Which cancers are related to this bacteria?

Answer 1

Helicobacter pylori - in stomach. Triggers inflammatory response, which atrophies mucous membrane, makes intestinal metaplasia (gastric changes to intestinal-style epithelium) that can lead to dysplasia or neoplasia (gastric adenocarcinoma)

Also causes MALT B-cell lymphoma: suppresses T-cell effect, and B-cells proliferate

Question 2

What is the one RNA virus example given that is related to cancer?

Answer 2

HTLV1 (Human T-cell lymphotropic virus type 1) - related to T cell lymphoma

Question 3

What are some DNA viruses related to oncogenesis? (4 are listed, they are the most frequent)

Answer 3

1. Epstein-Barr virus (EBV) related to nasopharyngeal carcinoma or Burkitt lymphoma
2. HPV - related to cervical and oral carcinomas
3. HHV8 - related to Kaposi’s sarcoma
4. Hepatitis B and C - related to hepatocellular cancers

Question 4

What are the 4 mechanisms that viruses can have a role in oncogenesis?

Answer 4

1. Integration of New Viral Gene - either oncogenic or inhibiting tumor suppression
2. Integration and Regulation: Viral gene upregulates oncogenes or downregulates tumor suppressors
3. Episomal: like 1 and 2, but are NOT integrated into the host genome
4. Activating Inflammatory Response: Virus kills cells and immune reaction releases lots of cytokines and ROS, plus non-infected cells proliferate to replace dead ones (Hep B and C)

Question 5

Where is Epstein-Barr virus endemic? How is it normally transmitted?

Which cancers are associated with it?

Answer 5

Endemic to places with malaria: it’s a coinfection of malaria. Endemic in Africa and many parts of Asia

In Africa: Burkitt lymphoma (a B cell lymphoma, also associated with HIV)

in Asia: Nasopharyngeal lymphoma

Question 6

What are the two oncogenic exons of Epstein Barr Virus (EBV)?

Answer 6

1. LMP1: initiates NFkB/JAK STAT pathway. Makes B cells proliferate. Also has BCL2 effect of suspending apoptosis
2. EBNA2: Has episomal effect - deregulating cyclin D1

B cell proliferate and acquire 8:14 translocation: c-Myc is upregulated (c-Myc mutation important to know in Burkitt lymphoma)

Question 7

What are the low risk serotypes of Human Papilloma Virus (HPV)?
What cancers/problems are they related to?

Answer 7

Serotypes 1, 2, 4, 7

Cause papilloma (benign epithelial tumors) aka common warts

Oncogenes are NOT integrated (episomal)

Question 8

What are the high-risk serotypes of HPV? Why are they more dangerous?

Answer 8

Serotypes 16, 18, 31

These make cancers - invasive tumors. Compared to the low risk ones, the oncogenes are not episomal but INTEGRATED

Question 9

What are the 2 important exons within the high-risk HPV serotypes?

Answer 9

E7: Makes heterodimer with retinoblastoma (RB), preventing it from making complex with E2F, and so cell proliferation is uninhibited. Also Cyclin-dependent kinase inhibitors are blocks, so cell cycle is sped up.

E6: blocks p53, so less DNA damage repair and apoptotic signals via BAX

Question 10

What is the classic example of chemical carcinogenesis, the first one that proved chemicals were related to cancer development?

Answer 10

Pott cancer: during industrial revolution, chimeny sweeps kept gettin’ the scrotal cancer. It was because the chimeny dust was getting trapped in their pubic hair.

Question 11

What are the 2 divisions of chemicals in relation to how they function as carcinogens? (hint: same idea of how to divide ionizing radiation)

Which one is more aggressive?

Answer 11

1. Direct: without modification, the chemicals cause direct DNA damage
2. Indirect: require metabolic conversion to be carcinogenic. Usually use CYP450 to make a more dangerous molecule

Indirect chemical carcinogens are more dangerous/aggressive. Both involve electrophiles that steal electrons from DNA, RNA, and proteins and disrupt them/

Question 12

What are some examples of direct chemical carcinogens?

And indirect chemical carcinogens?

Answer 12

Direct: weaker. Mostly alkylating agents, related to leukemia and lymphoma. These drugs are used in chemotherapy - may unfortunately cause a second type of cancer. Also: mustard gas, heavy metals (Beryllium, Nickel)

Indirect: polycyclic hydrocarbons, tar from smoke and burned meats.

Question 13

What is the 3 step process of chemical carcinogenesis?

Answer 13

1. Initiation: genotoxic effect on group of calls causes a cell to acquire genetic mutation
2. Promotion: there are selective pressures on the cell, and the mutated one has some advantage to help it grow
3. Progression: mutated clone has autonomous growth, independent of effects

Question 14

What are the two types of radiation? Examples of each?

radiation was also covered in topic A52

Answer 14

1. Ionizing radiation: X and γ rays, α and β particles

2. Non-ionizing radiation: UV light

Question 15

What are the 2 possible effects of ionizing radiation?

gonna skip non-ionizing because its well-covered previously

Answer 15

1. Direct: via α and β particles, causes random double-stranded DNA breaking
2. Indirect: X and γ rays interact with water, forming free radicals that damage DNA

Question 16

What is the most sensitive tissue for ionizing radiation?

What are the next most sensitive tissues?

What tissues are not sensitive?

Answer 16

Most sensitive: bone marrow. Most frequent problems are acute and chronic myeloid leukemias

Next most sensitive: breast, lung, salivary glands

Skin, bone, GI tract are not affected much

Question 17

What are the two categories of tumor antigens?

Answer 17

1. TSA: Tumor Specific Antigen. Doesn’t exist in normal tissue. May be targets for immune system to remove cancer cells. Examples: BCR-ABL protein in chronic myeloid leukemia.
2. TAA: Tumor Associated Antigen. Present in normal tissues but expressed in a different way in tumors. Not good for immunization, but may be good in diagnostics, including identifying the origin of metastases

Question 18

How might tumor antigens be recognized by the immune system? What occurs?

Answer 18

The antigen may be expressed on the cell surface via MHC-I. CD8+ T cells can then kill it, releasing antigens into the EC space. APCs can take up the fragments, then show them to Th cells who make a Th1 response via IFNγ and then stimulate macrophages to destroy those cells.

Tumor cells may also have “stress-induced antigens” which are recognized by NK cells that also are capable of eliminating them

Question 19

What is the main tumor associated antigen is used in part of the diagnosis for prostate cancer?

Answer 19

PSA: Prostate Specific Antigen. It’s normally present, but in low levels.

High levels may indicate prostate cancer, but there are many cases of false positives (e.g. prostatitis). PSA is not specific to tumor, but useful - especially for follow-up after treatment

Question 20

What is an example of a tumor associated antigen used in diagnosing testicular cancer?

Answer 20

Oncospermatogonal antigens
like MAGE1: Melanoma Antigen Gene Encoding 1 (it’s in melanoma as well as sperm)

Sperm don’t have MHC-I so they can survive in adults (immunoprotected zone) - so these antigens are associated with loss of MHC-I

Question 21

What are oncofetal antigens? An example of one?

Answer 21

Antigens that are expressed in fetus but normally downregulated later on, however they become expressed again in certain cancers. They are less able to evoke an immune response due to prior expression.

AFP (alphafetoprotein) is one

Question 22

What are two examples of virus-associated antigens that may be used as TAAs in the types of cancers associated with those viruses?
(was in earlier cards, but now with a focus on the tumor antigens)

Answer 22

EBNA2 and LMP1 in Epstein-Barr Virus

Related to nasopharyngeal carcinoma or Burkitt lymphoma

Question 23

What are some cell differentiation antigens that may be used as tumor antigens?

Answer 23

CD20 in B cells, CD3 in T cells, etc. May be used to differentiate B vs T cell lymphoma, also in targeted therapy

Question 24

What are 2 cell surface glycoproteins that can be used as tumor antigens?

Answer 24

1. MUC1: characteristic of breast cancer
2. CA125: characterstic of ovarian cancer

May be especially good for identifying the origin of metastases

Question 25

5 “tricks” for neoplastic cells to avoid immune rxn:

Answer 25

1. “Selective growth” - some neoplastic cells have antigens detected by immune system, those ones are eliminated and others survive - basically natural selection
2. Loss of MHC-I
3. Treg influence: neoplastic cells produce TGFβ -> uregulate Tregs -> inhibition of anti-tumor effects
4. Antigen masking: covers antigens with mucous or glycoproteins
5. Induce apoptosis of T cells: neoplasm produces FasL -> binding Fas induces apoptosis of T cells