Lab 10 - Oncogenesis 1

Question 1

Oncogenetic transformation/Carcinogenesis- Definition and what does it results from?

Answer 1

The way a physiological cell changes into a cancerous cell

Result from the action of one or a combination of chemical, physical, biologic and/ or genetic insults to cells.

Question 2

Stages of Carcinogenesis

Answer 2

1) Initiation
2) Promotion
3) Transformation
4) Progression

Question 3

Initiation

Answer 3

Exposure of cells to appropriate doses of carcinogens, either by environmental factors or due to hereditary traits.

Results from an irreversible genetic alteration, most likely one or more simple mutations, transversions, transitions, and/or small deletions in DNA.

Question 4

Promotion

Answer 4

Reversible stage, does not involve changes in the structure of DNA but rather in the expression of the genome mediated through promoter-receptor interactions

Question 5

Transformation

Answer 5

Conversion stage when it’s transformed to malignant cells

Question 6

Progression

Answer 6

Irreversible stage characterized by karyotypic instability and malignant growth.

Angiogenesis
Metastasis

Question 7

Angiogenesis

Answer 7

Formation of new blood vessels. Stimulates growth, induce malignancy and induce metastasis

Question 8

Metastasis

Answer 8

Is a pathogenic agent’s spread from a primary site to a secondary site within the host body.

Question 9

Two phases of metastasis:

Answer 9

1. Invasion and growth: invades the extracellular matrix:
   - Detachment of tumor cells from each other
   - Degradation of ECM and basement membrane
   - Attachment of tumor cells to matrix components
   - Migration of tumor cells/locomotion/intravasation
2. Spread, dissemination, metastasis
   - lymphatic spread
   - Diret seeding of body cavities and surfaces
   - Hematogenous spread
   - CSF spread

Question 10

Molecular targets during the stages of oncogenesis include

Answer 10

Protooncogenes
Cellular oncogenes
Tumor suppressor genes

Question 11

5 Cancer cell characteristics

Answer 11

1. Evasion of apoptosis
2. Limitless replicative potential
3. Sustained angiogenesis
4. Ability to invade and metastasize
5. They are tumorgenic

Question 12

Warburg effect

Answer 12

Cancer cells obtain their energy through aerobic glycolysis and not oxidative phosphorylation

Question 13

Does cancer cells induce autophagy?

Definition of autophagy

Answer 13

No

A process where the cell itself stops their own growth and cannibalizes their own organelles and membranes due to severe nutrient deficiency

Question 14

What does the cancer cells do with the normal stromal cells

Answer 14

The cancer secretes signal proteins and proteolytic enzymes that alter the stromal structure. The stroma then secretes signal proteins that stimulate cancel cell growth and division. The stroma also secretes proteases that remodel the ECM in favour of the tumor

Question 15

Cancer cells show mutations in genes that are important for

Answer 15

Mismatch repair
Nucleotide excision repair
Base excision repair

Question 16

Maintence of which enzyme is one of the most important characteristics for cancer cells?

Answer 16

Telomerase

Question 17

Cancer cells can elongate telomeres in two ways

Answer 17

1. Telomerase: is an enzyme that uses RNA as a template to restore the telomeres
2. Alternative lengthening of telomeres: elongates the telomeres by DNA recombination

Question 18

Tumors are describes by terms derived from

Answer 18

Appearance of the neoplasm, tissue of origin and degree of differentiation

Question 19

Classification of tumors according to biological properties

Answer 19

Benign, malignant, locally malignant/ semimalignant.

Question 20

Oma, carcinoma and sarcoma - suffix

Answer 20

Oma: benign
Carcinoma: malignant of epithelial or glandular origin, most common. Sarcoma: malignant of mesenchymal origin (connective tissue)

Question 21

Lipo, Leiomyo, rhabdomyo, osteo, chondro, adeno, cholangio – prefix

Answer 21

Lipo: adipose tissue 
Leiomyo: smooth muscle 
Rhabdomyo: striated muscle 
Osteo: bone
Chondro: cartilage
Adeno: glandular 
Cholangio: bile duct.

Question 22

Classification of tumors by grade

Answer 22

Increasing abnormality to respect for the surrounding tissues increases the grade.

Question 23

Classification of tumors by stage

Answer 23

Staging is a way of describing or classifying a cancer based on the extent of cancer in the body. Based on size and metastasis, from where it started and where it spread to. Ex: TNM staging.

Question 24

TNM stands for

Answer 24

T: size of primary tumor
N: lymph nodes involved
M: metastasis.

Question 25

Benign vs malignant tumor

Answer 25

Cancerous: Benign tumor is not cancerous while malignant is cancerous. Growth rate: Benign has slow, malignant has fast growth. Recurrence: Benign tumors is less likely to recur while malignant are more likely. Protective sac: Benign tumors is surrounded by a protective sac that restricts its growth and makes it easier to remove, malignant tumors does not have this sac. Treatment: Benign tumors respond well to treatment and prognosis is favourable. Invasive: Benign tumors are non-invasive while malignant are invasive. Benign tumors can be serious if they are pressing a primary nerve, main artery or compress brain matter. Metastasize: Malignant tumors can multiply uncontrollably, metastasize and invade surrounding tissue, this is not happening with benign tumors. Malignant tumors are formed from abnormal cells that are highly unstable and travel via the blood stream, circulatory system and lymphatic system.

Question 26

Apoptosis- Definition and why it happens

Answer 26

Programmed cell death (death of damaged cells). When a cell becomes mutated and does not repair itself, it can be sacrificed to prevent that mutation from being passed on to the next generation of cells. Causes cell to shrink, develop belbs, undergoes degradation of genetic and protein materials in the nucleus, and have their mitochondria breakdown, thus releasing cytochromes.

Question 27

What happens if DNA repair fails?

Answer 27

P53 protein activated the transcription of pro-apoptotic genes like BAX and PUMA

Question 28

What genes are activated when the amount of pro-apoptotic proteins outweight the amount of anti-apoptosis?

Answer 28

BAX and BAK

Question 29

Role of BAX

Answer 29

Punches holes in the mitochondrial membrane, which makes the mitochondria leak cytochrome c which leads to a series of events that initiate the apoptosis.

Question 30

Loss of p53 function leads to what?

Answer 30

DNA damage goes unrepaired, mutations accumulate in oncogenes and other cancer genes, and the cell goes in a path leading to malignant transformation.

Question 31

Necrosis- Definition and Cause

Answer 31

Premature death of cells and living tissue. Caused by factors external to the cell or tissue, such as infection, toxins or trauma. Cells may swell or forms vacuoles on their surface, with interior structures either distending or shrinking rapidly, destroying the cell’s process and chemical structures.

Question 32

Unregulated release of cytochrome and cell membrane’s phospholipid during necrosis causes what?

Answer 32

Immediate reactions in surrounding tissue, leading to swelling (inflammation) and edema.

Question 33

Macrophage-cleaning occurs in apoptosis or necrosis?

Answer 33

Apoptosis

Question 34

Where does oncogenes originate from?

Answer 34

Proto-oncogenes, which are genes involved in the four basic regulators of normal cell growth: Growth factors, growth factor receptors, signal transduction molecules and nuclear transcription factors

Question 35

When mutation occurs in proto-oncogenes

Answer 35

It can become an oncogenes, a gene whose excessively product can lead to unregulated cell growth and differentiation

Question 36

How are the oncogenes activated?

Answer 36

Typically by gain-of-function mutation, gene amplification (increased number of genes), hypomethylation of oncogene’s 5’ region (increases transcription), or chromosome rearrangements that upregulate the oncogene

Question 37

Oncogenes are typically found in which tumors?

Answer 37

Sporadic tumors

Question 38

Most oncogenes induce growth through the

Answer 38

Receptor tyrosine kinase pathway

Question 39

Less common pathways for oncogenes growth

Answer 39

WNT pathway Notch pathway JAK/STAT pathway

Question 40

Tumor suppressor gene

Answer 40

Is a gene that protects a cell from one step on the path to cancer. When this gene mutates to cause a loss or reduction in its function, the cell can progress to cancer, usually in combination with other genetic changes.

Question 41

Categorization of tumor suppressor genes

Answer 41

1. Inhibitors of mitogenic signaling pathways 2. Inhibitors of cell cycle progression 3. DNA repair factors 4. Inhibitors of "pro-growth" programs of metabolism and angiogenesis 5. Inhibitors of invasion and metastasis 6. Enablers of genomic stability

Question 42

Inhibitors of mitogenic signaling pathways

Answer 42

NF1 (neurofibromin-1): neurofibromatosis type 1, neuroblastoma, juvenile myeloid leukemia NF2: neurofibromatosis type 2, schwannoma, meningioma APC (adenomatous polyposis coli protein): carcinoma of the stomach, colon and pancreas

Question 43

Inhibitors of cell cycle progression

Answer 43

CDKN2A: INK4A and ARF: melanoma and different carcinomas RB (retinoblastoma protein): retinoblastoma

Question 44

DNA repair factors

Answer 44

BRCA1 and 2: breast and ovarian cancers MSH2 and 6, and MLH1: colon carcinoma

Question 45

Inhibitors of "pro-growth" programs of metabolism and angiogenesis

Answer 45

VHL: von vippel lindau protein

Question 46

Inhibitors of invasion and metastasis

Answer 46

CDH1: E-cadherin: gastric carcinoma and lobular breast carcinoma

Question 47

Enablers of genomic stability

Answer 47

TP53: p53 protein: Li-Fraumeni syndrome and most human cancers

Question 48

Function of microRNA

Answer 48

Inhibit RNA and protein-coding RNA molecules themselves. Regulate cellular processes; cellular proliferation, differentiation and survival. Some function as tumor suppressor genes (Let-7), while others function as oncogenes (Mi-372 and mi-373).

Question 49

How does the tumor cells affect miRNA?

Answer 49

They exhibit dramatic changes in miRNA expression. Loss/silencing or overexpression of miRNA is observes in many tumors. May therefore promote abnormal tumor cell survival.

Question 50

Angiogenesis is controlled by a balance between what?

Answer 50

Angiogenesis promoters and inhibitors.

Question 51

Angiogenesis promoters:

Answer 51

Basic fibroblast growth factors (bFGFs), VEGFs, proteases

Question 52

Angiogenesis inhibitors:

Answer 52

angiostatin and endostatin

Question 53

Angiogenic switch:

Answer 53

Increased production of angiogenic promoters and/or loss of angiogenic inhibitors

Question 54

Angiogenic switch activated by:

Answer 54

Lack of oxygen, mutations in TSGs or oncogenes, gain-of-function mutations in RAS or MYC (RAS-MAP kinase pathway).

Question 55

What are the effects of angiogenic switch on the tumor?

Answer 55

1) Stimulate growth: delivery of nutrients induces the secretion of growth factors by endothelial cells, IGFs and PDGFs. 2) Induce malignancy: newly synthesized blood vessels have an irregular pattern of connection --> irregular blood flow within the tumor, hypoxia in several areas within the tumor, areas of hypoxia favours the growth of mutant cancer cells seeing as they are more suitable to survive under harsh conditions. 3) Induce metastasis: tumors have access to the circulatory system and are able to metastasize.

Question 56

What leads to permanent inactivation of tumor suppressor genes?

Answer 56

Loss-of-function mutation in RB1, deletion of the gene, hypermethylation of it's 5' region