Lecture 7: Neoplasia I

Question 1

The Cancer problem

Answer 1

Primary tumours may be treatable by surgery, radiation and/or chemotherapy

BUT systemic disease is the cause of death

Question 2

Who gets cancer?

Answer 2

Primarily a disease of ageing

Many solid tumours develop over years (many genetic events accumulate over time)

50% of the population will receive a cancer diagnosis at some point in their life

See figure

Question 3

Points for cancer control

Answer 3

Prevention

Early diagnosis (research focus)

Therapies for primary tumor

Therapies for systemic disease (metastases)

Palliative care

Question 4

Diameter of tumour vs tumour cell population doublings

Answer 4

See figure

Question 5

Where does cancer arise

Answer 5

See figure

Question 6

How can we determine the success of cancer therapies?

Answer 6

Compare new cases to deaths per year

Question 7

Nomenclature of cancers

Answer 7

Epithelium - carcinoma (90% of human cancers)

Connective tissue - sarcoma

Hemopoietic - leukemia, lymphoma

Nervous system - glioma, neuroblastoma

Question 8

Cancer ethology: the role of genes

Answer 8

Cancer predispositions

Radiation/chemical damage of DNA

Tumours show genomic abnormalities

Cell culture and animal models of cancer

Question 9

Example of cancer predisposition

Answer 9

Association of BRCA1 and BRCA2 mutations and breast cancer in Ashkenazi Jewish women

Prostate cancer in men of african descent

Can help decide which populations should be screened for which cancers

Question 10

How does radiation and chemical damage of DNA lead to cancer?

Answer 10

Failure to repair DNA damage can lead to cancer

Question 11

What are some examples of genomic abnormalities that tumours can have?

Answer 11

Aneuploidy

Chromosomal rearrangement or loss

Question 12

How are cell culture and animal models of cancer created?

Answer 12

By altering genes that control cell cycle, cell survival and cell differentiation

Question 13

What occurs in a philadelphia chromosome?

Answer 13

DNA is damaged

Part of chromosome 22 is transferred to chromosome 9 = short 22, long 9

Question 14

Evolution and selection in cancer

Answer 14

If cell proliferation and cell death are balanced, tissue remains stable

Abnormal cells may undergo multiple rounds of replication, lose control of proliferation, create tumour

See figure

Question 15

Social control of normal cell vs cancer

Answer 15

Normal tissue: cells listen to neighbours, get info from circulating cytokines and growth factors, work to maintain consistent tissue structure.

When two normal cells touch each other, they stop proliferating

If this is not maintained (mutation) - over time this may cause multiple rounds of cell proliferation

Question 16

Genes critical for cancer

Answer 16

Normal cell cycle factors: cyclins, CDKs, retinoblastoma, MIC

Other factors (cell response to signals): Ras, APC

Molecules involved in cell death: BCL2

Question 17

Oncogenes

Answer 17

Gene that gets turned on (overactivity mutation/gain of function) to stimulate cell proliferation

Requires only single mutation event

See figure

Question 18

Tumour suppressor genes (TSG)

Answer 18

Require loss of function (under activity mutation) to cause tumour

Both copies of gene need to be wiped out to loose function completely

See figure

Question 19

How proto-oncogenes can lead to cancer:

• deletion or point mutation
• regulatory mutation
• gene amplification
• Chromosome rearrangement

Answer 19

See figure

Question 20

Examples of oncogenes

Answer 20

HER1 (EGFR) - mutated or amplified in half of gliobastomas

HER2 - mutated in 20% of breast cancers (poor prognosis)

Ras - mutated in 1/3 of human tumours

Question 21

Retinoblastoma (Rb1)

Answer 21

Tumour suppressor gene

Important in regulating cell cycle. Rb mutations cause proliferation to be out of control

See figure

Question 22

Examples of TSG

Answer 22

P53 - most common defect in human tumours (integrity of DNA)

Rb1 - lost in both sporadic and hereditary forms

PTEN - phosphatase that regulates intracellular singling (PI3K and Akt), lost in prostate cancer

Question 23

What are stability genes? Examples?

Answer 23

Involved in maintaining genome stability

DNA repair enzymes

Recognizing errors, UV damage

ex: BRCA1, BRCA2

Question 24

Model of colon carcinogenesis

Answer 24

Apc - associated with polyps on colon

Question 25

Environmental influences on cancer etiology

Answer 25

Rates of cancer around the world are different (due to environment, diet, genetics, exposures)

Cancer rates change in a population when they migrate, so it is more than genetics

Question 26

Known associations - exposures and cancers

Answer 26

Tobacco smoke - lung + others

Formaldehyde - nasopharyngeal, leukemia

Radon gas - lung

UV radiation - skin cancer (melanoma)

Asbestos - mesothelioma

Radioactive fallout - bone marrow, thyroid

Question 27

Suspected associations with cancer

Answer 27

Diet

Alcohol consumption

Question 28

Viruses and human cancer

Answer 28

see fig

Question 29

How do DNA viruses cause cancer?

Answer 29

Capture cell cycle control. Instead of switching on replication of their own genome, they cause consistent proliferation of the host genome

In HPV, viral proteins bind to RB, causing uncontrolled cell proliferation -> hyperplasia

Viral proteins bind fo p53 causing failure to repair DNA damage -> genomic instability

Question 30

Characteristics of cancer cells

Answer 30

Disregard the external and internal signals that regulate cell proliferation.

Avoid suicide by apoptosis (enhanced survival).

Circumvent programmed limitations to proliferation, escaping senescence and avoiding terminal differentiation.

Genetically unstable (amplification each cycle)

Disregard signals for tissue homeostasis and become locally invasive
(proteolysis).

Survive and proliferate in foreign sites (metastasis - requires expression of different genes in order to get out of original tissue)

May develop capacity to pump out drugs (MDR1).

Altered metabolism in response to hypoxia (continue to metabolize and proliferate)

Question 31

Tumor angiogenesis

Answer 31

Tumors more tha na few mm in size require blood supply

Tumors release factors that direct new blood vessel formation toward tumor (VEGF)

Question 32

what it Metastasis

Answer 32

Tumor cells shed from primary tumor may‘seed’ other regional tissues

[eg. Ovarian cancer in abdominal cavity]

Tumor cells may enter lymphatic system and populate regional lymph nodes

[eg. prostate cancer metastases in pelvic lymph nodes]

Tumor cells may enter blood vessels and exit at
another organ to re-establish tumor [eg. colorectal cancer metastatic to liver]

see figure

Question 33

What are examples of cancer critical pathways

Answer 33

cell-cell communication

regulated cell proliferation

cell differentiation

cell death

cell movement

and cell adhesion

Question 34

p53 role

Answer 34

Under normal circumstances, p53 is at low levels in the body

When there Is damage to DNA, the rate of degradation of p53 slows down, and p53 accumulates.

This drives the cell to either commit suicide (apoptosis) or bar the cell from dividing until it is repaired.

So, p53 plays a protective role.