Molecular Basis of Carcinogenesis I

Question 1

The phenotype of malignant or cancer cells is that the cells are

Answer 1

a. Unresponsive to normal signals for proliferation control.
b. De-differentiated, that is, lack many of the specialized structures and functions of the tissue in which they grow.
c. Invasive, that is capable of outgrowth into neighboring normal tissues to extend the boundaries of the tumor.
d. Metastatic, that is capable of shedding cells that can drift through the circulatory system and proliferate at other sites in the body.
e. Clonal in origin, that is, they are derived from a single cell.

Question 2

A benign tumor is made up of cells that are _______, but like the cancer cells _______.

Answer 2

• not invasive or metastatic

- have lost many of the growth controls and specialized functions of normal cells. They are immortalized

Question 3

For a cell to change from a normal to neoplastic state, changes in _______ must be involved. Early in life, _______ in somatic cells will produce tumors many years later. For example…

Answer 3

cellular heredity
mutagenic events
increased UV light exposure at an early age is associated with an increased incidence of melanoma

Question 4

The etiology of cancer is related to

Answer 4

the accumulation of somatic mutations produced by environmental factors. As this accumulation takes time, age is a big factor as well.

Question 5

susceptibility to cancer is _______

Answer 5

inherited

Question 6

Carcinogenesis is a multi-step process characterized by

Answer 6

the accumulation of many somatic, genetic alterations or mutations

Question 7

Tumor initiation occurs by mutations in at least two types of genes:

Answer 7

a. Oncogenes, which normally stimulate cellular proliferation (analogous to the “gas pedal” of your car), are activated.
b. Anti-oncogenes or tumor suppressors, which normally inhibit cellular proliferation (analogous to the “brake pedal” of your car), are inactivated.

Question 8

_______ and _______ may activate oncogenes or inactivate tumor suppressors. For example, chronic myelocytic leukemia (CML) is associated with the Philadelphia chromosome and also see Burkitt lymphoma.

Answer 8

Translocations and gene deletions

Question 9

Inactivation of tumor suppressors may occur by _______, which is associated with many. Some examples are retinoblastoma (RB) and APC gene in FAP (Familial Adenomatous Polyposis).

Answer 9

LOH (loss of heterozygosity)

Question 10

LOH can occur by several different ways, but the end result is the same-

Answer 10

loss of a tumor suppressor. “Knudson theory” said that two hits or events were needed to produce retinoblastoma

Question 11

Aneuploidy correlates with a _______ prognosis in many cancers.

Answer 11

poor

Question 12

Examples of cancers that are inherited as autosomal dominant disorders are:

Answer 12

• Familial Adenomatous Polyposis (FAP-APC gene)
• Familial Retinoblastoma (RB gene)
• familial Breast and Ovarian Cancer (BRCA1 and BRCA2 genes)
• Wilms tumor syndromes

Question 13

Examples of cancers that are inherited as autosomal recessive disorders are:

Answer 13

• Xeroderma pigmentosa (XP genes)
• Ataxia-telangiectasia (AT gene)
• Bloom’s syndrome
• Fanconi’s congenital aplastic anemia (FA genes)

Question 14

Inherited Retinoblastoma is

Answer 14

• a relatively rare, pediatric disorder (1/20,000 infants)

- antioncogene or a tumor suppressor gene.

Question 15

Cytogenetic analysis of cells from retinoblastomas showed that

Answer 15

the region around chromosome 13q14 often had an abnormal structure

Question 16

Retinoblastoma cells from some patients lack

Answer 16

RB completely
(Both copies of RB have been deleted as detected by genomic DNA analysis (PCR or Southern hybridization). Some patients have partial deletions or other rearrangements of RB)

Question 17

In cases of “inherited” retinoblastoma, the DNA from normal tissue of the patient or from other unaffected family members often shows

Answer 17

a defect in the retinoblastoma gene, but has one normal copy of the gene per cell.
***In these patients it appears that normal, nonmalignant retinal cells, are heterozygous for the retinoblastoma gene, but the tumor cells have descended as a clone from a single cell that has acquired homozygosity for the retinoblastoma susceptibility gene. This is the hallmark of a antioncogene or tumor suppressor gene

Question 18

The Rb protein is _______ in rapidly proliferating cells at _______ or _______ of the cell cycle, but is _______ in non-proliferating cells in _______ of _______ of the cell cycle.

Answer 18

hyperphosphorylated
S
G2
hypophosphorylated
G0
G1

Question 19

The hypophosphorylated form of the RB protein normally functions to

Answer 19

repress the entry of cells into the S phase of the cell division cycle

Question 20

When RB becomes hyperphosphorylated, it

Answer 20

no longer inhibits this transition and the cells begin a cell division cycle

Question 21

when there is no RB protein or it is all nonfunctional,

Answer 21

cells cannot down regulate their cell division and grow out of control

Question 22

Because RB is an inhibitor of cell proliferation, it is an _______ or _______

Answer 22

anti-oncogene

tumor suppressor

Question 23

Phosphorylation by CDKs (cyclin-dependent protein kinases) _______ the RB protein, thereby allowing the cell to _______

Answer 23

inactivates

proceed from G1 to the S phase of the cell cycle

Question 24

The RB protein is a target for many_______, for example, _______ and _______. These viruses drive a quiescent cell into the _______ phase of the cell cycle and to _______

Answer 24

animal tumor viruses
SV40 
HPV (human papilloma virus)
S 
proliferate by producing a viral protein(s), SV40 T antigen (T stands for transforming) or HPV E7 protein, that binds to and inactivate the RB protein

Question 25

E6 inhibits _______

Answer 25

p53

Question 26

If E7 and E6 expression is blocked,

Answer 26

the cells return to normal phenotype

Question 27

The loss of _______ by any number of events will produce a tumor.

Answer 27

the single, normal RB gene

Question 28

people who are heterozygotes for the RB gene are

Answer 28

likely to develop the disease and will pass on the defective gene to 1/2 of their children, so it appears to be autosomal dominant in its inheritance

Question 29

In reality, a cell must have a _______ RB mutation in order to become malignant, because _______

Answer 29

homozygous

both RB genes in that cell must be inactivated, if it is to grow out of control

Question 30

Sporadic cases of retinoblastoma (i.e. cases that occur without prior family history) are attributable to

Answer 30

two independent events occurring in a retinal cell. In other words, both RB genes must be inactivated as hypothesized by Knudson.

Question 31

Usually sporadic cases have _______ because the _______.

Answer 31

• unilateral retinoblastoma

- probability of two events is low and is unlikely to occur in a cell of both retinas

Question 32

Bilateral retinoblastoma occurs in _______, because _______

Answer 32

• inherited cases

- only one copy of RB needs to be inactivated

Question 33

Persons who survive inherited retinoblastoma have an increased risk for developing

Answer 33

• a second neoplasm, which is typically mesenchymal in origin (for example, osteosarcoma)
• Cells of these tumors are also defective in RB function

Question 34

Cells derived from_______ and from some _______ carry a defect in the RB gene.

Answer 34

a high frequency of small cell lung tumors

breast tumors

Question 35

In Rb -/- knockout mice, loss of RB results in

Answer 35

pituitary tumors with 100% penetrance