Molecular and Cellular Concepts of Oncology

Question 1

hallmarks of cancer (+ 2 new hallmarks and emerging factors)

Answer 1

• sustained proliferative signaling
• evading growth suppressors
• invasion and metastasis
• enabling replicative immortality
• angiogenesis (new blood vessel formation)
• resisting cell death

new 2 hallmarks (2011):

• deregulating cell energetics
• avoid immune destruction

2 emerging factors:

• tumor-promoting inflammation
• genome instability and mutations

Question 2

Why do skin cancer and lung cancer contain the most genetic mutations?

Answer 2

skin and lungs are exposed to the most CARCINOGENS–UV and air are the major causative factors

Question 3

cancers and mutations

Answer 3

• MULTIPLE genetic mutations are needed for cancer to develop
• different cancer requires DIFFERENT numbers of gene mutations (ex- lung cancer has different mutations than pancreatic cancer)
• the same cancer in different people may have different mutations in different sets of genes

mutations in both TUMOR SUPPRESSOR GENES and PROTO-ONCOGENES are needed for cancer to develop

Question 4

driver genes and rider genes

Answer 4

drivers: gene mutations at a given stage of oncogenesis that are the MOST IMPORTANT for oncogenesis to PROCEED
riders: gene mutations that play a MINOR role or NO role in oncogenesis at that stage

drivers and riders are different at different stages of oncogenesis

most effective anticancer THERAPIES are those that target DRIVERS

Question 5

development and metastasis of human colorectal cancer

Answer 5

1. loss of APC tumor suppressor gene
   - -> polyp forms on colon wall and benign precancerous tumor grows
2. activation of K-ras oncogene
   - -> class II adenoma (benign) grows
3. loss of DCC tumor suppressor gene
   - -> class III adenoma (benign) grows
4. loss of p53 tumor suppressor gene
   - -> malignant carcinoma develops
5. other changes in genes whose products are involved in assisting metastasis
   - -> cancer metastasizes

Question 6

cancer stem cell hypothesis

Answer 6

tumors originate from the transformation of normal stem cells

Question 7

cancer stem cells

Answer 7

• responsible for most of the cancer growth, metastasis, and drug resistance
• different cancers have different cancer stem cells
• different cancers have different percentages of cancer stem cells
• cancer stem cells may be a new target in cancer therapy

Question 8

clonal evolution model

Answer 8

tumor cells are heterogeneous, but most can proliferate extensively and form new tumors

Question 9

cancer stem cell model

Answer 9

tumor cells are heterogeneous and ONLY the cancer stem cell has the ability to proliferate extensively and form new tumors

Question 10

proto-oncogenes vs oncogenes

Answer 10

proto-oncogenes: NORMAL cell genes that encode proteins involved in various aspects of CELL GROWTH

oncogene: CANCER-PRODUCING genes that are derived from proto-oncogenes by various types of genetic MUTATIONS

a proto-oncogene can become an oncogene by mutations in regulatory sequence (promoter), coding sequence (gene), chromosomal translocation, or gene amplification

**both are growth promoting genes (tumor suppressor genes are growth-suppressing genes)

Question 11

7 types of proteins that participate in cell growth

Answer 11

1. growth factors
2. growth factor receptors
3. intracellular transducers
4. transcription factors
5. pro- or anti-apoptosis proteins
6. cell cycle control proteins
7. DNA-repair proteins

mutations in these can lead to cancer

Question 12

growth factors

Answer 12

normal growth factors become oncogenic when they are OVER-EXPRESSED by:

• mutation in promotor of proto-oncogene
• chromosomal translocation of proto-oncogene
• retroviral insertion into a regulatory sequence of a proto-oncogene

Question 13

growth factor receptors

Answer 13

usually tyrosine kinase receptors (Her2, EGF)
–> many new anticancer drugs target tyrosine kinases

• normally activated when they are dimerized (when growth factor binds)
• when there is a MUTATION in the transmembrane domain of the protein, they can become dimerized (without growth factor) binding and will be constitutively active

Question 14

growth signal transducers (ex: Ras)

Answer 14

normally, Ras can be active or inactive depending on the cell’s needs

when Ras is MUTATED, (usually at position 12 or 61) it can become constitutively active, transducing cell growth signal all the time –> leads to cancer development

Question 15

transcription factors

Answer 15

one of the earliest effects of growth factors is to induce transcription of c-fos and c-myc proto-oncogenes

activities are tightly controlled in normal cells and they aren’t active for long–in some cancer cells, Fos and Myc are constitutively active, causing over expression of genes involved in cell growth

Question 16

philadelphia chromosome

Answer 16

in CML
chromosome translocation
generated by the fusion of ch9 and ch22, which generates a fusion gene of bcr/abl
–> becomes constitutively active and causes cell proliferation, and ultimately leukemia

Question 17

tumor suppressor genes

Answer 17

“anti-oncogene”
-gene that protects a cell from becoming cancerous
-when mutated, the cell can progress to cancer
ex- Rb gene–when mutated, children can develop retinoblastoma early in life

Question 18

two-hit origin of cancer

Answer 18

proposed by Dr. Knudson

some forms of hereditary cancer might be initiated when a cell in a person HETEROZYGOUS for a germ line mutation undergoes a second mutation in the OTHER allele for the SAME gene, thus rendering the cell HOMOZYGOUS for loss of function mutations in tumor suppressing gene

applies only to TUMOR SUPPRESSOR GENES, not oncogenes
applies to the SAME tumor suppressor gene, not two different tumor suppressor genes

Question 19

p53

Answer 19

tumor suppressor, transcription factor

involved in DNA damage repair, cell cycle checkpoint control, and apoptosis

most important gene in HUMAN CANCER

“guardian of the human genome”

Question 20

oncogene vs tumor suppressor gene

Answer 20

oncogene-
normal function: cell growth
mutation consequence: GAIN of function
–dominant mutation

tumor suppressor gene-
normal function: cell growth-depressing
mutation consequence: LOSS of function
–recessive, but classified as dominant

Question 21

telomere and telomerase

Answer 21

telomere: region of repetitive DNA at the end of a chromosome, which protects the end of the chromosome from destruction

telomeres are SHORTENED during cell division and replenished by TELOMERASE

as the telomeres grow shorter, the cells eventually reach the limit of their replicative capacity and progress into senescence (blocks cell division)
–> prevents genomic instability and development of cancer by limiting the number of cell divisions

• cancer cells have long telomeres that don’t shorten and can replicate forever

Question 22

two key reasons that cancer cells are immortalized

Answer 22

cancer cells’ telomerase activity is HIGHER and the telomeres are LONGER

Question 23

RNA and DNA viruses as cancer-producing agents

Answer 23

• both RNA and DNA viruses can carry oncogenes
• both RNA and DNA viruses can induce cancer in animals and human
• oncogenes carried by RNA viruses do not have functions in the viral replication cycle, BUT oncogenes carried by DNA viruses do participate in the replication of viral hosts
• -> RNA oncogenes aren’t an intrinsic component of RNA viral genome, while DNA oncogenes are an intrinsic component of DNA virus genome

Question 24

cooperativity of oncogenes

Answer 24

one mutation leads to faster second mutation

once first and second mutations occur, subsequent mutations occur at faster and faster pace

“oncogenes work together to accelerate oncogenic process”

Question 25

How many mutations are needed for developing cancer?

Answer 25

MULTIPLE

occurrence rates for all cancers get higher over age, indicating that multiple mutations are needed for getting cancer

Question 26

targeting “regular cancer cells” vs cancer stem cells in treatment

Answer 26

previously don’t know about the cancer stem cells, so treatments focus on killing regular cancer cells–tumor initially shrinks, but the tumor comes back because the cancer stem cells are resistant to the drugs