MOD 21 - Carcinogenesis: molecular hallmarks of cancer cells

Question 1

what are the 2 key concepts for carcinogenesis?

Answer 1

oncogenes activation & tumour suppressor gene inactivation

Question 2

what are caretaker genes

Answer 2

maintain genetic stability by repairing damaged DNA and replication errors

Question 3

what happens to mutated caretaker genes

Answer 3

cause genomic instability - which enable specific genetic alterations to accumulate in carcinogenesis

Question 4

what is the real name of caretaker genes

Answer 4

tumour suppressor genes

Question 5

what are the different subtypes of tumour suppressor genes

Answer 5

gatekeepers & caretakers

Question 6

what does gatekeeprs do?

Answer 6

regulating normal growth

-ve regulators for cell cycle and proliferation, +ve regulator of apoptosis & cell differentiation

Question 7

what does caretakers do?

Answer 7

maintain genetic stability

• DNA repaire genes
• controlling accuracy of mitosis

Question 8

what is 2 hit theory?

Answer 8

inactivation of a TSG requires 2 mutations on each copy of the chromosome - first hit is normally a point mutation

Question 9

who will already have the first hit of the 2 hit theory

Answer 9

ppl with FH ie familial cancer syndromes

Question 10

what is proto-oncogenes

Answer 10

potential oncogenes which requires only a few mutation to become oncogenes

Question 11

what can proto-oncogenes do?

Answer 11

promote cell proliferation, survival, angiogenesis and negative regulation of apoptosis

Question 12

what can mutation of the oncogenes lead to?

Answer 12

activated versions of increased expression of proto-oncogenes - gain of function

Question 13

how many copies of mutated oncogenes is required to cause damage

Answer 13

only one copy - mutated genes is dominant to other normal parental gene`

Question 14

what are the 3 different mechanisms which can activate oncogenes

Answer 14

translocation of a proto-oncogenes (from a low transciptionally active site to a higher active sites - aberrant expresison of oncogenes

point mutation - cause hyperactive of the a.acid

ampllification - insert of multiple copies of oncogenes

Question 15

what does tumorigenesis involve

Answer 15

multi-step process - involves activation of oncogenes and inactivation of TSG

Question 16

what are the hallmarks of cancer cells

Answer 16

self-sufficency in growth signals, insensitivity to antigrowth signals, tissue invasion and metastasis, limitless potential for replication, sustained angiogenesis, evading apoptosis

Question 17

how can cancer cells achieve independences in acquiring growth factors

Answer 17

by modifying growth factor receptors and cause them to be over-expressed and activated.

Question 18

how can cancer cells achieve resistance to -ve growth factor?

Answer 18

retinoblastoma protein (RB) is important regulator as it is inhibited progression of cell cycle and the -ve GF activate the Rb protein and so it will prevent cell cycle

tumour cells will inactivat RB gene and so resistance to -ve growth factors

Question 19

how come cells have finite replicative lifespan

Answer 19

Due to shortening of chromosome ends (telomeres) after each cell division

Question 20

what is telomeres

Answer 20

act to prevent end to end fusion of chromosomal DNA molecules

Question 21

what is telomeres consist of

Answer 21

TTAGG - hexanucleotide sequence repeated thousand times

Question 22

what happens when the hexanucleotides run out?

Answer 22

Eventually the ends of the chromosomes become exposed and are able to fuse with each other resulting in karyotypic chaos, which usually triggers apoptosis

Question 23

can telomere be regenerated ?

Answer 23

Telomere regeneration can be accomplished by an enzyme called telomerase

Question 24

how can tumour cells achieve immortality

Answer 24

Rapidly proliferating tumour cells can overexpress the telomerase enzyme to maintain normal telomere length

Question 25

what genes involved in apoptosis?

Answer 25

TP53

Question 26

what does P53 do?

Answer 26

induces cell cycle arrest stoping the advancement of cell cycle allowing repair of DNA damage

apoptosis if too much damage

Question 27

how can tumour cells achieve resistance to apoptosis?

Answer 27

TP53 inactivation - lead to loss of apoptotic response

Question 28

when does tumour requires its own blood supply

Answer 28

tumours greater than 2 mm in diameter

Question 29

how does tumour cells achieve angiogenesis?

Answer 29

hypoxia stabilise HIF-1 tanscription factor which induces vascular endothelial growth factor (VEGF) ie recruit endothelial cells that proceed to construct new capillaries and vessels

Question 30

how is epithelial cells held tightly together

Answer 30

by adhesion molecule E-cadherin - many tumours how loss of this

Question 31

how does process of invading and metastasis take place

Answer 31

Epithelial cells are held tightly together by adhesion molecule E-cadherin

Many tumours show loss of E-cadherin through mutation/hypermethylation of the gene

Results in epithelial-mesenchymal transition (EMT)

Mesenchymal cells are motile and secrete proteases - allows them to break through basement membrane and invade the underlying stroma

Metastasis involves the spread of malignant cells via the blood/lymphatic system to secondary sites and the formation of secondary tumours