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BI407 Tumor Biology > Lec 1 to 5 > Flashcards

Lec 1 to 5 Flashcards

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1
Q

what is a tumor and another word for it

A

aka neoplasm, a group of cells which display unregulated proliferation

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2
Q

what are the properties of a benign tumor

A

clustered in a single mass, not capable of indefinite growth and not able to invade healthy surrounding tissue

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3
Q

what are the properties of a malignant/cancerous tumor

A

a tumor that continues to grow and becomes progressively more invasive

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4
Q

what is metastasis

A

the ability of a malignant tumor to form tumors (metastases) at other sites, occurs when cancerous tumor cells dislodge from the primary tumor and invade the blood and lymphatic systems to then relocate to a different area in the body and create a new tumor at this site

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5
Q

what are the majority of cancers called, arise from, and what percentage

A

80-90% of all cancers arise from epithelial tissue (skin, gut, epithelial lining of organ and glands), they are called carcinomas (prostate, lung, breast, colon, stomach, skin, liver, ovary, etc)

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6
Q

what are the non-epithelial cancers, arise from, and what percentage are they

A

9%, blood cancers (leukaemia, lymphoma, multiple myeloma), arise from hematopoietic cells derived from bone marrow

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7
Q

what is unique about lymphoma

A

begins as blood cancer but can give rise to solid cancer

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8
Q

are there sex differences in cancers

A

yes, one sex can be more susceptible to a type of cancer or better survival rates

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9
Q

what is the smallest percentage type of cancers

A

sarcomas, 1%, arise from mesenchymal cell types (osteoblasts - bone-forming cell form osteosarcoma, adipocyte - fat cell form liposarcoma, fibroblasts - connective tissue cell form fibrosarcoma

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10
Q

what are oncogenes

A

activated versions of normal cellular genes, involved in cell-growth promoting processes, usually ‘gain-of-function’ mutations and generally dominant

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11
Q

what are tumor suppressor genes

A

genes that when they fail to work properly allow cancer cells to survive, usually ‘loss-of-function’ mutations and generally recessive

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12
Q

what is apoptosis

A

process of natural cell death, when not working correctly leads to abnormal cell survival (aids cancer growth through cancer cell survival)

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13
Q

can 1 mutation cause cancer

A

1 oncogene mutation cant cause cancer, cancer is caused by a collaboration of oncogene mutations supported by inactivated tumor suppressor genes

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14
Q

what is the function of proto-oncogenes and some examples

A

proto-oncogenes are normal cellular genes, they generally encode elements of the cell’s signal transduction network and parts of the cell cycle control system, eg. growth factors, growth factor receptors, signal transduction molecules (proteins involved in signalling), nuclear proteins (transcription factors)

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15
Q

what can oncogenes become activated by

A

genetic mutations, chromosomal translocations, gene amplification, epigenetic factors, increased protein stability (deregulated upstream signalling or processing pathway)

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16
Q

what are the different methods of conversion of proto-oncogenes to oncogenes

A

point mutation leads to constitutively active or increased activity, gene amplification leads to normal protein overproduced, chromosomal rearrangement leads to nearness to strong enhancer causes increased protein expression they all lead to excessive growth aka cancer

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17
Q

example of a point mutation causing cancer

A

point mutation in H-ras gene in bladder carcinoma mutational event caused glycine to valine change in the H-ras protein which changed the structure of the protein and subsequently affected its functioning which led to constitutive Ras activity (Ras is located downstream of many growth factor signalling pathways including HER2 and EGFR

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18
Q

example of gene amplification causing cancer

A

HER2 is amplified in some breast cancers which often lead to increased expression levels of HER2 protein (HER2 positive breast cancer), FISH analysis method is used

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19
Q

example of chromosomal translocation causing cancer

A

Burkitt’s lymphoma (B cell cancer common to Africa), 3 alternative reciprocal chromosomal translocations are found involving the heavy or light chains on chromosomes 8, 14, 2 and 22 , the c-myc gene is located on chromosome 8 and due to the translocation events it is placed under control of a highly active transcriptional regulator which leads to overproduction of c-myc

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20
Q

are tumours the result of a change in DNA sequence and support your answer

A

yes usually, generally cancers arise due to genetic (DNA sequence) or epigenetic (acute leukaemia - hypermethylation of p15 and p16 genes) alterations in 3 types of genes: oncogenes, tumour suppressor genes, and caretaker genes (DNA repair genes)

evidence of this is that cells in a tumour usually share the same DNA abnormalities, and because there is correlation between mutagenesis (initiate changes in DNA sequence) and carcinogenesis (cancer formation)

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21
Q

are tumours derived from a single abnormal cell and give evidential examples

A

evidence suggests they are derived from a single abnormal cell
examples are: karyotyping/DNA analysis, and X chromosome inactivation

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22
Q

what is the multistep nature of cancer

A

the tendency of untreated tumours to develop from benign or small to malignant, large tumours over time
it states that an activating mutation on a single oncogene is not sufficient to cause cancer and oncogenes instead must collaborate with one another and with inactivation tumor supressors to generate cancer, chromsomal alterations can be seen in precancerous cells and will likely develop into cancerous cells with time

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23
Q

what is the evidence and examples of the multistep nature of cancer

A

during lag phase tumor cells are undergoing a succession of changes (multiple genetic/epigenetic changes)
examples are radiation exposure takes 8 following years to develop into leukaemia and tobacco smoke takes 20 following years to develop into lung cancer

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24
Q

describe the cumulative damage model

A

involves both cancer and age taking time for malignant tumors to develop, states that tumors arise from a population of abnormal cells derived from a single mutant ancestor acted upon by mutation and selection

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25
Q

what cancer is an example of the cumulative damage model

A

human colon cancer where small benign tumors (adenomas) develop in the colorectal epithelium, gene changes such as inactivation of tumor suppressors (particularly p53 in this cancer) and activation of oncogenes cause the adenomas to grow/disorganise thus becoming malignant/cancerous

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26
Q

what percentage of cancers (or cancer susceptibility) are caused by inherited gene defects and some examples of the inherited gene defects

A

5-10%, Rb tumor suppressor defect-retinablastoma (childhood eye cancer), p53 TS defect- Li-fraumeni syndrome (children and adolescents more likely to develop a range of cancers eg. brain, breast, leukaemia), BRCA1 and 2 defect- more likely to develop breast and/or ovarian cancer, APC (adenomatous polyposis coli) defect/mutation- develop inherited pre-cancerous polyps leading to colon cancer

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27
Q

what causes retinablastoma, give details about its two forms

A

tumour of the neural precursor cells in retina RB1 gene on chromosome 13q14
two forms are familial and sporadic: familial is hereditary, involves multiple tumours, affects both eyes, is early onset, individuals are at 6 times more likely risk of developing different types of cancer such as bone cancer (osteosarcoma), even after treatment (removal of eye/s and radiation) individual is likely still going to develop more cancer(s)
sporadic is not hereditary, later onset, affects only one eye, involves just a single tumour, and after removal of the affected eye and treatment if required the individual can usually live a normal life

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28
Q

what causes cancer

A

multifactorial cause, complex genetic basis with environmental triggers (10% infectious agents)

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29
Q

what are causes of lung cancer

A

radon gas, smoking (tobacco)

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30
Q

what can be a cause of colon cancer

A

diet/obesity,

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31
Q

what can be a cause of breast cancer

A

reproductive history, women who have had child(ren) are at less risk for developing breast (and ovarian) cancer

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32
Q

what can be a cause of melanoma skin cancer

A

UV exposure, there are non-melanoma skin cancers that are less invasive and easier to remove and treat

33
Q

what are causes of Li-fraumeni syndrome and retinablastoma

A

genetic background (genetic defects and/or mutations)

34
Q

what are some viruses and infectious agents that can cause cancers

A

HPV - cervical cancer, Hep C - liver cancer, H. pylori - gastric (stomach) cancer and gastric MALT lymphoma (many people have this pathogen for years without knowing as it requires a scope to be diagnosed, after diagnosis it can be easily treated with a month(s) course of antibiotics but as it more often goes untreated it has time to develop into bad outcome stomach cancer)

35
Q

in the cell division cycle what is in charge of the decision to divide

A

external and internal factors such as growth factors that give a GO signal or detection of DNA damage which stalls this GO signal (STOP and Repair) until the DNA has recovered (in cancer cases DNA damage is not detected hence the GO signal is not monitored and uncontrolled cell division and tumor growth occurs)

36
Q

what is the order of the cell cycle

A

interphase, prophase, prometaphase, metaphase, anaphase, telophase

37
Q

what phases does interphase include and what do they involve

A

G1 (first gap phase, decisions about growth vs quiescence/dormancy) , S phase (synthesis, period of DNA synthesis), G2 (second gap phase, is all the DNA replicated with fidelity/accuracy)

38
Q

what is the M phase

A

division of the genetic material into two new cells, mitosis (involving prophase, prometaphase, metaphase, anaphase, and telophase) and cytokinesis

39
Q

what is the G0 phase

A

resting, non-proliferating phase, reversible state of cells that have withdrawn from the active cell cycle - cells can remain on G0 phase for days or even years, involves reduced levels of growth, protein synthesis, and CDKs, and no G1 cyclins

40
Q

how is cell division controlled

A

by control points/checkpoints in the cell cycle where progression through the cycle can be halted, checkpoints must have two important features which are to allow internal feedback control and to allow control from external stimuli/cues

41
Q

what are the cell cycle checkpoints

A

G1/S phase checkpoint checks is the cell ready for cell division/can DNA synthesis begin, key regulators are RB and p53, checks for sufficient nutrients and absence of DNA damage
Intra S and G2/M checkpoint responds to DNA damage and prevents the replication of damaged DNA until it is repaired, if repair is not possible the cell permanently exits from replication or is killed
Spindle checkpoint checks if all chromosomes are aligned correctly to the spindle, if they are the cell does not proceed to anaphase

42
Q

what is the result of faulty checkpoints

A

genetic instability as damaged DNA is allowed to propagate/replicate

43
Q

what is the R (restriction point)

A

early/mid G1 phase is responsive to growth factors and inhibitory signals up until R restriction point, after the cell passes R growth factors no longer influence and the cell either progressed to S phase, where it will encounter further checkpoints, or enters G0 resting phase, many cancers shoe deregulation of the R-point decision making machinery

44
Q

what two interacting families of proteins is the cell cycle control system based

A

Cyclin Dependent Kinases (CDKs) and Cyclins
CDKs are serine/threonine kinases that depend on associated regulatory subunits (cyclin proteins), to function
Cyclins, associated with CDKs, activate the catalytic activity of their CDK partners

45
Q

comment on the concentration levels of CDKs and Cyclins

A

CDK concentration levels stay relatively constant throughout the cell cycle while Cyclin levels rise and fall depending on the phases with a different cyclin peaking at each stage (cyclin B at M phase, cyclin E at G1/S stage, and cyclin A at S/G2 stage, back to cyclin B peak at M stage)

46
Q

what are examples of broad specificity growth factors

A

epidermal growth factor (EGF), platelet derived growth factor (PDGF), insulin like growth factor (IGF), transforming growth factor beta (TGF-b), fibroblast growth factor (FGF)

47
Q

what is the role of CDKIs

A

cyclin dependent kinase inhibitors role is to block the activity of cyclins/CDKs when necessary (provide brakes on cell cycle progression which is important in cases of DNA damage response and cell growth decision making)
eg. input from growth inhibitory factor such as TGFB lead to increased expression of CDKIs p15 and p21

48
Q

what are the two main CDKI families and the cyclins they work on

A

INK4 family of proteins including p16, p15, p18, and p19, named for inhibition of CDK4 but also act on CDK6 (no affect on CDK1 or 2), they act by binding to CDK4/6 and thus affecting CDK4/6 ability to bind to cyclin D
other family is Cip, includes p21cip1 and p27kip1, can inhibit all other cyclin-CDK complexes, works by blocking the ATP binding site of the CDKs

49
Q

give an overview of the G1 stage (what drives the cell to divide)

A

growth factors activate signalling pathways that lead to the activation of transcription factors (such as AP1) that regulate the expression of key cyclins (such as Cyclin D1)
Once the D Cyclins are synthesized they move to the nucleus and associate with CDK4 and 6
CyclinD-CDK4/6 complexes are phosphorylated by CAK in the activation loop of CDK4/6 and these activated CyclinD-CDK4/6 complexes then phosphorylate Rb
CyclinD-CDK4/6 also binds/hides CKIs (which would block CyclinE-CDK2 activity) from CyclinE-CDK2 thus allowing for activation of CyclinE-CDK2
CyclinE-CDK2 role is to further phosphorylate Rb ie. hypERphosphorylation of Rb which leads to E2F release which then acts as a key transcription factor for S phase gene expression

50
Q

how is inhibitory phosphorylation removed

A

by a group of phosphatases called CDC25

51
Q

what are the unique transcription factors/signalling intermediaries of CyclinD 1, 2, and 3

A

CyclinD1 - AP1
CyclinD2 - Myc
CyclinD3 - STAT3/5

52
Q

is EGF receptor specific or broad

A

broad specificity as it is widely expressed in cells

53
Q

how is CyclinE-CDK2 activated

A

CyclinD-CDK4/6 complexes accumulate during mid-G1, cyclin D dependent kinases sequester (bind) CKIs of the CIP/KIP family, this allows for CyclinE-CDK2 activation and while this Cyclin E expression is happening E2F is being regulated

54
Q

what happens with CyclinE-CDK2 in late G1

A

active CyclinE-CDK2 phosphorylates p27 (which inhibits CyclinE-CDK2), this marks it for degradation by the proteosome which allows for more active cyclinE-CDK2 complexes to be generated leading to the hyperphosphorylation of RB

55
Q

what is the result of Rb hyperphosphorylation and why is it important

A

Rb hyperphosphorylation inactivates Rb
Rb inactivation is critical for cell cycle progression as Rb acts to inhibit the cell cycle by preventing the transcriptional activity of E2F transcription factors
hyperphosphorylation of Rb is a key regulatory event that happens in the G1 phase, essential for the cells to progress to the S phase

56
Q

what happens when Rb is hypophosphorylated (under phosphorylated)

A

hypophosphorylated Rb binds to HDAC (histone deacetylase) and E2F which blocks its transactivation domain hence late G1 phase genes that are required for S phase gene expression (Cyclin E/A) are not expressed

57
Q

how and why does Rb move out of its hypophosphorylated state

A

cyclins/CDKs phosphorylate the hypophosphorylated Rb which causes a conformational change in Rb protein leading to the sequential release of HDAC and E2F, this release of E2F allows for S phase gene expression

58
Q

what state does Rb remain in for the cell division cycle

A

Rb remains in its hyperphosphorylated state for the duration of the cell division cycle before it exits the M phase where it is then dephosphorylated and reset for a new cell division cycle

59
Q

what happens after a restriction site is passed in relation to growth factors

A

once a cell passes the restriction site (or R point) the growth factors/signals such as TGFb and E2F are no longer listened to as once the R point is passed the cell has committed to progressing forward and no amount of growth factors could change this progression decision AFTER the R point is passed (before the cell passes the restriction point growth factors are listened to and do influence whether a cell progresses or not)

60
Q

what does S phase gene expression lead to

A

synthesis of S phase machinery such as:
-DNA polymerase, topoisomerase, ligase etc
-initiation factors
-structural proteins such as histones
-proteins involved in synthesizing DNA precursor nucelotides such as thymidine kinase
-spindle assembly checkpoint protein MAD2

61
Q

what state is CDK1 kept in during G2

A

during G2 CDK1 is kept in its inactive state by an inhibitory phosphorylation event carried out by kinases WEE1 and MYT1
as M phase approaches the phosphatase CDC25 is activated which subsequently activates the CDK1/Cyclin B complex

62
Q

what 2 independent events are involved in the activation of CDK1 at the G2/M boundary

A

-CAK-mediated phosphorylation which is necessary for Cyclin B/CDK1 complex formation
-CDC25-mediated phosphorylation

63
Q

how many and what are the targets of active CDK1/Cyclin B

A

100s of targets for this complex to directly act on cell architecture such as:
-phosphorylates serine residues on lamin causing breakdown of cell membrane
-phosphorylates histones (used for packaging of DNA into nucelosomes, chromosome condensing)
-phosphorylates microtubule associated proteins (causes altered behaviour during mitosis)

64
Q

what controls the activity of CDC25 and how do CDC25 phosphatases inhibit CDK function

A

multiple phosphorylation events control the activity of CDC25 phosphatases, they inhibit CDK function by dephosphorylating specific tyrosine and threonine residues on CDKs

65
Q

what stage transitions are CDC25 phosphatases involved in

A

CDC25 phosphatases are involved in G1-S and G2-M transition

66
Q

how are CDC25 phosphatases used in checkpoints

A

they are used as targets of the checkpoint machinery during DNA damage, they are inactivated or degraded to stop cell cycle progression (this is in normal people, in cancer CDC25 is overexpressed and hence these checkpoints are lost)

67
Q

what CDC25 phosphatases is overexpression of a bad sign

A

CDC25A and CDC25B are frequently overexpressed in cancers with high grade tumours and poor prognosis

68
Q

what happens at the spindle assembly checkpoint

A

this checkpoint ensures proper segregation of sister chromatids by inhibiting metaphase to anaphase transition until all chromosomes are attached correctly to the mitotic spindle

69
Q

how does the spindle assembly checkpoint work

A

this checkpoint is carried out as sister chromatids are held together by cohesins so in the presence of unaligned chromosomes seperase (a protease which cleaves cohesins) is kept inactive by securin and CDK1-Cyclin B, once the chromosomes are properly aligned to the mitotic spindle, cyclinB and securin are ubiquitinated by the anaphase promoting complex/cyclosome (APC)-CDC20 complex and degraded. This leads to the activation of seperase causing the protein link (cohesins) between the sister chromatids to be cleaved hence releasing the sister chromatids and allowing for metaphase to anaphase transition

70
Q

how does TGFb block the cell division cycle

A

by preventing the phosphorylation of Rb, it is a major growth inhibitory signal for normal cells, and it also counteracts actions of MYC (which is growth promoting)

71
Q

what does MYC repress

A

MYC represses the expression of p21 and p15

72
Q

compare the actions of TGFb and MYC in a normal cell and in a cancer cell

A

in normal cells TGFb reduces c-MYC expression (Smad3 and E2F4/5 and p107 also act to shut down c-MYC expression)
on cancer cells such as breast cancer this TGFb-mediated repression of MYC is lost (hence excessive growth as MYC, now uncontrolled, is a growth promoter)

73
Q

how and what cancers evade TGFb growth inhibition

A

many cancers such as pancreatic cancers have mutant inactivated Smad4 proteins which allows for evasion of TGFb growth inhibition

74
Q

what is Akt and what are its functions

A

-Akt is a serine/threonine kinase that is activated downstream of Growth factor receptors
-its functions include inhibition of CDK inhibitors (through growth factors such as EGF signalling through Akt) and promoting progression of cell cycle by blocking GSK3b actions, also blocks Bad (pro-apoptotic protein) actions and promotes cell growth

75
Q

what is a hallmark trait in cancer cells

A

autonomous cell division meaning cells no longer depend on positive and negative growth factors

76
Q

what pathways are thought to play a central role in transmitting oncogenic signals

A

the PI3K-AKT pathway and the RAS-RAF-MEK-ERK pathway

77
Q

are expression levels and/or activity of proteins such as AKT, RAS or MYC altered in cancer cells compared to normal cells

A

yes for example in breast cancer - RAS and AKT are abnormally activated and MYC amplification are all frequently seen in breast tumours

78
Q

what can tumour grade of breast tumours be linked with

A

higher pAKT expression and reduced nuclear p27

BI407 Tumor Biology (4 decks)

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