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BMS2021 > TOPIC F: MOLECULAR BASIS OF CANCER > Flashcards

TOPIC F: MOLECULAR BASIS OF CANCER Flashcards

1
Q

Can cancer be both from inherited patterns and environmental factors?

A
  • YES
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2
Q

What cells does chemo kill?

A
  • Stem cells , immune cells
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3
Q

What are the physical characteristics of cancer cells?

A
  • Nucleus ENLARGES
  • Cytoskeleton changes (shape–> gives it the ability to move)
  • Loss of specialised features (cancer cells are immature and don’t carry out the function that a normal cell would)
    e. g. monocytes high count in leukemia
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4
Q

What do normal cells need to be attracted to in order to grow in body?

A
  • ECM (extracellular matrix)
  • Growth factors stimulate the cells to grow (when cells contact each other , contact inhibition occurs and they won’t grow anymore enter G0 phase) (NORMAL CELLS)
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5
Q

Do cancer cells follow the normal contact inhibition that normal cells do?

A
  • NO!

- they ignore the cell control cycles and pile up on each other (foci) (no G0 resting phase)

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6
Q

Are cancer cells actually attached to the ECM when growing?

A
  • NO!

- This is part of the metastasis process

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7
Q

What are the PHENOTYPIC characteristics of cancer cells? (4 things)

A
  • REDUCED requirement for GROWTH factors to sustain proliferation
  • RESISTANT to growth-inhibitory signals
  • IMMORTAL (don’t stop dividing after normal no. of generations)
  • CHANGES IN CHROMOSOME NUMBER AND STRUCTURE
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8
Q

Why are cancer cells not dependent on growth factors?

A
  • Because they secrete their own in an autocrine manner (stimulates their growth)
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9
Q

Which enzyme is important in theimmortalisation of cancer cells?

A
  • TELOMERASE

- Cancer cells reexpress this to lengthen (protects the ends of chromosomes)

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10
Q

Where is telomerase NORMALLY present (in normal cells)?

A
  • Only in ES cells and germ cells

- Normally it shortens each round of cell division (this is why we age)

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11
Q

What does it mean when we say cancer cells are clonal?

A
  • ## They originate from a single cell that can sustain and maintain in single growth regulatory gene–> gives cell ability to grow faster (cell cycle faster thus less time for DNA repair)
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12
Q

What do cancer cells require to reach a tumorous state in terms of mutations?

A
  • Requires many mutations to reach a tumorous state
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13
Q

What will all of the original mutated cell descendents inherit? (cancer cells)

A
  • They will inherit the mutation and thus grow faster with ADDITIONAL mutations
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14
Q

How many MAJOR genetic mutations are there for cells to become cancer cells?

A

-6

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15
Q

What are Benign tumors defined as?

A
  • LOW level genetic damage despite growing faster than neighboring cells
  • Still physically look like the cells they come from
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16
Q

How come benign tumors are localised (what makes them localised)?

A
  • They are in a FIBROUS CAPSULE
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17
Q

Can some benign tumors turn malignant?

A
  • YES!

- e.g. colon tumors, cervical tumors, bladder polyps

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18
Q

What are 4 signs of malignant tumors?

A
  • HIGH level of genetic damage
  • Doesn’t resemble cell of origin
  • Large nucleus, small cytoplasm, small strucutres (bc. not mature cells)
  • Can INVADE surrounding tissues
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19
Q

What is metastasis?

A
  • Where cancers can INVADE other tissues ansd SPREAD to other parts of body
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20
Q

Is metastasis local or distant or both?

A
  • It can be BOTH local and distant

e. g. tumor in breast can invade chest wall (lymph nodes in armpit)

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21
Q

What are the steps in metastasis?

A
  • Cells grow as BENIGN tumor in epithelium (e.g. colon epithelium)
  • over time further genetic damage occurs
  • Obtains ability to break through basal lamina (proteases)
  • Cells become invasive and ENTER capillary or lymph
  • Cells travel through bloodstream (e.g. colon cancer move through hepatic portal vein to liver)
  • Escape from blood vessel via EXTRAVASATION to form micrometastasis
  • Colonise liver forming FULL-BLOWN metastasis (secondary metastasis)
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22
Q

What is angiogenesis?

A
  • The ability to establish new microcirculation in tumor
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23
Q

Why does the cancer cell need angiogenesis?

A
  • Because primary tumor only grows to 0.2mm in size then it has PROBLEMS with lack of O2, nutirents and build up of waste products so they need new way of getting nutrients
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24
Q

What do the cancer cells secrete to allow for angiogenesis to occur?

A
  • Secrete growth factor (VEGF–> Vascular Endothelial Growth Factor)
  • This acts on nearby capillaries and binds to the VEGF receptor to stimulate them to outbranch
  • This feeds UP into the tumor
  • Therefore tumor can now get rid of waste, RECEIVE O2 and INCREASE in size
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25
Q

What is cancer casued by (definition)?

A

“Caused by acumulation of genetic alterations thast confer survival advantage to cancer cells”

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26
Q

What are 5 changes that result from the formation of cancer cells in general?

A
  • INCREASE in cell growth
  • RESISTANCE to apoptosis
  • ALTERED tissue invasiveness
  • ANGIOGENIC proliferation
  • Ability to escape immune surveillance
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27
Q

With inherited germline errors what does every cell in the body carry?

A
  • Every cell in the body carries one copy of the DNA with THAT genetic defect
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28
Q

In somatic mutations, does every cell carry the mutation?

A
  • NO

- Only the cancer cells do

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29
Q

Are there DNA repair enzymes to correct (or attempt to correct) DNA errors?

A
  • YES!
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30
Q

When do DNA repair enzymes fail?

A
  • Substantial mutations
  • Loss of DNA repair enzymes
  • LESS time for DNA repair enzymes (because cells are cycling rapidly through the cell cycle)
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31
Q

Which cancers are known to be caused by viruses?

A
  • Nasopharynx
  • Cervical cancer
  • Lymphomas
  • Liver cancer (Hep B)
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32
Q

What are the 3 types of genes that regulate cancer ?

A
  • ONCOGENES
  • TUMOR SUPRESSOR GENES
  • MISMATCH REPAIR GENES
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33
Q

What do oncogenes act to do?

A
  • Promote cancer (prevent apoptosis)
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34
Q

What do tumor suppressor genes act to do?

A
  • PREVENT cancer normally (without being mutated) -problems arise when these are not functional
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35
Q

What do mismatch repair genes do?

A
  • Genes that repair mutated DNA
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36
Q

What will most cancers have a combination of?

A
  • The three types of regulating cancer genes that are mutated
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37
Q

What are oncogenes the mutated form of?

A
  • Mutated form of protooncogenes -> promote cell growth and division
38
Q

What happens when protooncogenes SUSTAIN activating mutations?

A
  • They become ONCOGENES -overactive

- Promote growth in inappropriate circumstances

39
Q

What types of proteins are encoded by PROTOONCOGENES? (5 main ones)

A
  1. growth factors and receptors
  2. Protein kinases (Src and Ras)
  3. Cell cycle proteins (cyclins –> Cyclin D-bcl-1)
  4. Proteins affecting apoptosis (e.g. Bcl-2)
  5. TFs (e.g. Myc–> causes transcription of cell growth factors)
40
Q

Which 3 ways can a protooncogene become oncogenic?

A
  1. DELETION or pt. MUTATION in coding sequence
  2. GENE AMPLIFICATION
  3. CHROMOSOME REARRANGEMENT
41
Q

What occurs in deletion or point mutation in formation of an oncogene (example)?

A
  • Ras can sustain single base mutation–> becomes hyperactive (turned on all the time) –> permanently GTP bound –> stimulate the MAPK pathway –> thus GROWTH AND PROLIFERATION
42
Q

What occurs in the gene amplification of the formation of an oncogene?

A
  • Normal protein is OVERPRODUCED
  • e.g. EGF Receptor (HER2) can be overproduced
  • Cells grow TOO MUCH
43
Q

What is herceptin used to treat?

A
  • Breast cancer

- It is a monoclonal antibody and internalised the HER 2 receptors (EGFR) so it stops cell proliferation

44
Q

What occurrs in chromosome rearrangement in the formation of an oncogene?

A
  • Ds DNA BREAKS and fuses to the OTHER chromosome in homologous recombination e.g. Burkits lmyphoma
  • two actively transcribed genes fuse together (fusion proteins) –> hyperactive
45
Q

Do oncogenes act in a dominant manner and what does this mean for it?

A
  • YES!

- Only 1 mutation in 1 chromosome can cause an oncogene to form (gain of function)

46
Q

What are tumor suppressor genes?

A
  • they are NORMAL cellular genes seen in ALL cells
47
Q

What do the tumor suppressor genes encode for?

A
  • cell cycle proteins
  • TFs
  • Cell surface proteins
  • DNA repair proteins
  • Apoptosis related proteins
48
Q

What do tumor suppressor genes control?

A
  • Critical cell cylce chckpoints
  • Transcribe regulatory INHIBITORY genes
  • NEGATIVELY (slow) control cell growth
49
Q

What are 3 important results of tumor suppressor gene mutations?

A
  1. Mutations of these genes cause cells to LOSE adhesion to neighbours and SPREAD
  2. Mutated DNA repair enzymes can no longer repair DNA
  3. Mutant proteins NO LONGER block cell division
50
Q

What type of mutation results from mutated tumor suppressor genes?

A
  • LOSS OF FUNCTION (inactivating mutation)

- Inherited or acquired

51
Q

Do loss of function mutations require one or two (both) copies of the gene to be lost for cancer to develop?

A
  • BOTH copies must be lost
52
Q

What is the two hit hypothesis?

A
  • Where BOTH copies of the tumor suppressor gene (alleles) must be lost (deleted) for cancer to develop
53
Q

What happens when you only lose ONE copy of the tumor supressor gene?

A
  • Other is still healthy and can STILL carry out suppressor function BUT doesn’t work as well so PRTIAL INACTIVATION
  • Someone can be born with one functioning allele but can lose the second copy thus be PREDISPOSITIONED to cancer (get cancer younger than most)
54
Q

What are 85% of cancers?

A
  • Carcinomas (skin, epithelial cells lining organs, brast cancer ,colon c, lung c,)
55
Q

Where do Sarcomas originate from?

A
  • Bone, muscle, blood vessels
56
Q

Where do lymphomas arise from?

A

Lymphoid cells and leukemias from leukocytes of bone marrow

57
Q

Is cqncer formation BOTH genetic and environmental?

A
  • YES!

- Mostly a combination of both (cumulative genetic errors)

58
Q

What is the pathway from a normal epithelial cell to a cancerous cell in terms of the genetic changes?

A

NORMAL CELLS

  • LOSS OD TUMOR SUPPRESSOR GENE ‘APC’
  • Polyp forms on colon wall
  • Benign precancerous tumor grows
  • ACTIVATION OF ONCOGENE RAS (switched on permanently
  • Class II adenoma grows
  • LOSS OF TUMOR SUPPRESSOR GENE ‘DCC’
  • Class III adenoma grows (still benign)
    • LOSS OF TUMOR SUPPRESSOR GENE P53*
  • Carcinoma (malignant tumor) develops
  • Other changes occur and the loss of the anti metastasis gene
  • CANCER METASTASIZES (spreads to other tissues)
59
Q

What are 5 features of someone having inhertited a cancer susceptibility syndrome?

A
  • Close or 1 degreee relatives with a COMMON cancer (e.g. breast and ovary)
  • Two members of family with SAME rare cancer
  • Early age onset of cancer (<40)
  • Bilateral cancers in paired organs
  • Tumors in two different organs in one person
60
Q

What is penetrance?

A
  • Different individuals with SPECIFIC genetic defect who will get the disease can VARY depending on gene
    e. g. Colon cancer for the lost APC is 100 % penetrance (no matter how healthy you are, you will get the cancer) –> FAP coli –> born with one normal allele but at SOME stage in life SECOND copy will be lost and they will get colon cancer
61
Q

What does APC stand for?

A
  • Adenomatuous Polyposis Coli
62
Q

What role do the BRCA 1 and 2 genes play normally?

A
  • Important roles in DNA repair
  • Inherited mutation in EITHER one predisposes you to breast and/or ovarian cancer at a younger age
  • Penetrance is 30-40% in less than 65yrs
63
Q

Are other cancers attributed to the same BRCA 1 and 2 mutation?-

A
  • YES!

- Ovarian, colon, prostatic

64
Q

What are 4 outcomes for having an increased likelyhood of BRCA mutations?

A
  • MULTIPLE breast cancer cases (early onset) in family
  • Ovarin cancer (with family history of breast or ovarian cancer)
  • Breast and ovarian in same woman
  • Bilateral breast cancer
  • Ashkenazi jewish heritage
  • (Male breast cancer)
65
Q

What are cancers that have 1 or 2 mutations compared to 6 and what are some characteristics of it?

A
  • Retinoblastoma
  • from TUMOR suppressor gene Rb loss
  • rare childhood tumor of retina (neural precursor cells of retina)
  • Can be both hereditary or sporadic (both copies of Rb must be lost)
66
Q

What occurs in hereditary Rb?

A

Develops at a YOUNG AGE

  • Tumors in BOTH eyes
  • Mutant Rb allele on chr.13 in EVERY CELL IN BODY
67
Q

What occurs in non-hereditary Rb?

A
  • ONE tumor in ONE eye -
  • Develops at LATER AGE
  • Chromosomal changes only occur in tumor cells
68
Q

Which other cancers is Rb mutated in?

A
  • BREAST, LUNG , BLADDER

- Mutation is one of MANY mutations with activation of ONCOGENES

69
Q

What occurs when there is a mutation in the tumor suppressor gene p53?

A
  • Mutation in this gene allows tumor to EVADE apoptotic cell death pathway and PROMOTE PROLIFERATION
70
Q

What do 50% of all tumors show a mutation and loss of?-

A
  • Tumor suppressor gene p53
71
Q

What are the functions of P53 normally?

A
  • Important role in the G1S boundary at the checkpoint
  • It causes cells to halt at boundary if damages to DNA occur (won’t progress to S phase bc. needs to REPAIR DNA)
  • If DNA can’t be repaired P53 will instruct cell to undergo apoptosis
72
Q

If DNA can’t be repaired in cell replication then what will P53 instruct the cell to undergo?

A
  • APOPTOSIS
73
Q

What is ‘senescence’ ?

A
  • The loss of a cells ability to divide and grow

- Normal function of P53–> inhibit cell growth and prevent tumor development

74
Q

What happens in cancer cells defective in the functional P53?

A
  • ESCAPE apoptosis
  • DNA damage not repaired and NO halt at the cell cycel checkpoint to repair DNA
  • Cells can survive and proliferate with mutated genome (chromosomes fragmented, rejoined incorrectly after cell divisions)
75
Q

What do mismatch repair genes do?

A
  • Repair DNA if there are errors in DNA replication
76
Q

How many mismatch repair genes are there and how do they work?

A
  • 8 MMR genes (MSH, MLH, PMS)

- Work in DIMERS (if you knock out one the other one is knocked out :( )

77
Q

Do Mismatch repair genes follow the ‘two hit hypothesis’?

A
  • YES!
  • they are loss of function mutations and need to lose BOTH copies to lose mismatch repair function and predispose to cancer
78
Q

Which types of cancers show errors in mismatch repair genes?

A

-Both hereditary AND sporadic COLORECTAL cancers + endometrial, breast, prostate, lung and stomach cancers

79
Q

What is HNPCC and what is the penetracne and protective factors?

A
  • Hereditary Non Polyposis Colorectal Cancer
  • Loss of mismatch repair genes (80% penetrance thus STRONG MUTATION)
  • Can only inherit loss of ONE copy
  • Protective factors–> Be on a good diet and get screening
80
Q

What is an example of where a SINGLE oncogenic mutation is enough to cause cancer?

A

CML (chronic Myeloid Leukemia)

- Makes it easier to study the cancer

81
Q

When is CML caused (which group of oncogenes is it)?

A
  • TRKs (Tyrosine Receptor kinases)

- When overexpressed or mutated lead to cellular transformation (cancer-permanently switched ON)

82
Q

In CML where is the chromosomal translocation detected (cells)?

A
  • Leukemic cells
83
Q

Which chromosomes does the translocation occur in?

A
  • Chromosome 9 and 22
84
Q

Which tools can you use to demonstrate the translocation in CML (chromosome 9 and 22)?

A
  • Cytogenetics
  • FISH
  • PCR
85
Q

Which partiuclar oncogene causes CML?

A
  • ABl tyrosine kinase (important for the normal cell cycle) –> G1S boundary –> Rb regulates it)
86
Q

What occurs between the chromosomes in CML?

A
  • Chromosomes 9 and 22 undergo ds DNA breaks
  • End of chromosome 9 breaks off an FUSES to 22
  • End of 22 breaks of and FUSES to 9
  • Abl (end of chr.9) breaks off and fuses to the other end of the signalling protein BCR (break point cluster region) on chromosome 22–> forms a FUSION protein
  • Abl PERMANENTLY swithced on–> no cell death + more growth
87
Q

Why is chromosome 22 shorter in CML?

A
  • Because part of it breaks off and fuses to chromoome 9 –> this is how it is diagnosed via karyotyping
88
Q

What is chromosome 22 also known as (in terms of CML)?

A
  • Philadelphia chromosome (Ph)
89
Q

What is the actual cause of CML in terms of the protein produced and what does this protein do?

A
  • BCR-abl FUSION protein
  • Altered adhesion (to spread)
  • Mitogenic activation (can escape growth factor stimulation)
  • inhibition of apoptoiss
90
Q

What are THREE ways Tyrosine Kinases can be inhibited for cancer therapy?

A
  1. ATP competitive inhibitors (Tyrosine kinases can’t be activated without ATP) thus drugs that interfere with the binding of ATP
  2. Antibodies agaisnt receptors or ligands
    (Neutralise the ligand e.g. HER2 OR blocking the receptor)
  3. Antiangiogenics (tyrosine kinase INHIBITORS as target antiangiogenesis e.g. VEGF)

BMS2021 (7 decks)

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