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SMP - APP Part 1 > Lectures 3-6 - Cancer I-IV > Flashcards

Lectures 3-6 - Cancer I-IV Flashcards

1
Q

What is cancer?

A

Malignant neoplasia

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2
Q

What is neoplasia? Other name?

A

Abnormal growth of tissue resulting from loss of responsiveness to growth control signals

= tumor

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3
Q

What is a carcinoma?

A

Cancer of epithelial origin

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4
Q

What is a leukemia?

A

Cancer of the bloodstream

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5
Q

What is a lymphoma?

A

Cancer of lymph nodes

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6
Q

What is a sarcoma?

A

Cancer of mesenchymal origin

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7
Q

What are 5 carcinomas?

A
  1. Lung cancer
  2. Breast cancer
  3. Colon cancer
  4. Bladder cancer
  5. Prostate cancer
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8
Q

What are 3 sarcomas?

A
  1. Fat cancer
  2. Bone cancer
  3. Muscle cancer
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9
Q

What does the prefix “adeno-“ mean?

A

Gland

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10
Q

What does the prefix “chondro-“ mean?

A

Cartilage

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11
Q

What does the prefix “erythro-“ mean?

A

RBC

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12
Q

What does the prefix “hemangio-“ mean?

A

Blood vessels

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13
Q

What does the prefix “lympho-“ mean?

A

Lymphocyte

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14
Q

What does the prefix “melano-“ mean?

A

Pigment cell

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15
Q

What does the prefix “myelo-“ mean?

A

Bone marrow

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16
Q

What does the prefix “myo-“ mean?

A

Muscle

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17
Q

What does the suffix “-oma” mean? What to note?

A

Benign

Note: lymphoma and melanoma are exceptions

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18
Q

What do the suffices “-carcinoma” and “-sarcoma” mean?

A

Malignant

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19
Q

What are the 3 stages of abnormal growth? Describe each.

A
  1. Hyperplasia = increase in number of normal cells with normal tissue architecture
  2. Dysplasia = some cellular and nuclear changes leading to loss of cell uniformity and abnormal tissue architecture
  3. Anaplasia = undifferentiated cells variable in size/shape, numerous and atypical mitoses, lack of organized tissue architecture
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20
Q

What are the differences between benign and malignant tumors?

A
  1. Benign tumors are well differentiated cells with preserved specialized features of the parent cells (e.g. hormone release)/malignant tumors are not differentiated and have anaplasia
  2. Benign tumors are usually well demarcated, often are encapsulated masses without invasion of the surrounding tissue/malignant tumors are locally invasive and infiltrate surrounding tissues
  3. Benign tumors do not have distant metastases/malignant tumors do frequently
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21
Q

What is a leomyoma?

A

Uterine fibroid: neoplasm from uterine smooth muscle

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22
Q

Do normal adult cells proliferate? What to note?

A

In adult organisms most of the cells are quiescent, and cell proliferation is limited to certain types of cells and processes, such as:

  1. Bone marrow myeloblasts
  2. Immune cells
  3. Epidermal cells
  4. Epithelial cells (e.g. gut)
  5. Regenerating tissues (e.g. uterus)
  6. Adipose tissue

Note: cell proliferation is tightly regulated and involves factors stimulating/inhibiting cell divisions

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23
Q

What leads to apoptosis?

A

Cell damage or perturbation in cell cycle

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24
Q

What are the 10 hallmarks of cancer?

A
  1. Sustaining proliferative signaling
  2. Evading growth suppressors
  3. Activating invasion and metastasis
  4. Enabling replicative immortality
  5. Inducing angiogenesis
  6. Avoiding immune destruction
  7. Tumor-promoting inflammation
  8. Genome instability and mutation
  9. Resisting cell death
  10. Deregulated cellular energetics
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25
Q

How is normal growth regulated?

A
  1. Growth factors (PDGF, EGF) are released externally
  2. Growth factors bind to the GF receptors on cells
  3. Transduction signals leading to phosphorylation cascade that ends in the nucleus with transcription factors promoting DNA replication
  4. Gene expression
  5. Cell cycle progression
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26
Q

What are proto-oncogenes?

A

Genes encoding proteins which normally stimulate cell proliferation and are expressed and active in normal proliferating cells

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27
Q

What are oncogenes?

A

Altered (mutated) forms of proto-oncogenes

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28
Q

What is oncogene activation? What does it result from?

A

Process of neoplastic transformation often associated with gain-of-function mutations of proto-oncogenes converting them to constitutively active oncogenes or with overexpression of normal proto-oncogenes

May result from:

  1. Point mutations
  2. Chromosomal translocations
  3. Gene amplification
  4. Over-expression due to changes in regulatory elements
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29
Q

Are oncogene mutations usually dominant or recessive? What does this mean?

A

Usually dominant: mutation in one allele is sufficient to cause changes in cell phenotype

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30
Q

What do proto-oncogenes encode?

A
  1. Autocrine growth factors
  2. Growth factor receptors
  3. Signal transduction molecules
  4. Transcription factors
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31
Q

Describe gene amplification. Example?

A

Multiple copies of the gene are present in the nucleus and each of them is active and produces mRNA resulting in high levels of protein

Example: N-MYC in neuroblastoma

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32
Q

What are silent genes?

A

Genes are present in the nucleus, but they are not active (no mRNA produced)

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33
Q

Describe gene over-expression. Example?

A

Genes are “overactive”, meaning they produce high levels of mRNA, which results in high levels of protein

Example: Her2 in breast cancer

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34
Q

Describe chromosomal translocation. Example?

A

Transfers the gene resulting in:

  1. Transfer into a very active transcription region
  2. Transfer producing a chimeric protein

Example for #1: Burkitt’s lymphoma or Ig to c-myc

Example for #2: BCR-ABL

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35
Q

2 examples of growth factor proto-oncogenes?

A
  1. Platelet-derived growth factor (PDGF) overexpressed in glioblastomas
  2. Transforming growth factor α (TGF-α) overexpressed in sarcomas
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36
Q

3 examples of growth factor receptor proto-oncogenes?

A
  1. Epidermal growth factor receptor EGFR (ERBB1) truncated/mutated in glioblastoma (only left with intracellular portion of receptor leading to uncontrolled activation)
  2. HER-2 (ERBB2) overexpressed in breast cancer
  3. ERBB1 overexpressed in squamous cell carcinomas of the lung
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37
Q

3 examples of signal-transducing protein proto-oncogenes?

A
  1. Ras: encodes p21G protein, which transmits mitogenic signals from the activated growth factor receptors, through the phosphorylation cascade of other transducing proteins, to the nucleus => point mutations changing amino acids in the pocket binding GTP (codons 12 and 13) and region essential for GTP hydrolysis (codon 61) lead to constitutive activation of RAF-MAPK mitogenic cascade
  2. ABL: non-receptor tyrosine kinase that promotes apoptosis, but in myeloid leukemia, the gene is translocated from chromosome 9 to chromosome 22 where it fuses with part of the breakpoint cluster region (BCR) gene => chromosome 22 is now called chromosome Philadelphia => BCR-ABL fusion protein is retained in the cytoplasm and due to its high tyrosine kinase activity stimulates several pathways including RAS-RAF mitogenic cascade
  3. Src
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38
Q

What are the most common abnormalities with oncogenes in human cancer?

A

RAS mutations, particularly in colon and pancreatic cancers

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39
Q

5 examples of nuclear transcription factors proto-oncogenes? Which one is most commonly involved in human cancer?

A
  1. MYC***
  2. MYB
  3. JUN
  4. FOS
  5. REL
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40
Q

4 examples of MYC involvement in human cancers?

A
  1. Burkitt lymphoma: overexpressed due to a translocation from chromosome 8 to 14, in close proximity to an Ig gene
  2. Breast, lung and other cancers: gene amplification
  3. Neuroblastoma (sympathetic neurons): N-MYC amplification
  4. Small cell cancer of lung: L-MYC amplification
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41
Q

What is progression of the cell cycle driven by? What to note?

A

Cyclins and cyclin-dependent kinases (CDKs)

Note: dysregulation of cyclin and CDK expression or their mutations occur often in cancer cells and promote proliferation

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42
Q

What is the cell cycle tightly controlled by? What to note?

A

CDK inhibitors

Note: transition from G1 to S phase is a particularly important checkpoint

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43
Q

What are the most common perturbations of the cell cycle?

A

Perturbations affecting proteins involved in G1-S transition:

  1. Overexpression of cyclin D (breast, esophagus, liver cancers, lymphomas)
  2. Amplification of CDK4 (melanomas, sarcomas, glioblastomas)
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44
Q

What are tumor suppressor genes?

A

Genes that encode proteins, which in normal cells inhibit proliferation and/or stimulate cell death (apoptosis) and are often inactivated in cancer cells, which leads to uncontrolled cell growth, as well as accumulation and propagation of defective cells, which are normally eliminated via apoptosis

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45
Q

How can tumor suppressor genes be inactivated?

A
  1. Point mutations
  2. Deletions
  3. Chromosomal aberrations
  4. Epigenetic modifications (e.g. promoter methylation leading to block of transcription factor binding)
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46
Q

Are tumor suppressor gene mutations usually dominant or recessive? What does this mean? Implication?

A

Usually recessive: changes in both alleles are necessary to change cell phenotype because one of the alleles can do the job

Implication: mutations in tumor suppressor genes are often associated with hereditary cancers

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47
Q

What are the 4 best characterized tumor suppressor genes and their corresponding hereditary cancers?

A
  1. RB => retinoblastoma (pediatric cancer of retina)
  2. APC (adenomatous polyposis coli) => Familial Polyposis Coli (familial form of colon cancer) and colon polyps which transform into malignant cancers with the loss of the second APC allele
  3. p53 (upon cell damage, causes growth arrest and apoptosis) => Li Fraumeni Syndrome (multiple tumors of different types at a young age and in multiple locations: soft-tissue sarcomas, osteosarcomas, brain tumors, breast cancer, ovarian cancer, carcinoma)
  4. BRCA1 and BRCA2 (DNA repair) => familial form of breast cancer
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48
Q

What is the most commonly mutated tumor suppressor in human cancer?

A

p53

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49
Q

2 main differences between hereditary cancers or sporadic malignancies?

A
  1. Hereditary cancers develop earlier in life

2. Hereditary cancers often arise in multiple locations

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50
Q

What is the classical Knudson two-hit model? Explain it.

A

Familial vs sporadic forms of retinoblastoma:

  1. Sporadic form: both mutations in RB gene are acquired after birth, thus frequency of the tumor is relatively low
  2. Familial form: one mutation in RB protein is inherited, therefore only one additional mutation has to occur in one of the retinal cells => frequency of retinoblastoma is very high and the tumors often arise bilaterally
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51
Q

Why is a hypothesis for why an RB mutation lead to cancer of the retina? What to note?

A

Apoptosis is not active in the developing retina

Other tumors will eventually develop as well

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52
Q

How does RB cause cancer?

A

NORMAL: RB is a G1-S checkpoing cell cycle control protein => hypophosphorylation RB prevents activation of S-phase genes

CANCER: growth factor stimulation => RB is inactivated by cyclin-dependent phosphorylation

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53
Q

How does APC cause cancer?

A

NORMAL: APC is a regulator of cell division and adhesion: its protein reacts with β-catenin (signal molecule in WNT pathway) and in the absence of WNT on WNT receptor, it stimulates its degradation

CANCER: upon WNT stimulation or if APC is mutated, APC releases β-catenin which translocates to the nucleus and activates genes promoting the cell cycle

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54
Q

What are polyps?

A

Multiple benign tumors

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55
Q

Other than in hereditary cancers, in what other cancers are APC mutations present?

A

Majority of sporadic colorectal cancers

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56
Q

How does p53 cause cancer?

A

NORMAL: p53 protein is bound to the MDM2 gene, which causes its degradation and short half-life => upon cellular stress (hypoxia, DNA damage, overexpression of mitogenic factors), p53 protein is released from the complex with MDM2, which increases its half-life and activates its transcription factor activity => active p53 stimulates transcription of CDK inhibitor p21, which leads to G1 growth arrest + activation of DNA repair systems (GADD45) when necessary => apoptosis

CANCER: mutations (often affecting DNA-binding domain) or loss of p53 leads to accumulation and propagation of mutated and damaged cells because allows survival of the cells with overexpressed or deregulated mitogenic factors

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57
Q

What is an exception to tumor suppressor gene mutations being recessive?

A

Li Fraumeni Syndrome (p53 mutation)

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58
Q

Is cancer inherited?

A

NOPE - cancer susceptibility is

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59
Q

Functional form of p53 protein?

A

Tetramer

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60
Q

What are 3 types of p53 mutations? Describe each. Which one is the worst?

A
  1. Loss of function: the mutant allele is not functional but does not interfere with the actions of the wild type allele
  2. Dominant negative mutant: mutant p53 forms a complex with the wild type allele and prevents its binding to the target gene promoters
  3. Gain of function***: mutant p53 binds to different DNA sequences and activates different target genes, which can lead to stimulation of cell proliferation instead of cell cycle arrest and apoptosis
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61
Q

What kind(s) of p53 mutations cause Li Fraumeni Syndrome?

A

All 3 possible types: loss of function, dominant negative mutant, gain of function

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62
Q

What are 2 other factors contributing to Li Fraumeni Syndrome?

A
  1. Mutation of CHK2 gene (needed for p53 activation)

2. Polymorphism of wild type p53

63
Q

What are BRCA1 and BRCA2? Describe each.

A

Both tumor suppressor genes encoding nuclear proteins involved in response to DNA damage and DNA repair.

  1. BRCA1: germline mutations (truncation, inactivating frameshift mutations) are associated with increased risk of breast and ovarian cancers (85% and 50%, respectively) and have been found in 40-50% of families with multiple breast cancer cases
  2. BRCA2: germline mutations (truncation, inactivating frameshift mutations) lead to increased risk of breast cancer (80%), while ovarian cancers are not as common (risk -10%), and increased risk (6%) of male breast cancer
64
Q

Are BRCA1 mutations found in sporadic breast and ovarian cancers?

A

No BRCA1 mutations have been described in sporadic breast cancers, while incidence in sporadic ovarian cancers is only 5%

65
Q

7 risk factors for breast cancer? Which one is most significant?

A
  1. BRCA1-2 mutation***
  2. Early menarche
  3. Late age at birth of 1st child
  4. Benign breast disease
  5. Hormone replacement therapy
  6. Alcohol use
  7. Family history
66
Q

Why are DNA repair genes important in cancer?

A

They usually are not directly involved in cell cycle regulation, but lack of DNA repair activity => genetic instability => facilitates mutations in other genes, including oncogenes and tumor suppressors

AKA they are tumor suppressor genes

67
Q

What are 2 cancers associated with DNA repair genes (other than breast cancer)? Describe each.

A
  1. Hereditary nonpolyposis colorectal cancer (HNPCC): associated with defects of DNA mismatch repair genes
  2. Xeroderma pigmentosum: increased risk of UV-induced skin cancers due to the defects in the nucleotide excision repair system responsible for removal of UV-crosslinked residues
68
Q

What is an exception to the fact that hereditary cancers are caused by tumor-suppressor mutations? Describe it.
What to note?

A

Anaplastic lymphoma kinase (ALK) mutations and amplification in neuroblastomas

ALK is a receptor tyrosine kinase preferentially expressed in central and peripheral nervous systems and germline activating mutations have been associated with familial neuroblastoma, which segregates as autosomal-dominant disease with limited penetrance (due to need for other factors to cause cancer)

Note: mutations and amplification of ALK occur also in sporadic cases of neuroblastoma

69
Q

What are microRNAs?

A

Small non-coding RNAs that regulate the expression of other genes by causing the degradation of mRNAs or blocking their translation

70
Q

What is the role of microRNAs in cancer?

A
  1. Oncogenic miRNAs target tumor suppressors
  2. Tumor suppressor miRNAs target oncogenes

Overall, alteration of their balance can trigger/facilitate malignant transformation

71
Q

How do cancerous cells resist cell death?

A

Via the deregulation of apoptotic mechanisms, leading to the propagation of damaged mutated cells

72
Q

What leads to genomic instability? What does this allow?

A
  1. Deregulation of DNA replication
  2. Issues with cell cycle checkpoints
  3. Issues with DNA repair
  4. Issues with apoptosis

Genomic instability allows tumor cells to induce rapid changes in phenotype and adaptation to new conditions (e.g. hypoxia, chemotherapy)

73
Q

What kind of genomic instability leads to advantages for the cell?

A

Gaining chromosomes

74
Q

What are telomeres?

A

Region of repetitive DNA at the end of a chromosome, which protects the end of the chromosome from deterioration and shortens over time so that most normal cells have a capacity of 60-70 doublings => after this the cells enter a nonreplicative senescence

75
Q

How do cancerous cells have limitless replicative potential?

A

Telomerase is an enzyme, which in stem cells maintain normal telomere length preventing their senescence

In most of the cancers telomerase is up-regulated, which allows unlimited cell divisions

76
Q

What is tumor hypoxia? What to note? What is this called?

A

Tumors often grow faster than blood vessels, leading to hypoxia which kills cancer cells via p53-induced apoptosis

Note: some of them survive this and become more malignant by adapting to low oxygen levels and conducting aerobic glycolysis which allows them to produce side-products that serve as building blocks (4 mol ATP/mol glc), which puts proliferating cells at an advantage = Warburg effect

77
Q

How is the adaptation of tumors to low O2 used practically?

A

For cancer diagnosis: because these cells use a lot of glucose, we can radio-label glucose

78
Q

What is angiogenesis? What is it used for in cancer?

A

Process of capillary blood vessel formation, which is necessary to provide oxygen, nutrients and growth factors to the growing tissue

Indispensable for both tumor growth and metastases

79
Q

What is angiogenesis stimulated by?

A

Stimulated by angiogenic factors, such as vascular endothelial growth factor (VEGF), released from cancer cells

80
Q

What happens to tumors that do not perform angiogenesis?

A

They can stay dormant for years

81
Q

What are the 5 steps of angiogenesis?

A
  1. Proteolytic degradation of the parent vessel basal membrane
  2. Migration of endothelial cells and endothelial progenitors toward angiogenic stimulus
  3. Proliferation of endothelial cells
  4. Recruitment of endothelial progenitors
  5. Maturation of vessels: inhibition of endothelial cell proliferation, capillary tube formation, recruitment of pericytes and vascular smooth muscle cells
82
Q

What is the difference between vasculogenesis and angiogenesis? Which is used by tumors?

A

Angiogenesis is the sprouting of new blood vessels from existing ones

Vasculogenesis is the formation of new blood vessels

Both used by tumors, since they use progenitor cells and existing endothelial cells to form new blood vessels

83
Q

What is angiogenesis controlled by normally? What about in tumors?

A

NORMALLY: tightly controlled by:

  1. Angiogenic factors
  2. Inhibitors of angiogenesis

IN TUMORS: process is deregulated and there is an imbalance between those 2 causing disturbances in vessel architecture

84
Q

Origin of inhibitors of angiogenesis? Explain.

A

Products of cleavage of ECM proteins (e.g. collagen) because as angiogenesis is taking place, the endothelial cells growing need to degrade ECM proteins to make space => negative feedback

85
Q

List 6 angiogenic factors.

A
  1. Fibroblast growth factors (FGF)
  2. Vascular endothelial growth factor (VEGF)
  3. Placental growth factor (PLGF)
  4. Transforming growth factors (TGF)
  5. Platelet-derived endothelial cell growth factor (PDGF)
  6. Angiopoietins
86
Q

List 6 inhibitors of angiogenesis.

A
  1. Thrombospondin-1
  2. Angiostatin
  3. Endostatin
  4. Interferon alpha
  5. Tissue inhibitors of metallo-proteinases (TIMPS)
  6. Platelet factor 4
87
Q

What initiates the progressive growth of tumors?

A

The angiogenic switch

88
Q

How do tumors invade the local environment?

A
  1. Alteration of cell-cell adhesion molecules
  2. Alteration of cell-extracellular matrix adhesion within the tumor
  3. Degradation of extracellular matrix by proteases released from cancer cells
  4. Migration of cancer cells via autocrine motility factors, stimulated by chemokynes
89
Q

What are 2 examples of chemoattractants that stimulate the migration of cancer cells to invade the local environment?

A
  1. Growth factors

2. Cleaved matrix proteins

90
Q

Describe the steps of metastasis.

A
  1. Invasion of extracellular matrix by primary tumor
  2. Intravasation of tumor cells into blood and lymphatic vessels
  3. Evasion of cell death in blood stream induced by lack of attachment = anoikis
  4. Adherence of circulating tumor cells to the endothelium of the metastatic site
  5. Extravasation and invasion of extracellular matrix at the metastatic site
  6. Formation of colonies and growth of new tumors
91
Q

What does the site of cancer metastasis depend on? 2 factors. What is this called?

A
  1. Location of the primary tumor and its vascular and lymphatic drainage
  2. Tropism of the tumor cells: tumor-specific adhesion molecules recognize their ligands expressed in the endothelium of particular organs

= seed and soil theory

92
Q

How does the immune system react to tumors? What to note?

A

Genetic alterations in the malignant cells often result in expression of new, altered proteins which trigger host immune response => inhibition of tumor growth or its regression

However, tumor cells often acquire resistance to the host immune response

93
Q

How can tumors escape the immune response of the host? 3 mechanisms.

A
  1. Selective outgrowth of antigen negative cells
  2. Loss of expression of MHC-I and/or co-stimulators
  3. Secretion of immunosuppressants, such as transforming growth factor-β (TGF-β)
94
Q

What are the 3 cellular effectors of anti-tumor immunity? Describe how each works.

A
  1. Cytotoxic T lymphocytes (CD8+): recognize peptide antigens presented by MHC class I molecules and require sensitization in the presence of co-stimulatory molecules
  2. Natural killer cells (NK): capable of destroying cells without prior sensitization, do not require MHC-I co-stimulation, and recognize stress proteins
  3. Macrophages: activated by interferon-γ released from T lymphocytes and NK cells, kill tumor cells by release of ROS and TNF
95
Q

What is an example of a cancer that causes a strong host immune response? Why?

A

Melanoma because it has many mutations and abnormal proteins

96
Q

Why does removing the melanoma primary tumor cause metastasis?

A

Because the immune system won’t be as stimulated without the primary tumor

97
Q

What is the role of inflammation in cancer?

A

Non-specific innate immune response is activated by antigen proteins produced by cancer cells causing inflammation => immune cells produce factors that promote:

  1. Cell-death inhibition
  2. Genomic instability
  3. Fibroblast activation
  4. Matrix metabolism
  5. Angiogenesis

leading to:

  1. Pro-growth
  2. Tissue expansion
  3. Malignant conversion

+ inflammation inhibits anti-tumor immunity

98
Q

What 3 external factors can have the same effects as inflammation, which promotes cancer growth?

A
  1. Infections
  2. Obesity
  3. Dietary factors
99
Q

What do tumors contain?

A
  1. Tumor cells
  2. Fibroblasts
  3. Immune cells
  4. Blood vessels
  5. Lymphatic vessels
100
Q

What causes cancer susceptibility?

A
  1. Hereditary genes
  2. Diet
  3. Hormones
101
Q

What causes cancer?

A

Carcinogens:

  1. Some chemicals
  2. Some bacteria and viruses
  3. Radiation
102
Q

What are the 2 types of carcinogens? Describe each and provide examples.

A
  1. Genotoxic carcinogens: interact with DNA causing damage, mutations, and DNA replication errors (e.g. radiation, Benzo(a)pyrene forming DNA adducts)
  2. Non-genotoxic carcinogens: act by changes in expression of genes involved in DNA repair, DNA methylation, cell signaling and proliferation (e.g. estrogen)
103
Q

How does radiation cause cancer? What kinds of cancers is it associated with?

A

UV, x-rays, radionuclides act via direct damage of DNA, cause usually chromosome breakage and translocations

Associated with skin cancer, leukemia, as well as other cancers

104
Q

What is the effect of carcinogenic agents modified by?

A

Individual susceptibility to cancer development, defined by:

  1. Variations in host proteins, such as enzymes involved in metabolism of chemical carcinogens or DNA repair
  2. Variations in host immune response
105
Q

What is a DNA adduct?

A

Segment of DNA bound to a cancer-causing chemical

106
Q

How can viruses contribute to cancer development? 4 examples?

A

By interfering with the internal cell proliferation control molecules

  1. Burkitt’s lymphoma: Epstein-Barr virus
  2. Cervical cancer: Human papilloma virus (HPV)
  3. Liver cancer: Hepatitis B virus (HBV)
  4. T-cell leukemia: Human T-cell leukemia virus 1 (HTLV-1)
107
Q

Are AIDS patients more susceptible to cancer? Explain.

A

Yes because their immune system is suppressed

108
Q

What 2 types of viruses contribute to cancer development?

A
  1. RNA viruses

2. DNA viruses

109
Q

How do RNA viruses contribute to cancer development? Provide examples.

A
  1. Introduction of viral oncogenes, such as V-SRC, V-ABL, V-MYB (not known in humans)
  2. Insertion of strong retroviral promoters next to the cellular oncogene, which results in its overexpression, such Human T-cell leukemia virus-1 (e.g. HTLV-1)
110
Q

How do DNA viruses contribute to cancer development? Provide examples.

A
  1. Synthesis of proteins inactivating human genes involved in cell cycle control (e.g HPV)
  2. Synthesis of proteins stimulating cell proliferation (e.g. EBV, HBV)
  3. Tissue injury leading to the induction of regeneration processes (e.g. HBV)
111
Q

What 2 proteins does HPV inactivate? How?

A
  1. Rb
  2. p53

Both tumor-suppressor proteins

By binding to them

112
Q

What causes tumor progression: inactivation of tumor suppressor genes or activation of oncogenes?

A

Inactivation of tumor suppressor genes

113
Q

What is an example of a tumor that will always progress to become malignant?

A

Colorectal cancer with loss of APC locus

114
Q

Describe the 4 steps of the progression of colorectal cancer.

A
  1. Homozygous loss of APC locus on 5q => cells look normal
  2. Mutational activation of K-ras => cells proliferate and form an adenoma
  3. Loss of DCC and overexpression of COX-2 => more proliferation, larger adenoma, and cells look abnormal
  4. Loss of p53 and activation of telomerase => invasive carcinoma
115
Q

What is the clonal evolution model of tumor progression?

A

Tumor progression from localized, non-malignant lesions to aggressive, metastatic tumors results from progressive accumulation over years of genetic changes, which is facilitated by high genomic instability of cancer cells and leads to heterogeneity of the neoplasia => new clones of cancer cells vary in their phenotypes and acquire new, more malignant features under the pressure of environment (hypoxia, chemotherapy), but initial clones were normal

Overall: the tumor cells evolve, adapt to new conditions, become more malignant and evade treatment

116
Q

Do all tumors progress according to the clonal evolution pattern? Explain.

A

NOPE

E.g. in pediatric tumors changes are usually rapid and often dependent on a mutation in ONE of the crucial growth-controlling genes, so the initial clones can have a malignant phenotype

117
Q

What is the cancer stem cell model of tumor progression?

A

New theory indicating that tumor growth can be driven by small population of cells with self-renewal capacity and high tumorigenic potency called cancer initiating or cancer stem cells (CSCs), which are more resistant to chemo- and radiotherapy, as well as environmental factors as they sustain tumor growth and are responsible for its relapse after treatment

118
Q

What is the main difference between the clonal evolution and the cancer stem cell models of tumor progression?

A

Clonal evolution: all cancer cells can potentially form tumors

Cancer stem cell: cancer cells are heterogeneous and only a small population of cancer stem cells is capable of forming colonies in vitro, tumors in vivo and reproducing all other tumor cell clones and form tumors

119
Q

Can the progeny cells of the cancer stem cells form tumors?

A

NOPE

120
Q

What does it mean for cells to be tumorigenic?

A

Able to form colonies in culture without suspension

121
Q

What is the origin of cancer stem cells?

A

Uncertain and can vary between different tumor types - can be derived from:

  1. Normal stem cells
  2. Progenitor cells
  3. Differentiated cells
122
Q

What is the peak of invasive cancer incidence for both men and women?

A

84-89 yo

123
Q

Are men or women more likely to have invasive cancer?

A

Women until age 60, and then men

124
Q

Why does invasive cancer incidence drop after age 90?

A

Because the host is not as good (e.g. less angiogenesis , wound healing, etc.)

125
Q

Why can tumors stay dormant for a long time?

A
  1. Lack of sufficient genetic alterations
  2. Lack of vascularization
  3. Immune response of the host
126
Q

What are the 2 types of cancer symptoms?

A
  1. Specific

2. Non-specific

127
Q

What are 10 non-specific cancer symptoms? Which are due to cytokines?

A
  1. Unexplained weight loss
  2. Fever
  3. Fatigue*
  4. Pain*
  5. Skin changes
  6. Wasting*
  7. Cognitive changes*
  8. Anxiety*
  9. Depression*
  10. GI disturbances*
128
Q

What is a specific symptoms of lung cancer?

A

Persistent cough

129
Q

What are 3 specific symptoms of colon cancer?

A
  1. Long-term constipation
  2. Long-term diarrhea
  3. Blood in stool
130
Q

What are 3 specific symptoms of pcheochromocytoma?

A
  1. Sweating
  2. Heart palpitations
  3. HT
131
Q

Why do we die of cancer?

A

Wasting due to cytokine-induced cancer symptoms

132
Q

What are some cytokines and chemokines released by cancer cells?

A
  1. IL-1
  2. TNF-alpha
  3. IL-6
  4. IFN
133
Q

Can a benign cancer kill?

A

YUP, depending on the location

134
Q

Can a benign cancer kill?

A

YUP, depending on the location

135
Q

7 ways to diagnose cancer?

A
  1. Imaging: X-ray, ultrasonography, computed tomography (CT), positron emission tomography (PET), MRI, or combinations
  2. Biopsy: histopathological analysis
  3. Immunocytochemistry: biochemical assays detecting tumor-specific markers like antigens, enzymes and hormones (e.g. PSA for prostate cancer, CEA for gastrointestinal tumors)
  4. Molecular diagnosis detecting characteristic chromosomal aberrations or tumor markers: Fluorescent In Situ Hybridization (FISH) or tumor-specific proteins via gene amplification (Polymerase Chain Reaction, PCR)
  5. Molecular profiling: characterization of tumors in terms of their protein expression pattern to diagnose, facilitate their stratification or tailor tumor therapy
  6. Genetic screening: identification of high risk population (e.g. DNA screening for BRCA mutations)
  7. Flow cytometry: detection of residual disease using tumor-specific antibodies
136
Q

How does a PET scan work?

A

Radioactive tracer detecting areas of high metabolic activity

137
Q

2 examples of when FISH could be used to diagnose cancer?

A
  1. BCR-ABL in chronic myeloid leukemia

2. EWS-FLI1 in Ewing’s sarcoma (fusion protein)

138
Q

3 examples of when PCR could be used to diagnose cancer?

A
  1. HER-2 in breast cancer
  2. N-MYC in neuroblastoma
  3. EWS-FLI1 in Ewing’s sarcoma (fusion protein)
139
Q

1 example of when flow cytometry could be used to diagnose cancer? How does this work?

A

Childhood acute leukemia because leukemic cells express specific antigens on the surface, which can be detected with antibodies

Bone marrow cells are collected, stained with fluorescently-labeled tumor-specific antibodies and then sorted based on the level of fluorescence. There are no fluorescent cells detected in the normal bone marrow. However, some tumor cells are detected in the bone marrow of the child after therapy.

140
Q

Do high PSA levels mean prostate cancer?

A

Not necessarily

141
Q

What are the 3 conventional, non-specific cancer therapies?

A
  1. Surgery (local)
  2. Radiotherapy (local)
  3. Chemotherapy (systemic treatment – targets metastases and residual disease)
142
Q

What cells do chemo and radiotherapy target? What does this mean in terms of side effects?

A

Target all rapidly dividing cells and due to this cause side effects in growing tissues:

  1. Hair loss
  2. Gastrointestinal system dysfunction: mouth sores, difficulty in swallowing, nausea and vomiting, diarrhea
  3. Skin reaction
  4. Bone marrow: depletion of immune cells (susceptibility to infections) and erythrocytes (anemia)
143
Q

4 long-term effects of chemo and radiotherapy?

A
  1. Infertility
  2. Secondary cancers
  3. Osteoporosis
  4. Growth abnormalities
144
Q

3 issues with conventional cancer treatments?

A
  1. High toxicity of the conventional treatments
  2. Common acquired resistance to them
  3. Frequent tumor relapses
145
Q

Recent research on cancer therapies?

A
  1. Therapies to target not only proliferating cancer cells, but also cancer stem cells, often not sensitive to radio- and chemotherapy
  2. Tailored therapy designed based on specific cancer phenotype for the particular patient
146
Q

What are 7 types of cancer-specific therapies? Provide examples for each.

A
  1. Hormone therapies: anti-estrogen for breast cancer, anti-androgen for prostate cancer
  2. Inhibitors of cell signaling molecules: tyrosine kinase inhibitors, mTor inhibitors
  3. Anti-angiogenic therapies: VEGF targeting like Talidomide
  4. Immune therapies (therapeutic and preventing): cancer vaccines, antibodies, cytokine treatment, cell transfer therapies
  5. Gene therapy: modification of the immune response, replacement of mutated/missing tumor suppressor, knockdown of oncogenes, suicide gene therapy
  6. Therapies targeting tumor-specific proteins: inhibition of EWS-FLI 1 interactions with target proteins (RHA) in Ewing’s sarcoma
  7. Embolization: selective occlusion of blood vessels feeding the tumor (e.g. uterine fibroids)
147
Q

Why is it so difficult to treat cancer?

A
  1. Cancer cells use the same mechanisms of cell proliferation as normal cells, therefore conventional cancer therapies usually target all proliferating cells in the body
  2. Cancer is a very heterogeneous disease and cell aberrations vary significantly between different types of cancers, between patients with the same type of cancer, between subclones of the tumor cells derived from the same patient
  3. Genetic instability of cancer cells allows them to adapt to the new conditions, acquire drug resistance and develop more malignant phenotype
148
Q

What is a theory regarding what cancer cells are resistant to chemotherapy?

A

Cancer stem cells because they do not proliferate as fast as the other so are not targeted by the therapy

149
Q

3 examples of tyrosine kinase inhibitors to treat cancer?

A
  1. EGFR inhibitors
  2. BCR-ABL inhibitors for chronic myeloid leukemia
  3. ALK inhibitors for lung cancer and neuroblastoma
150
Q

2 types of immunotherapies to treat cancer? Describe each.

A
  1. Active: stimulate the body’s own immune system to fight cancer: cancer vaccines and cytokines
  2. Passive: rely on the immune system components created outside of the body: monoclonal antibodies and T-cell therapies (T cells then also prevent relapse)
151
Q

Issues with angiogenesis inhibitors to treat cancer? Explain. Solution?

A
  1. Vascular mimicry: hypoxic tumor cells are often able to form perfused vessel-like structures without endothelial cells and these pseudo-vessels (blood lakes) increase tissue perfusion and may confer resistance to anti-angiogenic therapies
  2. Hypoxia stimulates metastasis
  3. Chemotherapy treatment cannot access the tumor if it does not have blood vessels

Solution: use treatments along with chemotherapy as the tumor will undergo vessel normalization after treatment which will improve drug delivery

152
Q

What is epigenetic therapy to treat cancer? Is it specific?

A

Silencing by DNA methylation and histone modifications contributes to inhibition of tumor suppressor genes and carcinogenesis so epigenetic therapies (demethylating agents, histone deacetylase (HDAC) inhibitors) revert this process and suppress tumor cell proliferation and angiogenesis

Non-specific

153
Q

What is tumor necrosis a sign of?

A

Bad prognosis for the tumor as it reflects hypoxia => malignancy

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