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Pathology > Neoplasia > Flashcards

Neoplasia Flashcards

1
Q

What are the two basic components of all tumors (benign and malignant)?

A
  1. Clonal neoplastic cells that constitute their parenchyma.

2. Reactive stroma made up of connective tissue, blood vessels, and variable numbers of macrophages and lymphocytes.

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2
Q

What is desmoplasia?

A

The parenchymal cells stimulate the formation of an abundant collagenous stroma (some stony breast cancer).

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3
Q

What is a teratoma?

A

A tumor which contains recognizable mature or immature cells or tissues representative of more than one germ layer and sometimes all three.

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4
Q

On what basis can benign and malignant tumors be distinguished?

A

On the basis of :

  1. Differentiation
  2. Anaplasia
  3. Rate of growth
  4. Local invasion
  5. Metastasis
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5
Q

To what does differentiation refer?

A

To the extent to which neoplastic parenchymal cells resemble the corresponding normal parenchymal cells, both morphologically and functionally.

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6
Q

What is called anaplasia?

A

Lack of differentiation.

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7
Q

What is the hallmark of malignancy?

A

Lack of differentiation (anaplasia).

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8
Q

With what other morphologic changes is anaplasia associated?

A
  1. Pleomorphism : variation in size - shape.
  2. Abnormal nuclear morphology : hyperchromatic and 1:1 with cytoplasm.
  3. Large number of mitoses.
  4. Loss of polarity : the orientation of anaplastic is markedly disturbed.
  5. Other changes : formation of tumor giant cells - ischemic necrosis.
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9
Q

What is dysplasia?

A

Literally means disordered growth.
It is encountered principally in epithelia - constellation of changes : loss of uniformity of the individual cells + loss of architectural orientation.

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10
Q

How many population doublings must the original transformed cell undergo, before it is detectable?

A

30 population doublings to produce 10^9 cells - 1gm : the smallest clinically detectable mass.

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11
Q

What are the three major factors that determine the rate of growth of a tumor?

A
  1. The doubling time of the tumor cells.
  2. The fraction of tumor cells that are in the replicative pool.
  3. The rate at which cells are shed or die.
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12
Q

Is the cell cycle time for many tumors equal or longer than that of the corresponding normal cells?

A

Most times it is longer - growth of tumors is not associated with shortening of cell cycle time.

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13
Q

What is the growth fraction and what is its value even for rapidly growing tumors?

A

The proportion of cells within the tumor population that are in the proliferative pool - 20% or less.

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14
Q

What important conceptual and practical lessons can be learned from the studies of tumor cell kinetics?

A
  1. Fast growing tumors have a high cell turnover (both proliferation and apoptosis are high).
  2. The growth fraction of tumor cells has a profound effect on their susceptibility to cancer chemotherapy - most anticancer agents act on cells that are in cycle.
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15
Q

Is there a relationship between growth rate and level of differentiation?

A

Yes! Growth rate of tumors correlates with their level of differentiation - most malignant grow more rapidly than do benign lesions.

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16
Q

By what is accompanied the growth of cancers?

A
  1. Progressive infiltration
  2. Invasion
  3. Destruction of the surrounding tissues
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17
Q

Next to the development of metastases, what is the most reliable feature that differentiates malignant from benign tumors?

A

Invasiveness

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18
Q

What are the major exceptions of malignant tumors that do not metastasize (rarely)?

A
  1. Gliomas of CNS.

2. Basal cell carcinoma of the skin.

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19
Q

What are the three major pathways via which dissemination of cancers may occur?

A
  1. Direct seeding of body cavities and surfaces (ovarian carcinoma).
  2. Lymphatic spread (carcinomas mainly).
  3. Hematogenous spread (sarcomas mainly).
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20
Q

What is “skip metastasis”?

A

In lymphatic spread (metastasis), local lymph nodes may be bypassed : venous-lymphatic anastomoses / inflammation/ radiation has obliterated the lymphatic channels.

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21
Q

What is a sentinel node?

A

The first node in a regional lymphatic basin that receives lymph flow from the primary tumor.

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22
Q

Does nodal enlargement in proximity to a cancer always mean dissemination of the primary lesion ?

A

No! It can also mean reactive hyperplasia against the tumor cells.

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23
Q

Mention two important features that characterize inherited cancer syndromes.

A
  1. In each syndrome, tumors tend to arise in specific sites and tissues, although they may involve more than one site.
  2. Tumors within this group are often associated with a specific marker phenotype.
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24
Q

Mention some important features of familial cancers.

A
  1. Early age at onset.
  2. Tumors arise at two or more close relatives of the index case.
  3. Multiple or bilateral tumors.
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25
Q

Mention some precancerous conditions.

A
  1. Chronic atrophic gastritis of pernicious anemia.
  2. Solar keratosis of the skin.
  3. Chronic ulcerative colitis
  4. Leukoplakia of the oral cavity, vulva and penis.
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26
Q

Mention some fundamental principles of the molecular basis of cancer.

A
  1. Nonlethal genetic damage lies at the heart of carcinogenesis.
  2. Tumors are monoclonal - clonal expansion of a single precursor
  3. Four classes of normal regulatory genes - growth promoting oncogenes / growth inhibiting tumor suppressor genes / genes that regulate apoptosis / genes involved in DNA repair : principal targets of damage.
  4. Carcinogenesis is a multistep process at both the phenotypic and the genetic levels, resulting from the accumulation of multiple mutations.
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27
Q

Mention the 7 fundamental changes in cell physiology that together determine malignant phenotype.

A
  1. Self-sufficiency in growth signals.
  2. Insensitivity to growth-inhibitory signals.
  3. Evasion of apoptosis.
  4. Limitless replicative potential.
  5. Sustained angiogenesis.
  6. Ability to invade and metastasize.
  7. Defects in DNA repair.
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28
Q

What is called oncogene?

A

Genes that promote autonomous cell growth in cancer cells - their unmutated cellular counterparts are called proto-oncogenes.

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29
Q

What happens to the oncogenic versions of growth factor receptors?

A

They are associated with constitutive dimerization and activation without binding to the growth factor.

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30
Q

What is the RET protein?

A

A receptor for the glial-cell line-derived neurotrophic factor and structurally related proteins that promote cell survival during neural development.

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31
Q

With what are point mutations in RET proto-oncogene associated?

A

With dominantly inherited MEN types 2A and 2B + familial medullary thyroid carcinoma.

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32
Q

How many RAS genes exist in the human genome?

A

3 : HRAS, KRAS, NRAS.

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33
Q

What is the single most common abnormality of proto-oncogenes in human tumors?

A

Point mutation of RAS family genes.

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34
Q

What tumors have mutations in the KRAS, HRAS and NRAS genes respectively?

A
  1. KRAS : carcinomas of the colon and pancreas.
  2. HRAS : bladder tumors.
  3. NRAS : hematopoietic tumors.
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35
Q

On what depends the orderly cycling of the RAS protein?

A
  1. Nucleotide exchange (GDP by GTP) : activation of RAS protein.
  2. GTP hydrolysis : conversion of GTP bound active RAS to the GDP bound inactive form.
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36
Q

What is the function of GAPs (GTPase-activating proteins)?

A

Function as “brakes” that prevent uncontrolled RAS activity.

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37
Q

Mention one important example of alteration in non receptor tyrosine kinases.

A

c-ABL tyrosine kinase : oncogenic BCR-ABL tyrosine kinase.

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38
Q

Mention some important oncogenes of whom the proteins are transcription factors.

A
  1. MYC (most commonly involved)
  2. MYB
  3. JUN
  4. FOS
  5. REL
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39
Q

Mention some cancers with dysregulation of MYC expression.

A
  1. Burkitt lymphoma

2. Cases of breast/colon/lung + other carcinomas.

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40
Q

With what cancers are N-MYC and L-MYC associated?

A

N-MYC : neuroblastoma

L-MYC : small-cell carcinoma of the lung.

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41
Q

What is the main function of the products of tumor suppressor genes?

A

To apply brakes to cell proliferation.

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42
Q

What may the function of the protein product of tumor suppressor genes be?

A
  1. Transcription factors
  2. Cell cycle inhibitors
  3. Signal transduction molecules
  4. Cell surface receptors
  5. Regulators of cellular responses to DNA damage
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43
Q

In molecular terms, how can Knudson’s hypothesis for retinoblastoma be stated?

A
  1. Two mutations (hits), involving both alleles of RB at chromosome locus 13q14 are required to produce retinoblastoma.
  2. In familial cases, one defective copy of RB is inherited (one hit). The other is a result of spontaneous somatic mutation (second hit).
  3. In sporadic cases : both normal RB alleles must undergo somatic mutation in the same retinoblast (two hits).
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44
Q

Besides RB, mention other cases in which loss of heterozygosity plays a similar role.

A

One or more genes on 11p :

  1. Wilms’ tumor
  2. Hepatoblastoma
  3. Rhabdomyosarcoma
  4. von Hippel-Lindau gene
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45
Q

What are the two forms of RB?

A
  1. Active : hypophosphorylated in quiescent cells.

2. Inactive : hyperphosphorylated in the G1/S cell cycle transition.

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46
Q

Where does RB primarily act?

A

It binds to E2F transcription factors (with histone deacetylase and methyltransferase) and prevents transcription of cyclin E, thus preventing DNA replication and progression through the cell cycle.

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47
Q

What other functions does RB elicit?

A

It stimulates myocyte, adipocyte, melanocyte, and macrophage- specific transcription factors : couples control of cell cycle progression at G1 with differentiation.
+ can also induce senescence.

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48
Q

Why do patients with germline mutation of the RB locus develop mainly retinoblastomas?

A

Not fully understood.
RB family members may partially complement its function in cell types other than retinoblasts (pocket proteins : p107 and p130).

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49
Q

Why are inactivating mutations of RB not much more common in human cancers?

A

Mutations in other genes (p16/INK4a, cyclin D, CDK4) that control RB phosphorylation/pathway can mimic the effect of RB loss and such genes are mutated in many cancers that may have normal RB genes.

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50
Q

Where is p53 gene located?

A

17p13.1

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51
Q

What is the most common target for genetic alteration in human tumors?

A

p53

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52
Q

What is the Li-Fraumeni syndrome?

A

Individuals with one inherited mutant p53 allele : 25-fold greater chance of developing malignant tumor by age 50 than the general population.

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53
Q

What are the three interlocking mechanisms by which p53 thwarts neoplastic transformation?

A
  1. Activation of temporary cell cycle arrest (quiescence).
  2. Induction of permanent cell cycle arrest (senescence).
  3. Triggering of apoptosis.
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54
Q

What is the half-life of p53?

A

20 min

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55
Q

What are the two broad categories of genes whose transcription is triggered by p53?

A
  1. Those that cause cell cycle arrest.

2. Those that cause apoptosis.

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56
Q

What miRNAs does the p53 activate?

A

mir34 family (a,b,c) : bind to cognate sequences in the 3’ untranslated region of mRNA, preventing translation.

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57
Q

What are the two key initiators of the DNA-damage pathway?

A

Two related protein kinases :

  1. Ataxia-telangiectasia mutated (ATM).
  2. Ataxia-telangiectasia and Rad3 related (ATR).
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58
Q

What may be considered as the primordial response to DNA damage?

A

p53-mediated cell cycle arrest.

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59
Q

What other family members of p53 exist?

A

p63 and p73 : more tissue specific (p63 for differentiation of stratified squamous epithelia and p73 strong pro-apoptotic effects after DNA damage induced by chemo).

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60
Q

What is APC?

A
  1. Adenomatous polyposis coli.
  2. Class of tumor suppressors - down regulation of growth promoting signals.
  3. Germline mutations at the APC loci (5q21) : familial adenomatous polyposis.
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61
Q

Of what pathway is APC a component?

A

WNT signaling pathway : control of cell fate, adhesion and polarity during embryonic development + also for self-renewal of hematopoietic cells.

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62
Q

Mention one important function of APC protein.

A

Down-regulation of β-catenin - preventing its accumulation in the cytoplasm.

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63
Q

What is the function of β-catenin?

A
  1. Translocates to the nucleus.
  2. Forms a complex with TCF.
  3. TCF is a transcription factor that up-regulates cellular proliferation by increasing c-MYC and cyclin D1 + others.
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64
Q

What is the relationship between E-Cadherin and β-catenin?

A

E-Cadherin is a cell surface adhesion protein maintaining cell to cell contact.
β-catenin binds to cytoplasmic tail of E-Cadherin.
So, when loss of intercellular contact occurs (wound), β-catenin promotes proliferation.

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65
Q

Mention some other important genes that function as tumor suppressors.

A
  1. INK4a/ARF
  2. The TGF-β pathway
  3. PTEN
  4. NF1/2
  5. VHL (von Hippel Lindau)
  6. WT1
  7. PTCH 1/2 (patched)
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66
Q

Besides activation of oncogenes and inactivation of tumor suppressor genes, what other barrier must be surmounted for cancer to occur?

A

Apoptosis

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67
Q

What is termed anoikis?

A

Form of apoptosis that is induced by anchorage-dependent cell detaching from the surrounding ECM.

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68
Q

Mention some important sites of extrinsic and intrinsic pathway of apoptosis which are frustrated by cancer cells.

A
  1. Surface : reduced levels of CD95/Fas may render tumor cells less susceptible to apoptosis by CD95L/FasL.
  2. Some tumors : high levels of FLIP - prevents activation of caspase 8.
  3. Overexpression of BCL-2 : protecting tumor cells from apoptosis.
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69
Q

What cancers are associated principally with overexpression of BCL-2 ?

A

85% of B-cell lymphomas of the follicular type.

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70
Q

Besides loss of growth restraints, mention another important aspect that must be developed for the tumor cells to grow indefinitely.

A

They must also avoid both cellular senescence + mitotic catastrophe (telomerases).

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71
Q

What effects has neovascularization on tumor growth?

A
  1. Perfusion supplies needed nutrients and oxygen.
  2. Newly formed endothelial cells stimulate the growth of adjacent tumor cells - secretion of growth factors.
  3. Metastasis - correlate of malignancy.
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72
Q

Mention three potent angiogenesis inhibitors.

A
  1. Angiostatin
  2. Endostatin
  3. Vasculostatin
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73
Q

What are the two phases of metastatic cascade? (Division only for practical purposes).

A
  1. Invasion of the ECM.

2. Vascular dissemination, homing of tumor cells, and colonization.

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74
Q

What are the principal steps of the metastatic cascade?

A
  1. Clonal expansion - growth - diversification - angiogenesis.
  2. Metastatic subclone.
  3. Adhesion to and invasion of basement membrane.
  4. Passage through extracellular matrix.
  5. Intravasation.
  6. Interaction with host lymphoid cells.
  7. Tumor cell embolus
  8. Adhesion to basement membrane.
  9. Extravasation
  10. Metastatic deposit
  11. Angiogenesis
  12. Growth
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75
Q

What are the steps of invasion of the ECM in metastasis?

A
  1. Changes (loosening up) of tumor cell-cell interactions.
  2. Degradation of ECM.
  3. Attachment to novel ECM components.
  4. Migration of tumor cells.
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76
Q

Mention three important proteases that have been implicated in tumor cell invasion of the ECM.

A
  1. Matrix metalloproteinases (MMPs).
  2. Cathepsin D.
  3. Urokinase plasminogen activator.
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77
Q

Besides the classical mode of invasion (with proteases), is there another way for tumor cells to invade ECM?

A

Yes!
Ameboid migration + the tumor cells are able to switch between the two forms of migration (explaining the disappointing results of MMP inhibitors).

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78
Q

Mention some mechanisms that may explain the organ tropism of tumor cells that metastasize.

A
  1. Tumor cells may have adhesion molecules, whose ligands are expressed preferentially on the endothelial cells of the target organ.
  2. Chemokines - CXCR4 and CCR7 expressed in breast cancer - the chemokines that bind to these receptors are highly expressed in tissues to which breast cancer commonly metastasize.
  3. In some cases : tissue may be a nonpermissive environment - unfavorable soil for growth of tumor cells - skeletal muscle.
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79
Q

What are the three principal types of defects in DNA-repair systems?

A
  1. Mismatch repair
  2. Nucleotide excision repair
  3. Recombination repair
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80
Q

What is the major hallmark of patients with mismatch-repair defects?

A

Microsatellite instability

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81
Q

What are the microsatellites?

A

Tandem repeats of 1-6 nucleotides found throughout the genome.

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82
Q

What abnormality does UV radiation cause?

A

Cross-linking of pyrimidine residues, preventing normal DNA replication - repair by nucleotide excision repair system.

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83
Q

What role do the macrophages and fibroblasts have in the progression of the tumor?

A

Macrophages : secrete factors that promote metastasis.

Fibroblasts : secrete the matrix that results in the desmoplastic response to tumors.

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84
Q

What is the “eight hallmark” of cancer?

A

The Warburg effect : even in the presence of adequate oxygen, the tumor cells produce ATP via glycolysis.

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85
Q

What is the most plausible hypothesis for the explanation of the Warburg effect?

A

This altered metabolism of tumor cells provides them with glucose and aminoacids that are essential for the anabolic pathways - enables them to synthesize the building blocks that are required for cell division.

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86
Q

What is the main pathway by which growth factors stimulate glucose and amino acid uptake?

A

PI3K/AKT/mTOR pathway.

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87
Q

Why is the study of chromosomal changes in tumor cells important ?

A
  1. Molecular cloning of genes in the vicinity of chromosomal breakpoints or deletions has been extremely useful in identification of oncogenes and tumor suppressor genes.
  2. Certain karyotypic abnormalities have diagnostic value / predictive of clinical course.
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88
Q

What are the two types of chromosomal rearrangements that can activate proto-oncogenes?

A

Translocations (much more common) and inversions.

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89
Q

What are the two ways with which translocations can activate proto-oncogenes?

A
  1. Lymphoid tumors : overexpression of proto-oncogenes by swapping their regulatory elements with those of another gene.
  2. Hematopoietic tumors/sarcomas/certain carcinomas : translocation results in formation of chimeric proteins.
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90
Q

Compared with translocations, where are deletion more common?

A

In non hematopoietic solid tumors (RB).

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91
Q

What are the two mutually exclusive patterns that are seen in gene amplification?

A

Multiple small, centric structures called :

  1. Doubles minutes
  2. Homogenous staining regions
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92
Q

What is epigenetics?

A

Refers to reversible, heritable changes in gene expression, that occurs without mutation :

  1. Post translational modifications of histones.
  2. DNA methylation.
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93
Q

What are the miRNAs?

A

Small noncoding, single-stranded RNAs (22nt), that are incorporated into the RNA-induced silencing complex.

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94
Q

What is the major function of miRNAs ?

A

Mediate post transcriptional gene silencing.

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95
Q

How many mutant genes does a tumor have in average ?

A

90 mutant genes.

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96
Q

Mention some important concepts relating to the initiation-promotion sequence in carcinogenesis.

A
  1. Initiation results from exposure of cells to a sufficient dose of a carcinogenic agent (initiator).
  2. Initiation causes permanent DNA damage (mutations). It is therefore rapid and irreversible and has “memory”.
  3. Promoters can induce tumors in initiated cells, but they are nontumorigenic by themselves.
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97
Q

What features do all initiating chemical carcinogens have?

A
  1. Highly reactive electrophiles.

2. Can react with nucleophilic (electron-rich) sites in the cells (DNA, RNA, proteins).

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98
Q

What are the two categories of chemicals that cause initiation of carcinogenesis?

A
  1. Direct acting (no metabolic conversion)

2. Indirect acting (require metabolic conversion)

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99
Q

What determines the carcinogenic potency of a chemical?

A
  1. The inherited reactivity of its electrophilic derivative.

2. The balance between metabolic activation and inactivation reactions.

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100
Q

What metabolizes most of the known carcinogens?

A

Cytochrome P450-dependent mono-oxygenases. (Quite polymorphic genes - cancer risk…).

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101
Q

What are the promoters?

A

Agents that do not cause mutation, but instead they stimulate the division of mutated cells.

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102
Q

What can UV rays cause?

A

Cancers of the skin :

  1. Squamous cell carcinoma
  2. Basal cell carcinoma
  3. Melanoma
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103
Q

Where is the carcinogenicity of UVB light attributed?

A

The formation of pyrimidine diners in DNA. (Repaired by the nucleotide excision repair pathway)

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104
Q

What are the most frequent ionizing radiation-induced cancers?

A

Acute and chronic myeloid leukemia.

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105
Q

What is the first bacterium that has been classified as carcinogen ?

A

Helicobacter pylori - gastric adenocarcinoma and gastric lymphoma.

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106
Q

What is the only retrovirus that is associated with the causation of cancer in humans?

A

HTLV-1 : adult T-cell leukemia/lymphoma.

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107
Q

What is the gene of HTLV-1 mainly responsible for its oncogenic abilities?

A

The Tax gene.

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108
Q

What are the main functions of the Tax protein?

A
  1. Essential for viral replication
  2. Activation of the transcription of host genes involved in proliferation and differentiation of T-cells.
  3. Inactivation of cell cycle inhibitor p16/INK4a.
  4. Enhancement of cyclin D.
  5. Activation of NF-kB.
  6. Interferes with DNA -repair functions - inhibits ATM-mediated cell cycle checkpoints.
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109
Q

Mention some important oncogenic DNA viruses.

A
  1. HPV (high risk 16, 18, 31)
  2. EBV
  3. HBV
  4. Kaposi sarcoma herpesvirus - HHV8
  5. Merkel cell polyomavirus
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110
Q

What are the main functions of high risk HPVs?

A

Expression of oncogenic proteins that :

  1. Inactivate tumor suppressors
  2. Activate cyclins
  3. Inhibit apoptosis and combat cellular senescence
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111
Q

What are the tumors that EBV is related to?

A
  1. African form of Burkitt lymphoma.
  2. B-cell lymphomas in immunosuppressed individuals.
  3. Subset of Hodgkin lymphoma.
  4. Nasopharyngeal and some gastric carcinomas.
  5. Rare forms of T-cell lymphoma and NK cell lymphomas.
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112
Q

What evidence support the causative relationship between Burkitt lymphoma and EBV ?

A
  1. More than 90% of African tumors carry the EBV genome.
  2. 100% have elevated body titers against viral capsid antigens.
  3. Serum antibody titers against viral capsid antigens are correlated with the risk of developing the tumor.
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113
Q

What are the principal observations that suggest the existence of additional factors in the causation of Burkitt lymphoma (besides EBV)?

A
  1. EBV is not limited to the geographic locales of Burkitt lymphoma.
  2. EBV genome is found in only 15-20% of sufferers of Burkitt lymphoma outside Africa.
  3. There are significant differences in viral gene expression in EBV-transformed (but not tumorigenic) B cells and Burkitt lymphoma cells. (Burkitt lymphoma cells do not express LMP-1 and EBNA2).
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114
Q

For what is the term cancer immunoediting being used?

A

To describe the effects of the immune system in preventing tumor formation and also in “sculpting” the immunogenic properties of tumors to select tumor cells that escape immune elimination.

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115
Q

How are the tumor antigens classified ?

A

Based on their molecular structure and source.

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116
Q

What are the basic types of tumor antigens?

A
  1. Product of oncogene or mutated tumor suppressor gene.
  2. Mutated self protein.
  3. Over expressed or aberrantly expressed self protein.
  4. Oncogenic virus.
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117
Q

Mention some examples of oncogene and mutated tumor suppressor gene products that act as tumor antigens.

A
  1. Mutated RAS
  2. Mutated BCR/ABL fusion proteins
  3. Mutated p53 protein
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118
Q

Mention some basic examples of overexpression or aberrant expression of self proteins that act as tumor antigens.

A 
In melanomas :
1. Tyrosinase
2. gp100
3. MART
Aberrantly expressed :
Cancer-testis antigens (MAGE, BAGE).
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119
Q

Mention some tumor antigens from oncogenic viruses.

A
  1. HPV : E6 and E7 proteins in cervical carcinoma.

2. EBNA proteins in EBV-induced lymphoma.

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120
Q

What are the oncofetal antigens?

A

Proteins that are expressed at high levels on cancer cells and in normal developing (fetal) but not adult tissues.

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121
Q

What are the two most thoroughly characterized oncofetal antigens?

A
  1. Carcinoembryonic antigen (CEA)

2. α-fetoprotein (AFP)

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122
Q

What is the dominant antitumor mechanism in vivo?

A

Cell-mediated immunity

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123
Q

What are the cellular effectors that mediate immunity?

A
  1. CTLs
  2. NK cells (first line of defense)
  3. Macrophages
  4. Antibodies
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124
Q

The tumor cells must develop mechanisms to escape or evade the immune system in immunocompetent hosts. Mention some principal ones.

A
  1. Selective outgrowth of antigen-negative variants.
  2. Loss or reduced expression of MHC molecules.
  3. Lack of costimulation.
  4. Immunosuppression.
  5. Antigen masking.
  6. Apoptosis of CTLs.
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125
Q

Although the neoplastic cells largely determine the tumor’s behavior and pathologic consequences, on what does their growth and evolution depend on?

A

On their reactive stroma made up of connective tissue, blood vessels, and variable numbers of lymphocytes and macrophages.

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126
Q

What is a papilloma?

A

Benign epithelial neoplasms producing microscopically or macroscopically visible finger-like or warty projections from epithelial surfaces.

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127
Q

What is a polyp?

A

A neoplasm, benign or malignant, that produces a macroscopically visible projection above a mucosal surface and projects into the gastric or colonic lumen.

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128
Q

What is a sarcoma and what is a carcinoma?

A

Sarcomas : malignant tumors arising in mesenchymal tissue.

Carcinomas : malignant neoplasms of epithelial cell origin, derived from any of the three germ layers.

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129
Q

What is a mixed tumor?

A

Infrequently, divergent differentiation of a single neoplastic clone along two lineages creates what are called mixed tumors (i.e. mixed tumor of salivary gland origin).

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130
Q

What is an ovarian cystic teratoma (dermoid cyst)?

A

It is a teratoma consisting of cells which differentiate principally along ectodermal lines to create a cystic tumor lined by skin replete with hair, sebaceous glands, and tooth structures.

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131
Q

What is an Hamartoma?

A

A disorganized but benign appearing mass composed of cells indigenous to the particular site.

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132
Q

What is a carcinoma in situ?

A

When dysplastic changes are marked and involve the entire thickness of the epithelium but the lesion remains confined by the basement membrane, it is considered a preinvasive neoplasm and is referred to as carcinoma in situ.

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133
Q

After they become clinically detectable, what is the average volume-doubling time for such common killers as cancer of the lung and colon?

A

2-3 months.

134
Q

What are the main implications of the concept of cancer stem cells?

A
  1. If cancer stem cells are essential for tumor persistence, it follows that elimination of these cells should lead to cure.
  2. It is hypothesized that like normal stem cells, these cells have a high intrinsic resistance to conventional therapies, because of their low rate of division and expression of factors, such as multiple drug resistance-1 (MDR-1).
135
Q

From where do cancer stem cells arise?

A
  1. From normal tissue stem cells.

2. From more differentiated cells that as part of the transformation process acquire the property of self renewal.

136
Q

What are the tumor initiating cells? (T-ICs)

A

Cells that allow a human tumor to grow and maintain itself indefinitely, when transplanted into an immunodeficient mouse.

137
Q

Mention some cancers that seem to evolve from a preinvasive stage referred to as carcinoma in situ?

A
  1. Carcinomas of the skin
  2. Carcinomas of the breast
  3. Carcinomas of the uterine cervix
138
Q

What percentage of newly diagnosed individuals with solid tumors present with metastases?

A

30%

139
Q

Mention two carcinomas that seed the peritoneal cavity.

A
  1. Ovarian carcinoma

2. Mucus-secreting appendiceal carcinomas

140
Q

In breast cancer, why it is important to determine the involvement of axillary lymph nodes?

A

For assessing the future course of the disease and for selecting suitable therapeutic strategies.

141
Q

Besides spread of breast cancer, in what other cancers has sentinel node biopsy been used for detecting the spread?

A

For detecting the spread of :

  1. Melanomas
  2. Colon cancers
  3. Other tumors
142
Q

What are the two sites that are most frequently involved in hematogenous spread?

A
  1. Liver

2. Lungs

143
Q

Where do thyroid and prostate cancers frequently spread hematogenously?

A

In the vertebral column.

144
Q

What tumors have a propensity for invasion of veins?

A
  1. Renal cell carcinoma

2. Hepatocellular carcinoma

145
Q

Is intravenous tumor growth accompanied by widespread dissemination?

A

Remarkably, it is not!

146
Q

Mention some “weird” metastases.

A
  1. Breast carcinoma spreads to bone.
  2. Bronchogenic carcinomas tend to involve the adrenals and the brain.
  3. Neuroblastomas spread to the liver and bones.
147
Q

Although the neoplastic cells largely determine the tumor’s behavior and pathologic consequences, on what does their growth and evolution depend on?

A

On their reactive stroma made up of connective tissue, blood vessels, and variable numbers of lymphocytes and macrophages.

148
Q

What is a papilloma?

A

Benign epithelial neoplasms producing microscopically or macroscopically visible finger-like or warty projections from epithelial surfaces.

149
Q

What is a polyp?

A

A neoplasm, benign or malignant, that produces a macroscopically visible projection above a mucosal surface and projects into the gastric or colonic lumen.

150
Q

What is a sarcoma and what is a carcinoma?

A

Sarcomas : malignant tumors arising in mesenchymal tissue.

Carcinomas : malignant neoplasms of epithelial cell origin, derived from any of the three germ layers.

151
Q

What is a mixed tumor?

A

Infrequently, divergent differentiation of a single neoplastic clone along two lineages creates what are called mixed tumors (i.e. mixed tumor of salivary gland origin).

152
Q

What is an ovarian cystic teratoma (dermoid cyst)?

A

It is a teratoma consisting of cells which differentiate principally along ectodermal lines to create a cystic tumor lined by skin replete with hair, sebaceous glands, and tooth structures.

153
Q

What is an Hamartoma?

A

A disorganized but benign appearing mass composed of cells indigenous to the particular site.

154
Q

What is a carcinoma in situ?

A

When dysplastic changes are marked and involve the entire thickness of the epithelium but the lesion remains confined by the basement membrane, it is considered a preinvasive neoplasm and is referred to as carcinoma in situ.

155
Q

After they become clinically detectable, what is the average volume-doubling time for such common killers as cancer of the lung and colon?

A

2-3 months.

156
Q

What are the main implications of the concept of cancer stem cells?

A
  1. If cancer stem cells are essential for tumor persistence, it follows that elimination of these cells should lead to cure.
  2. It is hypothesized that like normal stem cells, these cells have a high intrinsic resistance to conventional therapies, because of their low rate of division and expression of factors, such as multiple drug resistance-1 (MDR-1).
157
Q

From where do cancer stem cells arise?

A
  1. From normal tissue stem cells.

2. From more differentiated cells that as part of the transformation process acquire the property of self renewal.

158
Q

What are the tumor initiating cells? (T-ICs)

A

Cells that allow a human tumor to grow and maintain itself indefinitely, when transplanted into an immunodeficient mouse.

159
Q

Mention some cancers that seem to evolve from a preinvasive stage referred to as carcinoma in situ?

A
  1. Carcinomas of the skin
  2. Carcinomas of the breast
  3. Carcinomas of the uterine cervix
160
Q

What percentage of newly diagnosed individuals with solid tumors present with metastases?

A

30%

161
Q

Mention two carcinomas that seed the peritoneal cavity.

A
  1. Ovarian carcinoma

2. Mucus-secreting appendiceal carcinomas

162
Q

In breast cancer, why it is important to determine the involvement of axillary lymph nodes?

A

For assessing the future course of the disease and for selecting suitable therapeutic strategies.

163
Q

Besides spread of breast cancer, in what other cancers has sentinel node biopsy been used for detecting the spread?

A

For detecting the spread of :

  1. Melanomas
  2. Colon cancers
  3. Other tumors
164
Q

What are the two sites that are most frequently involved in hematogenous spread?

A
  1. Liver

2. Lungs

165
Q

Where do thyroid and prostate cancers frequently spread hematogenously?

A

In the vertebral column.

166
Q

What tumors have a propensity for invasion of veins?

A
  1. Renal cell carcinoma

2. Hepatocellular carcinoma

167
Q

Is intravenous tumor growth accompanied by widespread dissemination?

A

Remarkably, it is not!

168
Q

Mention some “weird” metastases.

A
  1. Breast carcinoma spreads to bone.
  2. Bronchogenic carcinomas tend to involve the adrenals and the brain.
  3. Neuroblastomas spread to the liver and bones.
169
Q

What is mutated in MEN-1 and MEN-2, respectively?

A

MEN-1 : mutation in the gene encoding the menin transcription factor.
MEN-2 : mutation in the gene encoding the RET tyrosine kinase.

170
Q

What organs are involved in MEN-1/2?

A

MEN-1 : Pituitary, parathyroid, and pancreas.

MEN-2 : Thyroid, parathyroid, and adrenals.

171
Q

Mention 3 rare autosomal recessive “defective DNA-repair” syndromes.

A
  1. Xeroderma pigmentosum
  2. Ataxia-telangiectasia
  3. Bloom syndrome
172
Q

What is estimated for the familial basis of breast or ovarian cancer?

A

10-20% of patients with breast/ovarian cancer have a first- or second-degree relative with one of these tumors.

173
Q

What is true about the BRCA1/2 genes?

A

Although they are susceptibility genes for breast cancers, mutation of these genes occurs in no more than 3% of breast cancers. (similar situation with familial melanomas and p16 mutation.)

174
Q

Mention some chronic inflammations in the GI tract that are predispose to cancer.

A
  1. Ulcerative colitis
  2. Helicobacter pylori gastritis
  3. Viral hepatitis
  4. Chronic pancreatitis
175
Q

What is the most common method used to determine tumor clonality?

A

The analysis of methylation patterns adjacent to the highly polymorphic locus of the human androgen receptor gene, AR.

176
Q

What is called haploinsufficiency?

A

Loss of gene function caused by damage to a single allele.

177
Q

What is called tumor progression?

A

The well established fact that over a period of time many tumors become more aggressive and acquire greater malignant potential.

178
Q

What is true about the monoclonality of tumor cells by the time they become clinically evident?

A

Their constituent cells are extremely heterogeneous!

179
Q

What is the main difference between oncoproteins and the normal products of proto-oncogenes?

A

They are often devoid of important internal regulatory elements, and their production in the transformed cells does not depend on growth factors or other external signals.

180
Q

What may be the role of the proteins encoded by proto-oncogenes?

A
  1. Growth factors or their receptors.
  2. Signal transducers.
  3. Transcription factors.
  4. Cell cycle components.
181
Q

How do the cancer cells utilize an autocrine loop?

A

They acquire the ability to synthesize the same growth factors to which they are responsive, generating an autocrine loop.

182
Q

Is increased growth factor production sufficient for neoplastic transformation?

A

NO!

183
Q

Mention the three main mechanisms by which the growth factor receptors are constitutively activated in tumors.

A
  1. Mutations
  2. Gene rearrangements
  3. Overexpression
184
Q

Where is the RET protein normally expressed?

A
  1. Neuroendocrine cells (parafollicular C cells of the thyroid)
  2. Adrenal medulla
  3. Parathyroid cell precursor
185
Q

What has been observed in 90% of GI stromal tumors?

A

Constitutively activating mutation in :

  1. The receptor tyrosine kinase c-KIT
  2. PDGFR
    - Amenable to specific inhibition by tyrosine kinase inhibitor imatinib mesylate (targeted therapy).
186
Q

Where is the ERBB1 overexpressed?

A
  1. Up to 80% of squamous cell carcinomas of the lung.
  2. In 50% or more of glioblastomas.
  3. In 80% to 100% of head and neck tumors.
187
Q

Where is the ERBB2 (also called HER-2/NEU) overexpressed?

A
  1. 25% of breast cancers.

2. Adenocarcinomas arising within the ovary, lung, stomach, and salivary glands.

188
Q

To what growth factors can abrogation of RAS function block the proliferative response?

A
  1. EGF
  2. PDGF
  3. CSF-1
189
Q

What is the main pathway that is stimulated downwards from the activated RAS protein?

A

The MAP kinase cascade.

190
Q

Where do the point mutations of RAS lie structurally?

A

The affected residues lie within either
1. The GTP-binding pocket
or
2. The enzymatic region essential for enzymatic hydrolysis.
- Markedly reduce the enzymatic activity of the RAS protein.

191
Q

What mutated GAP is associated with NF-1?

A

Neurofibromin.

192
Q

How do transcription factors work?

A

They contain specific amino acid sequences or motifs that allow them to bind to DNA or to dimerize for DNA binding, in order to activate transcription of genes.

193
Q

What is generally the MYC proto-oncogene?

A

It is expressed in all eukaryotic cells and belongs to immediate early response genes, which are rapidly induced when quiescent cells receive a signal to divide.

194
Q

Mention some principal targets of MYC.

A
  1. Gene for ornithine decarboxylase
  2. Gene for cyclin D2
  3. Histone acetylation
  4. Reduced cell adhesion
  5. Increased cell motility
  6. Increased telomerase activity
  7. Increased protein synthesis
  8. Decreased proteinase activity
  9. Interactions with the DNA-replication machinery - role in selection of origins.
195
Q

What happens if MYC activation occur in the absence of surrvival signals?

A

APOPTOSIS

196
Q

How many cyclins have been identified?

A

15

197
Q

Mention the 4 major cyclins that appear sequentially during the cell cycle.

A

Cyclins D, E, A, B.

198
Q

With what tumors is overexpression of cyclin D associated with?

A
  1. Breast
  2. Esophagus
  3. Liver
  4. Subset of lymphomas
199
Q

In what tumors does amplification of CDK4 occur?

A
  1. Melanomas
  2. Sarcomas
  3. Glioblastomas
200
Q

With what tumors are mutations of p16 (CDKN2A) associated?

A
  1. 25% of melanoma-prone kindreds.
  2. 75% of pancreatic carcinomas.
  3. 40-70% of glioblastomas.
  4. 50% of esophageal cancers.
  5. 20-70% of acute lymphoblastic leukemias.
  6. 20% of non-small-cell lung carcinomas, soft tissue sarcomas, and bladder cancers.
201
Q

What are the two principal checkpoints in the cell cycle?

A
  1. G1/S transition (most important)

2. G2/M transition

202
Q

What do the cell cycle checkpoint need to function properly?

A
  1. Sensors of DNA damage
  2. Signal transducers
  3. Effector molecules
203
Q

Mention 2 important sensors and 1 important transducer for the cell cycle checkpoints.

A 
Sensors : 
1. Proteins of the RAD family
2. Proteins of the ataxia-telangiectasia (ATM)
Transducers :
1. The CHK kinase families
204
Q

Besides retinoblastoma, for what other tumors do patients with familial retinoblastoma have increased risk for?

A

Osteosarcoma and other soft-tissue sarcomas.

205
Q

What does the term “loss of heterozygosity” mean?

A

A patient that was heterozygous for a mutated allele, has now become homozygous for that allele, hence he has lost his heterozygosity.

206
Q

What are the two ways by which the RB protein function?

A
  1. It sequesters E2F, preventing it from interacting with other transcriptional activators.
  2. RB recruits chromatin-remodeling proteins, such as histone deacetylases and histone methyltransferases, which bind to the promoters of E2F-responsive genes such as cyclin E.
207
Q

How is the stability of the cell cycle inhibitor p27 controlled?

A

By Rb

208
Q

What is the “RB pocket”?

A

The region of Rb binding to E2F, where the mutations of RB genes in tumors are localized.

209
Q

What percentage of human tumors contain mutations in the p53 gene?

A

A little over 50%.

210
Q

What percentage of the p53 mutations are contained in the DNA-binding domain of the protein?

A

Approx. 80%.

211
Q

Besides a p53 mutation, what other mutations can block the p53 pathway?

A

Mutations in MDM2 and MDMX - proteins that stimulate the degradation of p53.

212
Q

Why in non-stressed cells p53 has a short half-life (20min)?

A

Because of its association with MDM2, a protein that targets it for destruction.

213
Q

What happens in patients with ataxia-telangiectasia?

A

It is a disease characterized by an inability to repair certain kinds of DNA damage, leading to an increased incidence of cancer.

214
Q

What causes the p53-mediated cell cycle arrest that occurs late in the G1 phase?

A

It is caused mainly by p53-dependent transcription of the CDK inhibitor CDKN1A (p21).

215
Q

Mention briefly some actions of p53 that are helpful to the DNA repair system.

A
  1. Induces GADD45 (growth arrest and DNA damage), that help in DNA repair.
  2. Also stimulates DNA-repair pathways by transcription independent mechanisms.
  3. If DNA damage is repaired successfully, p53 up-regulates transcription of MDM2 - leading to its own destruction.
  4. If the damage is not repaired - p53-induced senescence or p53-directed apoptosis.
216
Q

What is p53-induced senescence?

A

A permanent cell cycle arrest characterized by specific changes in morphology and gene expression that differentiate it from quiescence or reversible cell cycle arrest.

217
Q

What are the main requirements for senescence?

A

p53 and/or RB activation and expression of their mediators - It is generally irreversible.

218
Q

What are the mechanisms of senescence?

A

Unclear - involve epigenetic changes that result in the formation of heterochromatin at different loci throughout the genome (including pro-proliferative genes regulated by E2F).

219
Q

What is the p53-induced apoptosis of cells with irreversible DNA damage?

A

The ultimate protective mechanism against neoplastic transformation.

220
Q

What is postulated about the mechanism by which the p53 induces apoptosis or repair?

A

It appears that the affinity of p53 for the promoters and enhancers of DNA-repair genes is stronger than its affinity for pro-apoptotic genes.
Thus the DNA repair pathway is stimulated first, while p53 continues to accumulate.

221
Q

What therapeutic implications has the ability of p53 to control apoptosis in response to DNA damage?

A

Irradiation and chemotherapy, the two common modalities of cancer treatment, mediate their effects by inducing DNA damage and subsequent apoptosis.
Tumors that retain normal p53 are more likely to respond to such therapy than tumors that carry mutated alleles of the genes.

222
Q

What happens in patients with germ-line mutations at the APC (5q21) loci?

A

It is associated with familial adenomatous polyposis, in which all individuals born with one mutant allele develop thousands of adenomatous polyps in the colon during their teens or 20s.
Almost invariably, one or more of these polyps undergoes malignant transformation, giving rise to colon cancer.

223
Q

Besides colon adenomas, what other tumors show a strong hereditary predisposition with the APC loss?

A

70-80% of nonfamilial colorectal carcinomas and sporadic adenomas show homozygous loss of the APC gene.

224
Q

What cell surface receptors does the WNT pathway utilizes?

A

A family of cell surface receptors called frizzled (FRZ) and stimulates several pathways, the central one involving β-catenin and APC.

225
Q

Is dysregulation of the APC/β-catenin pathway restricted to colon cancers?

A

No - mutations in the β-catenin gene are present in more than 50% of hepatoblastomas and 20% of hepatocellular carcinomas.

226
Q

In what cancers has reduced cell surface expression of E-Cadherin been noted?

A

In many types of cancers including :

  1. Esophagus
  2. Colon
  3. Breast
  4. Ovary
  5. Prostate
227
Q

What are the IAPs?

A
  1. Inhibitors of apoptosis - Proteins that inhibit caspases.
  2. Some tumors can avoid apoptosis by upregulating these proteins.
  3. There is interest in developing drugs that can block the interaction between IAPs and caspases.
228
Q

Where is the IgH gene located?

A

14q32

229
Q

How many doubling are most normal human cells capable of?

A

60-70 doublings. After this, they lose their ability to divide and become senescent.

230
Q

What is the relationship between telomerase and cancer?

A

Telomerase, active in normal stem cells, is normally absent, or expressed at very low levels in most somatic cells.
By contrast, telomerase maintenance is seen virtually in all types of cancer. In 85-95% of cancers, this is due to upregulation of the enzyme telomerase.

231
Q

What is interesting in the progression from colonic adenoma to colonic adenocarcinoma?

A

Early lesions had a high degree of genomic instability with LOW telomerase expression, whereas malignant lesions had complex karyotypes with high levels of telomerase activity, consistent with a model of telomerase-DRIVEN tumorigenesis in human cancer.

232
Q

Can cancer cells stimulate vasculogenesis?

A

Yes - they can stimulate NEOANGIOGENESIS, during which new vessels sprout from previously existing capillaries, or, in some cases, VASCULOGENESIS in which endothelial cells are recruited from the bone marrow.

233
Q

What characterizes the tumor vasculature?

A

It is abnormal - the vessels are leaky and dilated and have a haphazard pattern of connection.

234
Q

What is the dual effect of neovascularization?

A
  1. Perfusion supplies needed nutrients and oxygen.
  2. Newly formed endothelial cells stimulate the growth of adjacent tumor cells by secreting growth factors, such as IGFs, PDGF, GM-CSF.
235
Q

By what is tumor angiogenesis controlled?

A

By a balance between angiogenesis promoters and inhibitors.

236
Q

Do tumors induce angiogenesis early in their growth?

A

No - they remain small or in situ, possibly for YEARS, until the angiogenic switch terminates this stage of vascular quiescence.

237
Q

What cells produce pro-angiogenic factors?

A
  1. Tumor cells themselves.
  2. Inflammatory cells (macrophages)
  3. Stromal cells associated with tumors.
238
Q

How are the three potent angiogenesis inhibitors produced?

A

Angiostatin - proteolytic cleavage of plasminogen.
Endostatin - proteolytic cleavage of collagen.
Vasculostatin - proteolytic cleavage of transthyretin.

239
Q

The angiogenic switch is controlled by several physiologic stimuli, such as hypoxia. What cytokines does the oxygen sensitive transcription factor HIF-1α stimulate?

A

VEGF + bFGF

240
Q

Besides promoting growth of endothelial cells and guidance of the growth of new vessels, what else does VEGF do?

A

Increases the expression of ligands that activate the Notch signaling pathway, which plays a crucial role in regulating the branching and density of the new vessels.

241
Q

Besides the common, mention one “extraordinary” event that loss of p53 can lead to.

A

The loss of p53 in tumor cells not only removes the cell cycle checkpoints, but also provides a more permissive environment for ANGIOGENESIS.

242
Q

Is there an anti-VEGF monoclonal antibody in use?

A

YES - bevacizumab has been recently approved for use in the treatment of multiple cancers.

243
Q

In brief, why is the metastatic process so inefficient?

A

Each step in the process is a subject to multiple controls.

244
Q

What effects do cleavage products from collagen and proteoglycans have?

A

Chemotactic, angiogenic, and growth-promoting effects. (i.e. MMP9 is a gelatinase that cleaves type IV collagen and ALSO stimulated the release of VEGF from ECM-sequestered pools.)

245
Q

Besides the classic way of metastasis, can the tumor cells utilize another way of metastasizing?

A

YES - a much quicker one - AMEBOID MIGRATION.

246
Q

How is locomotion of tumor cells achieved?

A
  1. Such movement seems to be potentiated by tumor cell-derived cytokines (such as autocrine motility factors).
  2. ALSO : cleavage products of matrix components and some GF have chemotactic ability for tumor cells.
  3. Stromal cells ALSO produce paracrine factors (i.e. HGF scatter factor).
247
Q

Once in the circulation, what mechanisms can lead to destruction of tumor cells?

A
  1. Mechanical shear stress
  2. Apoptosis stimulated by loss of adhesion (anoikis)
  3. Innate and adaptive immune defenses
248
Q

Within the circulation, tumor cells tend to aggregate in clumps. Why is this happening?

A

This is favored by homotypic adhesions among tumor cells as well as heterotypic adhesion between tumor cells and blood cells, particularly platelets.

249
Q

What is the CD44 adhesion molecule?

A

A molecule of particular interest in metastasis - expressed in T cells and used for migration within the lymph node.
Migration accomplished by the binding of CD44 to hyaluronate on high endothelial venules - overexpression of CD44 may favor metastatic spread.

250
Q

What is the concept of dormancy?

A

A concept referring to the prolonged survival of micrometastases without progression - well described in melanoma/breast/prostate cancer.

251
Q

Have genes that promote or suppress metastasis been found?

A

YES - recent work has suggested 2 miRNAs (mir335 and mir126) to suppress metastasis of breast cancer + a second set (mir10b) to promote metastasis.

252
Q

What happens to EMT (epithelial-to-mesenchymal) carcinoma?

A

The tumor cells down-regulate ceeertain epithelial cell markers (e.g. E-cadherin) and up-regulate certain mesenchymal markers (e.g. vimantin and smooth muscle actin).
THESE CHANGES are believed to FAVOR a PROMIGRATORY phenotype that is essential fro metastasis.

253
Q

What are the two candidates for metastasis oncogenes ?

A

SNAIL and TWIST genes - encode transcription factors promoting the EMT process.

254
Q

What characterizes the HNPCC?

A

Familial carcinomas of the colon affecting predominantly the cecum and proximal colon - results from defects in genes involved in DNA-MISMATCHED REPAIR.

255
Q

In respect to microsatellites, what difference is present between normal individuals and people with HNPCC syndrome?

A

In normal people the length of these microsatellites remains constant - in people with HNPPC syndrome, these satellites are unstable in lenght, creating alleles not found in normal cells of the same patient.

256
Q

What germline mutations account for approximately 30% of cases of HNPCC?

A

Germline mutations in the MSH2 (2p16) and MLH1 (3p21) genes.

257
Q

Although HNPCC account for 2% to 4% of all colonic cancers, in what percentage of sporadic colon cancers do we detect microsatellite instability?

A

15%

258
Q

What growth-regulating genes are involved in HNPCC?

A
  1. TGF-β receptor II
  2. TCF component of the β-catenin pathway
  3. BAX
  4. Other oncogenes and tumor suppressor genes
259
Q

Mention 3 autosomal recessive disorders that are characterized b hypersensitivity to DNA-damaging agents.

A
  1. Bloom syndrome (sensitivity to ionizing radiation)
  2. Ataxia-telangiectasia (sensitivity to ionizing radiation)
  3. Fanconi anemia (sensitivity to DNA cross-linking agents -chemotherapy)
260
Q

Where does the defective gene in Bloom syndrome located?

A

Chromosome 15

261
Q

How many genes have been found for Fanconi anemia?

A

13 - anyone mutated will do the trick.

262
Q

Besides breast cancer, to what other cancers does a BRCA1 mutation predispose?

A

High risk of epithelial ovarian cancer and slightly higher risk of prostate cancer.

263
Q

In what cancers does the BRCA2 increase the risk?

A
  1. Increase the risk of breast cancer in both men and women.
  2. Ovary
  3. Prostate
  4. Pancreas
  5. Bile ducts
  6. Stomach
  7. Melanocytes
264
Q

With what functions are th BCRA1 and 2 genes associated with?

A

Have been shown to associate with a variety of proteins involved in the homologous recombination repair pathway.

265
Q

What clinical method takes advantage of the Warburg effect?

A

PET - 18F-fluorodeoxyglucose, a non metabolizable derivative of glucose that is preferentially taken up into tumor cells.

266
Q

What is the role of the LKB1 tumor suppressor gene?

A
  1. It encodes a threonine kinase, which is associated with benign and malignant epithelial proliferation of the GI tract.
  2. Tumor suppresive activity : activation of AMP-dependent protein kinase - a conserved sensor of cellular energy status that is an important negative regulator of mTOR pathway.
  3. Thus LKB1 suppresses tumor formation, at least in part, by putting breaks on anabolic metabolism.
267
Q

Besides LKB1, mention 2 other tumor suppressor genes that also negatively regulate mTOR.

A

TSC1 and TSC2.

268
Q

What is the relationship between cancer cells and autophagy?

A

Tumor cells often live under marginal environmental conditions WITHOUT triggering autophagy, suggesting that the pathways that induce autophagy are DERANGED.

269
Q

What is the most common form of translocation in Burkitt lymphoma?

A

t(8;14)(q24;q32) - MYC placed cloze to IGH gene.

270
Q

What happens in Ewing sarcoma/primitive neuroectodermal tumor (PTEN)?

A

It is defined by translocation of the Ewing sarcoma (EWSR1) gene at 22q12 - involved in numerous translocations.

271
Q

What deletions have been noted in colorectal cancer?

A

Deletions of 17p, 5q, 18q.

272
Q

What deletion have been noted in small-cell lung carcinoma?

A

Deletion of 3p.

273
Q

What are the two most interesting cases of gene amplification?

A
  1. N-MYC in neuroblastoma

2. ERBB2 in breast cancer.

274
Q

In how many neuroblastomas is N-MYC amplified?

A

25-30%

275
Q

Where is the N-MYC amplification present and with what prognosis is it associated with?

A

It is present BOTH in double minutes and homogeneous staining regions and it is also associated with a POOR prognosis.

276
Q

Are the cancer cell DNA hypo- or hypermethylized?

A

Cancers cells are characterized by a global DNA hypomethylation and selective PROMOTER-localized hypermethylation.
- Tumor suppressors are silenced by hypermethylation of promoter sequences rather than mutation.

277
Q

Mention one example of tumor suppressor silencing due to hypermethylation of the promoters.

A

CDKN2A encodes 2 tumor suppressor genes :

  1. p14/ARF : silenced in colon and gastric cancers.
  2. p16/INK4a : silenced in a wide variety of cancers.
278
Q

Do most chemical carcinogens require metabolic activation or not?

A

Most of them require metabolic conversion into ultimate carcinogens - INDIRECT-acting agents.

279
Q

What enzymes metabolize most of the known carcinogens?

A

CytP450-dependent mono-oxygenases.

280
Q

With what interesting factor may carcinogenesis be associated with?

A

With the highly polymorphic CytP450 enzymes that metabolize most of the known carcinogens.

281
Q

The carcinogenicity of some initiators is augmented by subsequent administration of promoters. Are these substances by themselves tumorigenic?

A

NO!

282
Q

What substances can function as promoters?

A
  1. Phorbol esters
  2. Hormones
  3. Phenols
  4. Drugs
283
Q

With what are nonmelanoma skin cancers and melanomas associated?

A

Non-melanoma skin cancers : total cumulative exposure to UV radiation.
Melanomas : intense intermittent exposure - as occurs in sunbathing.

284
Q

To what cells has HTLV-1 tropism?

A

For CD4+ T cells - hence this subset of T cells is a major target of neoplastic transformation.

285
Q

How is HTLV-1 transmitted?

A
  1. Sexual intercourse
  2. Blood products
  3. Breastfeeding
286
Q

What percentage of patients infected with HTLV-1 develop leukemia?

A

Leukemia develops in only 3-5% of the infected individuals after a long latent period of 40-60 years.

287
Q

How many distinct types of HPV have been identified?

A

70!

288
Q

What HPV are the “high-risk” ones?

A

16 and 18 : implicated in the genesis of several cancers, particularly squamous cell carcinoma of the cervix and anogenital region.
THUS, cervical cancer is a sexually transmitted disease!

289
Q

Besides cervical cancer, what other cancer is associated with HPV infection?

A

At least 20% of oropharyngeal cancers.

290
Q

What is the function of E7 produced by high-risk HPV?

A
  1. Binds to RB and displace the E2F transcription factors that are normally sequestered by RB, promoting PROGRESSION through the cell cycle.
  2. Inactivates the CDKIs p21 + p27.
  3. ALSO binds and presumably activates cyclins E and A.
291
Q

What is the function of E6 produced by high-risk HPV?

A

Complementary : Binds and degrades p53 and BAX (pro-apoptotic member of the BCL2 family) + activates telomerase.

292
Q

Is HPV infection by itself sufficient for carcinogenesis?

A

NO!

293
Q

What receptor does EBV use to attach to B cells?

A

The complement receptor CD21.

294
Q

What is the function of LMP-1 (latent membrane protein-1) of EBV?

A
  1. LMP-1 behaves like a CONSTITUTIVELY active CD40 receptor : a KEY recipient of helper T cell signals that stimulate B cell growth.
  2. It also prevents APOPTOSIS by activating BCL2.
295
Q

Most notably, what EBV proteins Burkitt lymphoma cells DO NOT express?

A

LMP-1 and EBNA2.

296
Q

What should be noted about non endemic Burkitt lymphoma?

A

Although 80% of non endemic BL do NOT harbor the EBV genome, ALL tumors possess the t(8;14) that dysregulates c-MYC.
This suggests that the same oncogenic pathways underlie both EBV-BL and non endemic BL.

297
Q

What seems true about the action of EBV in BL?

A

EBV is NOT directly oncogenic, but by acting as a polyclonal B-cell mitogen, it sets the stage for the acquisition of the t(8;14) translocation.

298
Q

With what tumor is EBV 100% associated?

A

Nasopharyngeal carcinoma - endemic in southern China.

299
Q

What percentage of hepatocellular carcinomas are due to HBV or HCV?

A

70-85%.

300
Q

What seems to be the action of HBV/HCV in the pathogenesis of hepatocellular carcinoma?

A

The oncogenic effects are indeed multifactorial, but the dominant effect seems to be IMMUNOLOGICALLY MEDIATED CHRONIC INFL. with hepatocyte death leading to regeneration and genomic damage.

301
Q

To what tumors does H.pylori infection predispose?

A
  1. Gastric adenocarcinoma

2. Gastric lymphoma

302
Q

What is the “scenario” for the development of gastric adenocarcinoma?

A

Similar to HBV/HCV-induced liver cancer.

Increased epithelial cell proliferation in a background of chronic inflammation.

303
Q

What is the sequence of events from H.pylori infection till tumorigenesis?

A
  1. Development of chronic gastritis
  2. Gastric atrophy
  3. Intestinal metaplasia of the lining cells
  4. Dysplasia
  5. Cancer
    Takes several DECADES and occurs only in 3% of infected patients.
304
Q

H.pylori is also associated with gastric lymphomas. What is the cell of origin in these lymphomas?

A

B-cell origin.

305
Q

What it is believed about oncofetal antigens?

A

The genes encoding these proteins are silenced during development and are derepressed upon malignant transformation.

306
Q

What is the main importance of oncofetal antigens?

A

They can be used as markers that aid in tumor diagnosis.

307
Q

What altered cell surface glycoproteins and glycolipids are expressed in tumor cells?

A
  1. Gangliosides
  2. Blood group antigens
  3. Mucins
308
Q

What are the differentiation antigens?

A

Antigens expressed by tumor cells, that are normally present on the cells of origin.

309
Q

What is the great help that NK cells provide against tumors?

A

Tumors that fail to express MHC class I antigens cannot be recognized by T cells, but these tumors may trigger NK cells because the latter are INHIBITED by recognition of normal autologous class I molecules.

310
Q

How can malignant and benign tumors cause problems?

A
  1. Location and impingement on adjacent structures.
  2. Functional activity such as hormone synthesis or the development of paraneoplastic syndromes.
  3. Bleeding and infections when the tumor ulcerates through adjacent surfaces.
  4. Symptoms that result from rupture or infarction.
  5. Cachexia or wasting.
311
Q

What is cachexia?

A

Individuals with cancer commonly suffer progressive loss of body fat and lean body mass accompanied by profound WEAKNESS, ANOREXIA, and ANEMIA, referred to as cachexia.

312
Q

Are the nutritional demands of the tumor causing the cachexia?

A

NO!

313
Q

Is there a satisfactory treatment for cancer cachexia?

A

No!

314
Q

What percentage of cancer-related deaths are attributed to cachexia?

A

One THIRD!

315
Q

What is known as a paraneoplastic syndrome?

A

Symptom complexes in cancer patients that cannot be readily explained, either by the local or distant spread of the tumor or by the elaboration of hormones indigenous to the tissue from which the tumor erose, are known as paraneoplastic syndromes.

316
Q

In what percentage of malignancies does paraneoplastic syndrome occur?

A

10%

317
Q

Why it is important to recognize a paraneoplastic syndrome?

A
  1. They represent the earliest manifestation of an occult neoplasm.
  2. In affected patients they may represent significant clinical problems and may even be lethal.
  3. They may mimic metastatic disease and therefore confound treatment.
318
Q

What is the most common endocrinopathy seen in paraneoplastc syndrome?

A

Cushing syndrome : approx. 50% have small-cell lung carcinoma.

319
Q

What is the difference between an excess of ACTH from the pituitary and an excess of ACTH from an ectopic hormone production?

A

The high serum pro-opiomelanocortin.

320
Q

What is the most common paraneoplastic syndrome?

A

Hypercalcemia

321
Q

What are the two major processes that are involved in cancer associated hypercalcemia?

A
  1. Osteolysis induced by cancer, whether primary in bone, such as MM, or metastatic to bone from any primary lesion.
  2. The production of calcemic humoral substances by extraosseous neoplasms.
322
Q

Is hypercalcemia due to skeletal metastases a paraneoplastic syndrome?

A

NO!

323
Q

Where is PTHRP produced?

A

In small amounts by many normal tissues :

  1. Keratinocytes
  2. Muscles
  3. Bones
  4. Ovary
324
Q

Mention some tumors that are most often associated with paraneoplastic hypercalcemia.

A

Carcinomas of :

  1. Breast
  2. Lung
  3. Kidney
  4. Ovary
325
Q

Where is hypertrophic osteoarthropathy encountered ?

A

In 1-10% of patients with bronchogenic carcinoma.

326
Q

What characterizes hypertrophic osteoarthropathy?

A
  1. Periosteal new bone formation, primarily at the distal ends of long bones, metatarsals, metacarpals, and proximal phalanges.
  2. Arthritis of the adjacent joints.
  3. Clubbing of the digits.
327
Q

What is the Trouseau syndrome?

A

Migratory thrombophlebitis - thrombosis in cancer.

328
Q

On what is grading of a tumor based on?

A

On the degree of differentiation of the tumor cells, and in some cancers, the number of mitoses or architectural features.

329
Q

Clinically, what is more useful? Grading or staging of the tumor?

A

Staging - with a few exceptions, such as soft tissue sarcomas.

330
Q

On what is staging of the cancer based?

A
  1. On the SIZE of the primary lesion (T)
  2. Its extend to regional lymph nodes (N)
  3. The presence or absence of blood-borne metastases (M)
331
Q

What is a neoplasm?

A

A neoplasm is an abnormal mass of tissue, the growth of which exceeds and is uncoordinated with that of the normal tissues and persists in the same excessive manner after cessation of the stimuli which evoked the change.

Pathology (16 decks)

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