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BLOCK 2 FINAL > Neoplasia Book > Flashcards

Neoplasia Book Flashcards

1
Q

What are the four classes of normal regulatory genes?

A

Proto-oncogenes (promote growth)
Tumor suppressor genes (suppress growth)
Genes that regulate apoptosis
Genes involved in DNA repair

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2
Q

Oncogenes

A

Genes that induce a transformed phenotype when expressed in cells - most are mutated or overexpressed versions of normal cellular genes (proto-oncogenes)

Mutation of a single allele can lead to cellular transformation (DOMINANT)

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3
Q

Tumor Supressor Genes

A

Genes that normally prevent uncontrolled growth and when they are mutated or lost form a cell, allow the transformed phenotype to develop.

Both normal alleles of tumor suppressor genes must be damaged for transformation to occur.

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4
Q

What are the two groups of tumor suppressor genes

A

GOVERNERS (classic tumor suppressor genes) that when mutated lead to transformation by removing an important break in cellular proliferation (e.g. Rb)

GUARDIANS (responsible for sensing genomic damage and lead to cessation of proliferation or induction of apoptosis) e.g. TP53 (guaridan of genome) - mutation does NOT directly cause altered proliferation, it allows acquisition of mutations that can lead to cancer

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5
Q

what are the genetic lesions of cancer

A

point mutations in PROTO-ONCOGENES result in overactivity of protein.

point mutations in TUMOR SUPPRESSORS reduce or disable the function of encoded protein

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6
Q

what are the karyotypic changes in tumors

A

common types of nonrandom structural abnormalities in tumor cells are balanced translocations, deletions, and cytogenetic manifestations of gene amplification

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7
Q

Balanced Translocations can activate proto-oncogenes in what two ways

A

1) overexpression of proto-oncogenes by removing them from normal regulatory elements and placing them under control of an inappropriate, highly active promoter (e.g. translocation of MYC gene on chromosome 8 in Burkitt lymphoma or BCL2 on chromosome 18 in follicular B cell lymphoma under Ig heavy chain gene regulatory elements)
2) creation of fusion genes encoding novel chimeric proteins (e.g. philadelphia chromosome - balanced translocation of chromosome 22 and 9 - in CML)

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8
Q

what is the second most prevalent karyotypic abnormality in tumor cells?

A

DELETIONS - loss of particular tumor suppressor genes with deletion of other, nonmutated allele leading to loss of heterozygosity

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9
Q

proto-oncogenes may be converted to oncogenes by what process?

A

AMPLIFICATION - may produce several hundred copies of the proto-oncogene in the tumor cell (e.g. HER2/NEU amplification in 20% of breast cancers)

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10
Q

What two patterns are seen with amplification

A

DOUBLE MINUTES: multiple small, extrachromsomal structures

HOMOGENOUSLY STAINING REGIONS: derive from insertion of the amplified genes into new chromosomal locations, which may be distant from the normal location of the involved genes; because regions containing amplified genes lack a normal banding pattern, they appear homogenous in G-banded karyotype

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11
Q

MicroRNAs and CAncer

A

overexpression of miRNAs can contribute to cacinogenesis by reducing the expression of tumor suppressors, while deletion or loss of expression of miRNA can lead to overexpression of proto-oncogenes

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12
Q

Epigenic Changes

A

reversible, heritable changes in gene expression that occur without mutation. main mechanisms are DNA methylation and histone modification.

cancer cells are characterized by: global DNA hypomethylation and selective promoter localized hypermethylation

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13
Q

Categories of oncogenes include…

A

GF, GFR, signal transducers, nuclear regulators, and cell cycle regulators

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14
Q

Growth Factors

A

many cancer cells acquire GROWTH SELF-SUFFICIENCY by acquiring the ability to synthesize the same growth factors to which they are responsive

  • glioblastomas secrete PDGF express receptor
  • sarcomas secrete TGFa express receptor
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15
Q

GFR and Non-Tyrosine Kinases

A

Mutant receptor protein deliver continuous mitogenic signals to cells
More common is overexpression of growth factor receptors that can render cells hyperresponsive to growth factors that would not normally trigger proliferation

ERBB1 - EGF receptor is overexpressed in squamous cell carcinoma of lung
ERBB2 (HER2/NEU) - breast cancer

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16
Q

What are the two important genes that encode various components of the signaling pathway

A

RAS

ABL

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17
Q

RAS Mutation

A

MOST COMMONLY MUTATED PROTO-ONCOGENE IN HUMAN TUMORS (either point mutation in GTP-binding pocket or enzymatic region essential for GTP hydrolysis that prevent inactivation of RAS)

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18
Q

RAS Pathway

A

1) Ras is associated with GFRs in an inactive GDP-bound state
2) Receptor binding causes GDP to be replaced with GTP, activating Ras
3) Ras inactivates itself by cleaving GTP to GDP

Mutated Ras inhibits the activity of GTPase activating protein. This prolongs the activated state of ras, which stimulates growth and cell cycle progression through RAF/ERK/MAP kinase pathway or PI3K/AKT pathway

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19
Q

ABL

A

non-receptor-associated tyrosine kinase whose gene is translocated from chromosome 9 to chromosome 22 where it fuses with breakpoint of BCR gene

hybrid protein (BCR-ABL) maintains tyrosine kinase activity

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20
Q

what is the ultimate consequence of signaling oncoproteins such as RAS or ABL?

A

continuous stimulation of nuclear transcription factors that drive the expression of growth-promoting genes

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21
Q

MYC Protein

A

MYC protein can either activate or repress the transcription of other genes

  • activates CDKs (products drive cells into cell cycle)
  • represses CDK inhibitors (enforces cell cycle checkpoints)

Dysregulation of MYC promoters tumorigenesis by increasing the expression of genes that promote progression through the cell cycle or repressing genes that slow or prevent progression through the cell cycle

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22
Q

What other effect is MYC protein responsible for?

A

Warburg effect - upregulating genes that promote aerobic glycolysis and increased utilization of glutamine

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23
Q

What is the restriction point in the cell cycle?

A

G1 to S transition - cells committed to DNA replication

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24
Q

Normal Cell Cycle

A

1) Cyclins (D,E,A,B) help stimulate progression through the cell cycle
2) Cyclins bind CDKs and activate them, leading to phosphorylation of crucial target proteins (e.g. Rb) that drive cell cycle
3) CDK inhibitors enforce cell cycle checkpoints
4) if DNA damage is too severe to continue when checked at checkpoints, p53 eliminates cell through apoptosis or enters them in a non-replicative state (senescence)

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25
Q

Cell Cycle in Cancer

A

Mutation in CDKs and cyclins favor cell proliferation - ALL CANCERS have genetic lesions that disable the checkpoint

Increasing expression of CDK4 and cyclin D is common in neoplastic transformation. CDKIs are also frequently disabled by mutations or gene silencing.

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26
Q

What cyclins regulate the G1 to S transition and what do they do?

A

cyclin D-CDK4
cyclin D-CDK6
cyclin E-CDK2
regulate the G1-S transition by phosphorylating the Rb protein

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27
Q

What cyclins are active in S phase?

A

cyclin A-CDK2

cyclin A-CDK1

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28
Q

What cyclin is active in G2 to M transition?

A

cyclin B-CDK1

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29
Q

What are the two families of CDK inhibitors that can block activity of CDKs and progression through cell cycle?

A

1) INK4 INHIBITORS - act on cyclin D-CDK4 and cyclin D-CDK6 (p16, p15, p18, p19)
2) p21, p27, p57 can inhibit all CDKs

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30
Q

RB GENE is known as the…

A

GOVERNOR OF THE CELL CYCLE

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31
Q

Two-Hit Hypothesis

A
  • 2 mutations (hits) are required to produce retinoblastoma.
  • familial: children inherit one defective copy of the Rb gene in the germline. Retinoblastoma occurs when the other normal RB gene is lost as a result of somatic mutation (AD inheritance pattern)
  • sporadic: both normal RB alleles lost by somatic mutation
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32
Q

Homozygous loss of RB gene is a common feature of which tumors?

A

breast, small cell cancer of lung, and bladder cancer

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33
Q

RB gene product is a DNA-binding protein that exists in which states?

A

active hypophosphorylated state

inactive hyperphoshporylated state

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34
Q

What does the RB gene regulate?

A

G1/S checkpoint !!!!!!!!

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35
Q

Loss of normal cell control is central to malignant transformation and at least one of four key regulators of the cell cycle is mutated in most cancers

A

CDKN2A
Cyclin D
CDK4
Rb

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36
Q

RB gene activity

A

1) Rb is in its hypophosphorylated active form where it inhibits E2F and prevents transcription of cyclin E
2) GF signaling (e.g. EGF, PDGF) leads to activation of cyclin D-CDK4/6 complex, which phosphorylates Rb
3) Rb releases E2F to induce target genes such as cyclin E
4) cyclin E expression stimulates DNA replication and progression through cell cycle

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37
Q

What are the two mechanisms that RB uses to inhibit E2F?

A

1) Rb sequesters E2F, preventing it from interacting with transcriptional activators
2) Rb recruits chromatin remodeling protein (e.g. histone deacetylases and histone methyltransferases), which bind to promoters of E2F-responsive genes such as cyclin E and modify chromatin at the promoters to make DAN insensitivie to transcription factors

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38
Q

What else can bind to Rb and render it nonfunctional

A

oncogenic DNA viruses such as HPV, which encodes proteins (e.g. E7) which can bind to Rb

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39
Q

TP53 Gene is known as the…

A

GUARDIAN OF THE GENOME

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40
Q

What are some stressors that trigger p53?

A

anoxia
inappropriate oncoprotein activity (e.g. MYC or RAS)
damage to integrity of DNA

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41
Q

In non-stressed cells, discuss p53

A

short half-life (20 min) because of its association with MDM2, which targets p53 for destruction

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42
Q

In stressed cells, discuss p53

A

sensors that include protein kinases such as ATM (ataxia telangiectasia mutated) are activated, which catalyze post-transcriptional modifications in p53 that release it from MDM2 and increase its half-life and ability to drive the transcription of target genes

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43
Q

p53 stops neoplastic transformation via what 3 mechanisms?

A

1) Quiescence (temporary cell cycle arrest)
2) Sensecence (permanent cell cycle arrest)
3) Apoptosis (ultimate protective mechanism against neoplastic transformation - mediated by several pro-apoptotic genes)

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44
Q

Discuss Quiescence

A
  • Occurs late in G1 phase and is caused mainly by p53-dependent transcription of the CDKI gene CDKN1A (p21), which inhibits cyclin-CDK complexes and prevents phosphorylation of Rb, thereby arresting cell in G1 phase.
  • Pause allows cells to repair DNA damage and p53 induces expression of damage repair genes.
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45
Q

More than 70% of human cancers have a defect in which gene?

A

p53!
Biallelic loss of TP53 gene is found in virtually every type of cancer, including carcinomas of the lung, colon and breast - three leading causes of cancer death

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46
Q

Li-Fraumeni Syndrome

A

Patient inherit a mutant TP53 allele

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47
Q

Can DNA viruses (HPV, HBV, EBV) render p53 nonfunctional?

A

YES, just like they render Rb nonfunctional

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48
Q

TGF-B Function?

A

potent inhibitor of proliferation by activation of growth-inhibiting genes such as CDKIs and suppression of growth-promoting genes such as MYC and those encoding cyclins

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49
Q

Is TGF-B function compromised is tumors?

A

YES by mutations in its receptor (colon, stomach, endometrium) or mutation inactivation of SMAD genes that transduce TGF-B signaling (pancreas)

In 100% of pancreatic cancers, and 83% of colon cancers, at least one component of the TGFB pathway is mutated.

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50
Q

In many late stage tumors, TGF-B signaling activates what?

A

eptihelial-to-mesenchymal transition (EMT), which promotes migration, invasion and metastasis

SNAIL and TWIST are transcription factors whose primary function is to promote EMT and are primary candidates for metastasis oncogenes.

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51
Q

In EMT, carcinoma cells do what?

A

downregulate certain epithelial markers (e.g. E-cadherin) and upregulate certain mesenchymal markers

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52
Q

What is the function of E-cadherin

A

maintains contact inhibition, which is lost in maligant cells

53
Q

Neurofibromin-2 (i.e. merlin)

A

product of the tumor suppressor gene NF2 that facilitates E-cadherin mediated contact inhibition

54
Q

Adenomatous polyposis coli (APC) Disorder

A

characterized by development of numerous adenomatous polyps in the colon that have a high incidence of transcription into colonic cancers

loss of tumor suppressor APC gene - mutations in 70-80% of sporadic colon cancers

55
Q

APC Function

A

APC exerts anti-proliferative actions by regulating the destruction of cytoplasmic protein B-catenin.

56
Q

APC Mutation

A

B-catenin is not destroyed, and the WNT signaling response is inappropriately activated in the absence of WNT. B-catenin translocates to the nucleus, where it acts as a growth-promoting transcription factor in conjugation with TcF –> transcription of growth promoting genes (e.g. cyclin D1 and MYC) and transcriptional regulators (e.g. TWIST and SLUG) that repress E-cadherin expression adn reduce contact inhibition

57
Q

Extrinsic Death Receptor Pathway

A

1) CD95 (Fas) bound to its ligand, leading to trimerization of the receptor and its cytoplasmic death domains, which attracts the intracellular adaptor protein FADD
2) FADD recruits procaspase-8 which is celeaved and activated to caspase-8
3) caspase-8 activates downstream caspase-3 (executioner caspase) that cleaves DNA to cause cell death

58
Q

Intrinsic (mitochondrial) Pathway

A

Mitochondrial outer membrane permeabilization is regulated by the balance between pro-apoptotic (e.g. BAX and BAK) and anti-apoptotic molecules (BCL2, BCL-XL).

BH3-only molecules activate apoptosis by tilting the balance in favor of pro-apoptotic molecules –> BAX and BAK activation leads to formation of pores in mitochondrial membrane –> cytochrome c leaks to cytosol and binds APAF-1 and activates caspase-9 which can activate executioner caspases

59
Q

What proteins are the BH3-only proteins

A

BAD, BID, PUMA

60
Q

In 85% of follicular B cell lymphomas, what is activated?

A

The anti-apoptotic gene BCL2 is activated by the t(14;18) translocation

61
Q

Tumor cells reactivate what to allow for limitless replicative potential?

A

telomerase - thus staving off mitotic catastrophe and achieving immortality

62
Q

What is the angiogenesis inducer

A

VEGF

63
Q

What is the angiogenesis inhibitor

A

thrombospondin-1 (TSP-1)

64
Q

What induces the synthesis of TSP-1?

A

p53

65
Q

In normal oxygen situations, what happens in relation to angiogenesis?

A

von Hippel-Lindau protein (VHL) acts as a tumor suppressor gene that binds to hypoxia-inducible factor-1a (HIF-1a), leading to ubiquitination and destruction of HIF-1A

66
Q

In hypoxia induced cancer, what happens in relation to angiogenesis?

A

lack of oxygen prevents HIF-1a recognition by VHL, and it is not destroyed. HIF-1a translocates to the nucleus and activates transcription of its targeted genes such as VEGF.

67
Q

What else is involved in regulating the balance between angiogenic and anti-angiogenic factors?

A

Proteases - elaborated either by the tumor cells directly or from stromal cells. Many proteases can release the angiogenic basic FGF stores in the ECM; conversely, three potent angiogenesis inhibitors (angiostatin, endostatin, and vasculostatin) are produced. TSP-1 is produced by stromal fibroblasts in response to signals from the tumor cells

68
Q

What are the four steps that are involved in the invasion of the ECM?

A

1) Loosening of tumor cells
2) Degradation of the BM and interstitial CT
3) Changes in the attachment of tumor cells to ECM proteins
4) Locomotion

69
Q

Degradation of the BM and Interstitial CT via…

A

tumor cells may either secrete proteolytic enzymes themselves or induce stromal cells (e.g. fibroblasts and inflammatory cells) to elaborate proteases. multiple different families of proteases, such as MMPs, have been implicated

70
Q

What is an important MMP to take note of?

A

MMP-9 is a gelatinase that cleaves type IV collagen or the epithelial and vascular BM and stimulates release of VEGF from ECM-sequestered pools

overexpression of MMPs have been reported in many tumors

71
Q

Locomotion is directed by…

A

tumor cell-derived cytokines, such as autocrine motility factors. In addition, cleavage products of matrix components (e.g., collagen, laminin) and some GFs (e.g., insulin-like growth factors I and II) have chemotactic activity for tumor cells.

Stromal cells also produce paracrine effectors of cell motility, such as hepatocyte growth factor/scatter factor (HGF/SCF), which binds to receptors on tumor cells. Concentrations of HGF/SCF are elevated in glioblstoma multiforme

72
Q

How can you predict the metastatic site of many tumors?

A

Many tumors metastasize to the organ that presents the first capillary bed they encounter after entering the circulation. In many cases, however, the natural pathways of drainage do not readily explain the distribution of metastases.

73
Q

Organ Tropism

A

some tumors show organ tropism, probably due to activation of adhesion or chemokine receptors whose ligands are expressed by endothelial cells at the metastatic site

74
Q

Breast Cancer cells express high levels of which chemokine receptors

A

CXCR4 and CCR7 - the ligands for these receptors are highly expressed only in those organs to which breast cancer cells metastasize

75
Q

How do cancer cells shift their energy metabolism?

A

Shift their glucose metabolism to glycolysis (Warburg effect or Aerobic Glycolysis). Tumors that adopt aerobic glycolysis (e.g. Burkitt lymphoma) are the most rapidly growing of human cancers.

76
Q

Genomic instability as an enabler of malignancy

A

persons born with inherited defects in DNA repair proteins are at greatly increased risk for the development of cancer. There can be defects in three types of DNA repair systems: mismatch, nucleotide excision, and recombination repair

77
Q

Herediatary Nonpolyposis Colon Cancer Syndrome (HNPCC syndrome)

A

Defect in MISMATCH REPAIR SYSTEM, leading to development of carcinomas of the colon. These patient’s genomes show microsatellite instability (MSI), characterized by changes in length of short tandem repeating sequences

78
Q

Xeroderma Pigmentosum

A

Defect in NUCLEOTIDE EXCISION REPAIR and are at an increased risk for the development of cancers of the skin exposed to UV light, because of an inability to repair pyrimidine dimers

79
Q

What are the disorders that involve defects in homologous recombination DNA repair systems and what are they characterized by?

A 
Bloom Syndrome (ionizing radiation)
Ataxia Telangiectasia (ionizing radiation)
Fanconi Anemia (nitrogen mustard - DNA cross-linking agent)

Characterized by hypersensitivity to DNA-damaging agents (see parenthesis)

80
Q

BRCA1 and BRCA2 are involved in

A

mutated in familial breast cancer and involved in DNA repair

81
Q

What are the 3 classes of carcinogenic agents?

A

1) Chemicals
2) Radiant Energy
3) Microbial Agents

82
Q

Chemical Carciongens Definition

A

Contain highly reactive electrophile groups that directly damage DNA, leading to mutations and eventually cancer.
Commonly mutated oncogenes and tumor suppressor genes, such as RAS and TP53 are imortant targets.

83
Q

Direct-Acting Agents

A

require no metabolic conversion to become carciongenic. some of them are weak chemotherapy drugs (e.g., alkylating agents) that promote a second form of cancer, usually leukemia

84
Q

Indirect-Acting Agents

A

require metabolic conversion to an ultimate carcinogen. include polycyclic hydrocarbons (principle active products are epoxides).

85
Q

Initiator vs. Promoter

A

After exposure of a cell to a mutagen or an initiator, tumorigenesis can be enhanced by exposure to promoters, which stimulate proliferation of the mutated cell

86
Q

Radiation Carcinogenesis

A

ionizing radiation causes chromosomal breakage, translocations, and less frequently, point mutations leading to genetic damage and carciongenesis

UV rays induce formation of pyrimidine dimers within DNA, leading to mutations.

87
Q

What is the one retrovirus/oncogenic RNA virus that has been shown to cause cancer?

A

HTLV-1

88
Q

HTLV-1 is associated with what form of cancer?

A

T cell leukemia/lymphoma

leukemia develops in about 3-5% of infected persons after a long latent period of 20-50 years

89
Q

HTLV-1 has tropism for what cells?

A

CD4+ T cells

90
Q

HTLV-1 genome encodes what protein?

A

TAX protein, which turns on genes for cytokines and their receptors in infected T cells. This sets up autocrine and paracrine signaling loops that stimulate T cell proliferation.
Drives progression through cell cycle by binding to/activating cyclins
Represses the function of several tumor suppressor genes that control the cell cycle (e.g., CDKN2A/p16 and TP53)

91
Q

What cytokine appears to be most important in HTLV-1

A

IL-15

92
Q

What DNA viruses are strongly associated with human cancer?

A

HPV
EBV
Kaposi-sarcoma herpesvirus (KSHV or human herpesvirus-8)
HBV

93
Q

Is HCV a DNA virus?

A

No, but it is strongly linked to the pathogenesis of liver cancer!

94
Q

What are the high-risk HPVs

A

Types 16 and 18; associated with several cancers, particuarlly squamous cell carcinoma of the cervix and angiogenital region

95
Q

What are the low-risk HPVs

A

Types 1, 2, 4, and 7 cause benign squamous papillomas (warts)

96
Q

The oncogenecity of HPV is related to what?

A

The expression of two viral oncoproteins, E6 and E7.

E6 binds to and mediated degradation of p53
E7 binds to Rb and releases the E27 transcription factor that is normally sequestered by Rb, promoting progression through the cell cycle

97
Q

EBV was the first virus linked to what human cancer?

A

Burkitt lymphoma (endemic in certain parts of Africa)

98
Q

The oncogenecity of EBV is related to what?

A

LMP-1 (latent membrane protein 1) acts as an ocogene –> promotes B cell proliferation by activating signaling pathways such as NFkB and JAK/STAT, which mimic B cell activation by the B cell surface molecule CD40. Also prevents apoptosis by activating BCL2

99
Q

EBV genome contains what viral cytokine

A

VIL-10, which prevents macrophages and monocytes from activating T cells and killing virally infected cells

100
Q

When is LMP1 not expressed?

A

LMP1 is note expressed in EBV-associated Burkitt lymphoma, because would be recognized by the immune system. However, the B lymphoblasts in immunocompromised patients do express LMP-1 that are recognized by T cells

101
Q

HBV and HCV cause what cancer

A

Between 70-80% of carcinomas worldwide are due to infection with HBV or HCV.

102
Q

The oncogeneicity of HBV/HCV is related to what?

A

The oncogenic effects are multifactorial but the dominant effect seems to be immunologically mediated chronic inflammation, with hepatocellualr injury, stimulation of hepatocyte proliferation, and production of ROS that damage DNA.

The HBx protein of HBV and HCV core protein can activate a variety of signal transduction pathways that may also contribute to carcinogenesis

103
Q

H. pylori infection has been implicated in what cancers?

A

Gastric adenocarcinoma

MALT lymphoma

104
Q

Mechanism of H. pylori induced gastric adenocarcinoma?

A

Initial developmetn of chronic inflammation/gastritis –> gastric atrophy –> intestinal metaplasia of lining cells –> dysplasia –> cancer

105
Q

The oncogenecity of H. pylori is related to what?

A

cytotoxin-associated A gene (CagA)

106
Q

What cell type is responsible for the major immune defense mechanism against tumors?

A

CTLs - play a protective role, chiefly against virus-associated neoplasms (e.g. EBV-induced Burkitt lymphoma, HPV induced tumors)

107
Q

Different classes of tumor antigens include products of…

A

Mutated proto-oncogenes
Tumor suppressor genes
Overexpressed or aberrantly expressed proteins
Tumor antigens produced by oncogenic viruses
Oncofetal Antigens
Altered glyclolipids and glycoproteins
Cell type-specific differentation antigens

108
Q

Overexpressed or aberrantly expressed cellular proteins - tumor antigens

A

Melanoma - tumor antigens (e.g. tyrosinase involved in melanin biosynthesis) are structurally normal proteins that are produced at low levels in normal cells and overexpressed in tumor cells

Cancer-testis antigens are encoded by genes that are silent in all normal adult tissues except the testis, and are deregulated in cancer cells - MAGE (melanoma antigen gene) family of genes

109
Q

Oncofetal Antigens

A

Carcinoembryonic antigen (CEA) and alpha fetoprotein are expressed during embryogenesis but not in normal adult tissue.s Depression of the genes that encode these antigens cause their reexpression in colon and liver cancers

110
Q

Altered Cell Surface Glycolipids and Glycoproteins

A

Altered molecules include: gangliosides, blood group antigens, and mucins

111
Q

MUCINS

A

CA-125 and CA-19-9 are expressed in ovarian carcinomas, and MUC-1 is expressed in breast carcinomas.

112
Q

NK Cells

A

may provide the first line of defense against tumor cells. after activation with IL-12, NK cells can lyse a wide range of human tumors.

tumors that fail to express MHC class I antigens cannot be recognized by T cells, but these tumors may trigger NK cells.

113
Q

What proteins are expressed on NK cells?

A

NKG2D proteins expressed on NK cells and some T cells are important activating receptors that recognize stress-induced antigens that are expressed on tumor cells and on cells that have incurred DNA damage and are at risk of neoplastic transformation

114
Q

Macropahges

A

IFNy is secreted by T and NK cells that activates macrophages
Kills tumors via production of ROS or secretion of TNF

115
Q

Cachexia

A

results from the action of soluble factors such as cytokines produced by the tumor and the host

TNF produced by macrophages in response to tumor cells or by the tumor cells themselves mediates cachexia - suppresses appetite and inhibits the action of LPL, inhibit the release of free FAs from lipoproteins

116
Q

Paraneoplastic Syndrome Definition

A

symptom complexes that occur in patients with cancer that cannot be readily explained by local or distant spread of the tumor of by elaboration of hormones not indigenous to the tissue of origin of the tumor. appear in 10-15% of cancer patents

117
Q

What are the most common syndromes associated with Paraneoplastic Syndrome

A

hypercalcemia
Cushing syndrome
nonbacterial thrombotic endocarditis

118
Q

Hypercalcemia results from synthesis of..,

A

parathyroid hormone-related protein (PTHrP)
other tumor-derived factors implicated include: TGFa, a polypeptide factor that activates osteoclasts, and the active form of vitamin D

119
Q

Cushing syndrome is usually related to the ectopic production of…

A

ACTH

120
Q

MORPHOLOGIC METHODS for diagnosis of cancer

A

Excision or biopsy
Fine needle aspiration (readily palpable lesions)
Cytologic (Pap) smears
Immunocytochemistry (detection of cytokeratin by specific monoclonal antibodies labeled with peroxidase points to a diagnosis of undifferentiated carcinoma; detection of PSA)
Flow cytometry

121
Q

Tumor Marker Usage

A

cannot be utilized for definitive diagnosis of cancer; however, they can be useful screening tests and in some instances have utility in quantitating the response to therapy and detect disease recurrence

LOW SPECIFICITY AND SENSITIVITY

122
Q

Tumor Markers Include

A

PSA - prostatic carcinoma, but can be elevated in benign prostatic hyperplasia
CEA - elaborated in colon, pancreas, stomach and breast
Alpha fetoprotein - produced by hepatocellular carcinomas, yolk sac ruminants in gonads, and teratocarcinomas

123
Q

Molecular Diagnosis of Maligancy

A

Diagnosis of malignancy with FISH and PCR
Prognosis and Behavior: FISH and PCR to detect amplification of oncogenes such as HER2/NEU and NMYC
Detection of minimal residual disease (e.g. detection of BCR-ABL transcripts by PCR gives a measure of residual CML)
Diagnosis of hereditary predisposition to cancer
Therapeutic decision making

124
Q

Melanoma

A

tumors with a valine for glutamate substitution in amino acid 600 (V600E) of the serine/threonine kinase BRAF respond well to BRAF inhibition, whereas melanomas without this mutation show no response.

125
Q

Expression Profiling

A

1) extraction of mrNA from samples, reverse transcribed to cDNA, and labeled with fluorescent molecules
2) labeled cDNA are mixed and applied to a gene chip, which contains thousands of DNA probes representing known genes
3) labeled cDNAs hybridize to spots that contain complementary sequences. Hybridization is detected by laser scanning of the chip, and the results are read in units of fluorescence intensity –> expression level of genes is obtained

126
Q

Whole Genome Sequencing

A

sequences the entire tumor genome, when compared with the normal genome from the same patient, can reveal all the somatic alternations present in a tumor

127
Q

What are the two types of mutations?

A

DRIVER MUTATIONS

PASSENGER MUTATIONS

128
Q

Driver Mutations

A

“drive the neoplastic process” and could be therapeutic targets; subvert normal control of cell proliferation, differentiation, and homeostasis.
generally are recurrent and present in a substantial percentage of patients with a particular cancer (e.g. BCR-ABL fusion genes are present in all cases of CML)

129
Q

Passenger Mutations

A

fall in noncoding regions of the genome or have a neutral effect on growth, not conferring any advantage or disadvantage.
some have roles in drug resistance (e.g. the mutations in BCR-ABL that confer resistance to imatinib in CML are present as passenger mutations) - because they confer a powerful selective advantage, these mutations are converted to driver mutations in the face of drug therapy

BLOCK 2 FINAL (10 decks)

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