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Foundations of Disease > Exam 2: Cancer > Flashcards

Exam 2: Cancer Flashcards

1
Q

Cancer

Definition

A

Group of diseases characterized by the uncontrolled growth and spread of abnormal host cells.

Represents > 100 disorders with varying causes, clinical presentations, response to treatment, and prognoses.

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2
Q

of new cases of cancer dx in the US each year…

A

> 1.6 million

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3
Q

% of Americans dx with cancer sometime in their lifetime is…

A

39.6%

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4
Q

5-year relative survival rate for all cancers is…

A

69%

(2002-2011)

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5
Q

Cancer is the ___ most common cause of death in the US.

A

2nd

(1 in 4 deaths)

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6
Q

Women

Common Cancers

A
  • Breast
  • Lung
  • Colon/rectum
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7
Q

Men

Common Cancers

A
  • Prostate
  • Lung
  • Colon/rectum
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8
Q

___ is the leading cause of cancer death for both men and women.

A

Lung cancer

(Incidence represents ~14% of new cancers each year)

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9
Q

Cancer Rates

Worldwide

A
  • 14 million new cases dx annually worldwide in 2012
  • Expected to ↑ to 22 million by 2023 d/t move towards Westernized lifestyles
    • Africa, Asia, Central and South America account for ~70%
  • Significant geographical variation in incidence of specific cancers suggests disparate environmental and genetic influences
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10
Q

Cancer

Indicence Rates

A
  • Overall incidence of CA constant
  • Prevention strategies in US has ↓ incidence of certain cancers
    • Colon and rectum
      • Due to screening and removal of precancerous polyps
    • Lung CA in men
  • ↑ incidence of lung CA in women
    • Due to ↑ smoking
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11
Q

Neoplasm vs Tumor

A

Neoplasm ⇒ abnormal growth of new cells

Tumor ⇒ historically meant swelling

Both terms have become synomymous with a tissue mass comprised of cells that exhibits abnormal growth characteristics caused by a series of heritable, new somatic mutations.

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12
Q

Tumor

Composition

A

All solid tumors include:

  • Neoplastic cells ⇒ “tumor parenchyma”
    • Determines the classification of the tumor
  • Reactive stroma
    • Composed of CT, blood vessels, and infiltrating leukocytes
    • Important in tumor growth, progression, and presentation
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13
Q

Benign Tumors

Characteristics

A
  • Localized overgrowth of tissue
  • Do not:
    • Infiltrate local tissues
    • Metastasize to distant sites
  • Usually grow and expand slowly
    • Often results in a capsule
      • Ring of fibrous tissue
      • Seperates them from host tissue
        • Discrete, palpable, movable
  • Can cause significant morbidity due to compression of normal tissues
    • Esp. in defined anatomical regions like the brain, thorax, pelvis
  • Removal/destruction generally curative
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14
Q

Benign Tumors

Appearance

A

Gross and histological appearance relatively innocuous:

  • Often encapsulated
  • Resembles adjacent tissue
  • Parenchyma and stromal cells generally not prominent
  • Usually well-differentiated
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15
Q

Malignant Tumors

Characteristics

A

Cancerous growths that possess the capacity to invade local tissues and metastasize to distant sites throughout the body to cause death.

  • Classified as malignant due to:
    • Notable histological changes
    • Evidence of invasion
  • Not readily demarcated from adjacent tissues
    • Penetrates margins
    • Infiltrates neighboring tissues
    • Slow-growing tumors can have fibrous “pseudo-encapsulation”
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16
Q

Malignant Tumors

Appearance

A
  • Poorly demarcated
    • Evidence of invasion
  • ↓/poor differentiation ⇒ anaplasia
    • Can show an immature phenotype
  • Variation of cell size and shape ⇒ pleomorphism
  • Unusally large nuclei with hyperchromatic staining clumped around the nuclei
  • ↑ # of mitotic cells
  • Loss of polarity
  • Areas of ischemic necrosis
    • Neoplasia growth outpaces vascular stroma
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17
Q

Primary Tumor

A

The orginal tumor.

Guides treatment and provides a more accurate prognosis.

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18
Q

Secondary Tumor

A

Distant settlements of cancer cells ⇒ metastases

  • Due to invasion into local tissues ⇒ blood or lymphatics ⇒ distant sites
  • Induce significant morbidity and mortality
  • Causes ~90% of cancer deaths
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19
Q

Carcinogenesis

A

Multi-step process of carginogenesis:

  • Cells accumulate somatic mutations
    • Non-lethal mutations
    • Promotes changes in cell physiology
    • Promotes tumor formation, malignancy, and metastasis
  • Cancer-causing mutations tends to accumulate slowly over time
    • Cells evolve from bad to worse
    • Involves successive rounds of mutation
    • Selection of cells with fewer constraint on growth and pro-cancer traits
  • Cancer cells usually possess > 60 mutations
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20
Q

Cancer

Subclones

A

Cancers are clonal in origin:

  • Accumulates somatic mutations
  • Selective pressures allows malignant cells to outcompete normal neighboring cells
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21
Q

Malignant Transformation

Essential Alterations

A

11 essential alterations in cell function:

  1. Sustained proliferative signaling
    • Growth factor independent
    • Usually a gain-of-function mutation
      • Protooncogene ⇒ oncogene
  2. Insensitivity to growth-inhibitory factors
    • Fail to produce or recognize anti-growth factors
      • Ex. Loss of contact inhibition
  3. Evasion of apoptosis
    • Able to survive intracellular abnormalities which usually lead to cell death
      • Genome instability, chromosome breakage & other DNA damage
      • Cell stress such as hypoxia and metabolic changes
    • Inactivation of p53 present in > 50% of all human cancers
  4. Limitless replicative potential ⇒ immortality
    • Many upregulate telomerase to avoid cellular senescence & mitotic catastrophy
  5. Sustained angiogenesis
    • Angiogenic ability needed to obtain O2 and nutrients, remove waste
    • Many ↑ expression of VEGF
    • Some ↓ expression of angiogenesis inhibitors
  6. Tissue invasion and metastasis
    • Ability to invade surrounding normal tissues & move through tissue boundaries
  7. Deregulation of cellular energetics
    • Have higher energy and biosynthetic requirements to sustain growth
    • Consume glucose at 10-100x normal
    • Favors lactic acid fermentation over oxidative phosphorylation ⇒ Warburg effect
  8. Genomic instability
    • Nucleotide, microsatellite, or chromsomal variations
    • ↑ mutation rate
      • Malignant transformation
      • Tumor heterogeneity
      • Tumor progression
      • Cancer evolution
    • Detrimental vs advantagous ∆
  9. Epigenetic modifications
    • Inappropriate epigenetic silencing or upregulation of gene expression
    • Often contain abnormal nuclei & high proportion of heterochromatin
  10. Immune evasion
    • Crosstalk between tumor and immune system ⇒ inhition and enhanced tumor growth
    • Mutations ⇒ avoid detection ⇒ avoid killing
  11. Promote inflammation
    • Modifies microenvironment
    • Cell stress, tissue damage, persistent infection ⇒ inflammation ⇒ initation/progression of maligancy
    • Tumors can produce cytokines and chemokines
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22
Q

Genomic Instability

A
  • Caused by defects in DNA repair systems and/or cell cycle regulation
    • Failure to repair DNA damage
    • Repair in error-prone manner
  • Accumulation of mutations in somatic cells
    • ∆ genes for regulation of cell growth ⇒ cancer
  • Examples:
    • BRCA1 and BRCA2 in homologous recombination repair ⇒ breast & other cancers
    • Nucleotide excision repair (NER) system defect ⇒ xeroderma pigmentosum (XP) and skin CA
    • Mismatch repair (MMR) system defect ⇒ Lynch syndrome “Hereditary nonpolyposis colon cancer (HNPCC)”
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23
Q

Epigenetic Changes

A

Malignant cells often have extensive reprogramming of every component of the epigenetic machinery:

  • DNA methylation
  • Histone methylation/acetylation
  • Nucleosome positioning
  • Non-coding RNA expression

Can silence tumor suppressor genes.

Chromatin regulation involved in tumorigenesis.

New target for therapies.

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24
Q

Tumor-Associated Macrophages

(TAMs)

A

Tumors release cytokines/chemokines that promote Mφ ⇒ TAMs.

TAMs are tumor promoting via 4 main routes:

  1. Secrete growth factors
    • EGF, FGF, IL-6, TNF
    • Might feed tumor cells
  2. Stimulate angiogenesis
    • VEGF, PDGF
  3. Secrete metalloproteases
    • Aid in tumor invasion and metastasis
  4. Secrete cytokines
    • Recruit ineffective immune cells
    • Generate immunosuppressive substances that inhibit immune response
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25
Q

Natural Barriers

A

Epithelial cell adherence & presence of ECM ⇒ natural barrier against invasion & metastasis

Malignant cells develop ways of untethering attachments

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26
Q

Contact Inhibition

A
  • Cell adhesion molecules (CAMs)
    • Involved in cell-cell & cell-matrix adhesions
    • Form dynamic connections ⇒ links cell function & growth to adhesion
  • Growing epithelial cells coupled by E-cadherin
    • Interaction results in anti-mitotic signal ⇒ contact inhibition
      • The stop of growth once cells touch
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27
Q

Invasion

A
  • Detachment
    • Tumor cells untheter from ECM
    • Infiltrate neighboring tissues
    • Loss of contact inhibition
  • Secretion of metalloproteases @ invading edge
    • Helps break down ECM
    • Remodels basement membrane
    • Facilitates invasion
  • Allows cancer to penetrate body cavities and metastasize
    • Blood vessels ⇒ hematogenous spread
    • Lymphatic spread
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28
Q

Metastasis

A

Cancer cells break away from the primary tumor and establish growth at a distant site ⇒ direct seeding

  • Many cancers tend to metastasize to a specific site or organ
  • Can penetrate a body cavity
    • Peritoneal, pleural, or pericardial spaces
    • Can block drainage sites or actively secrete fluids ⇒ fluid accumulation
  • Highly inefficient process
    • <0.01% of detached, circulationg tumor cells ⇒ secondary tumor
    • Still ~ 30% of new solid tumors have metastasis
  • Cells @ secondary tumor represent a distinct subpopulation of cells
    • Undergone significant selective pressures
    • Demonstrate clinically significant differences
    • ↑↑ rate of mutation ⇒ rapid phenotypic diversification
    • Can confer resistance to therapeutic interventions
  • Undetected micrometastases may remain dormant and lead to recurrance after treatment
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29
Q

Sentinel Lymph Node

Biopsy

A
  • ID the lymph node to which cancer cells are most likely to have spread ⇒ sentinel node
  • Mapped using colored dye or radioactive tracer injected into primary tumor
  • Node removed and evaluated for metastasis
  • Can help in staging & avoid extensive LN removal
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30
Q

Hematogenous Spread

A
  • Spread via blood vessels
  • Often results in metastasis to bone, lung, liver, or brain
  • Venous invasion more common than arterial
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31
Q

Seed and Soil

Hypothesis

A

Favorable interactions between metastatic tumor cells (the seed) and organ microenvironment (the soil) ⇒ organ-preference patterns during metastasis

  • Ex. bone is a common site for metastasis
    • Constant growth and cell turnover
    • Osteoblasts produce abundant cytokines and non-collagen proteins
      • Act as fertile “soil”
      • Allows malignant cells to survive, proliferate, spread, and invade bone matrix
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32
Q

Cell Cycle

Processes

A

Multiple coordinated processes during interphase and M phase:

  • Cell growth
  • DNA replication
  • Distribution of duplicated chromosomes
  • Cell division
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33
Q

Cell Cycle

Phases

A

4 successive phases:

  1. Gap 1 ⇒ G1 phase
  2. Synthesis ⇒ S phase
  3. Gap 2 ⇒ G2 phase
  4. Mitosis ⇒ M phase
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34
Q

Quiescent cells are in the ___ phase.

A

G0

  • Usually due to lack of growth factors or nutrients
  • Some cells remain in G0 once they reach maturity
    • Ex. nerve cells, cardiac myocytes
  • Some enter semi-perminant G0 and will only divide under specific circumstances
    • Ex. liver and kidney parenchymal cells
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35
Q

Cell Cycle

Checkpoints

A

Checkpoints and feedback controls prevent entry into the next phase until all events of preceding phase have been completed correctly.

Ensures that incomplete/damaged chromosomes are not replicated and passed onto daughter cells.

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36
Q

Cell Cycle

Regulators

A

Depend on interaction of two key components:

  1. Cyclin-dependent kinases (Cdks)
    • Serine/threonine kinases
    • Provide the enzyme activity
    • Constitutively expressed
    • Function dependent on cyclin binding
  2. Cyclins
    • Determines substrate specificity
    • [Cyclin] cycles up and down during the cell cycle
    • Presence/absence regulated by both synthesis and degradation pathways
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37
Q

G1 Checkpoint

Overview

A

Controls commitment to the cell cyle.

  • Assesses:
    • Appropriate growth factors
    • Adequate size
    • Adequate energy stores
    • Intact genome
  • If any criteria are not met ⇒ cell cycle halted until issue resolved
  • If criteria met ⇒ signaling via cyclins and cyclin-dependent kinases (Cdks) ⇒ pass through restriction point
    • Becomes committed to cell division
  • Once this restriction point passed, no additional extracellular signals required
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38
Q

G1 Checkpoint

Regulation

A

Cyclin D-Cdk 4/6 complex initiates the release of Rb-dependent cell cycle inhibitory ‘brake’ on the growth factor dependent G1 restriction point controlling transition into the cell cyle.

  • Entry into S phase blocked by “hypophosphorylated” retinoblastoma tumor suppressor protein (Rb, pRb)
    • Rb binds and sequesters E2F transcription factors
  • When a cell reaches a critical size in the presence of specific growth factors and nutrients ⇒ Cyclin D generated
    • Cyclin D binds either Cdk4 or Cdk6
    • Cyclin D-Cdk 4/6 complex“hyperphosphorylates” Rb
    • Rb no longer able to bind/inhibit E2F components
    • E2F activates genes needed for transition into S phase and DNA synthesis
    • Rb remains hyper-℗ throughout S, G2, and M phases
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39
Q

Retinoblastoma Gene

(RB1)

A
  • Encodes retinoblastoma protein (Rb)
  • Tumor suppressor gene
  • Loss-of-function mutations in RB1 linked to malignancy
    • Retinoblastoma
    • Bladder CA
    • Breast CA
    • Lung CA
    • Osteosarcoma
    • Melanoma
    • Leukemias
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40
Q

Retinoblastoma Protein (Rb)

Inhibition

A

Rb is a target for viral oncoproteins.

Ex. E7 protein of HPV binds and inhibits Rb.

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41
Q

Cyclin D

Regulation

A

Growth factor binding ⇒ Ras/Raf/ERK signaling ⇒ Cyclin D synthesis

  • Continues to be made if GF present
  • Rapidly degraded ⇒ [Cyclin D] quickly falls if GF removed
  • Illustrates the molecular mech of GF dependent proliferation
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42
Q

Cyclin D

Abnormalities

A
  • Most are gain-of-function mutations ⇒ ↑ cyclin D activity
    • ↑ transcription of cyclin D
    • Gene amplification
    • ↑ stability of mRNA via 3’ modifications
    • ↑ protein function
    • ↑ protein stability
    • Inhibition of Cdk inhibitor (CKI) binding
  • Implicated in many human cancers
    • Overexpression found in > 50% of human breast CA
      • CDK4/6 inhibitors used to treat
      • ↓ risk of breast CA progression or death
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43
Q

S Phase Checkpoint

A

Controls DNA replication.

  • Assesses fidelity/completion of DNA replication
  • Blocks cell cyle if problem detected
    • Presence of long stretches of ssDNA
    • Chromome damage
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44
Q

DNA Damage Response

Overview

A

DNA damage or replication fork failure during replication ⇒ mitotic delay

Blocks cell cycle at G1, S phase, and G2/M checkpoints.

Allows time for DNA repair or stimulates apoptosis if unrepairable.

  • Sensor proteins
    • Recognize damage
    • Recruits other modulators to the site
    • “Marks” the damage
  • Up-regulation of inhibitor molecules
    • Ex. p53 from TP53 gene
  • Down-regulation of stimulatory molecules
    • Cdc 25 family
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45
Q

DNA Damage Response

Mechanism

A

Tumor suppressor gene

  • Under normal circumstances:
    • p53 bound by Mdm2 (ubiquitin ligase)
      • Targets p53 for proteasomal degradation
      • Cell has little functional p53
    • Allows other components to control cell cycle e.g. growth factors
  • Under conditions of cellular stress:
    ⇒ DNA damage, hypoxia, certain cytokines, metabolic changes, viral infection, telomere shortening, oncogene-based degregulation
    • p53 phosphorylated ⇒ ubiquitylation suppressed ⇒ p53 stabilized and accumulates in the nucleus
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46
Q

p53

Actions

A
  • Transcriptional regulator
    • Binds both DNA and transcription factors
    • Halts cell cycle
    • Can lead to cycle arrest or apoptosis
  • p53 actions:
    • Binds to response elements throughout genome ⇒ ∆ transcription
    • ↑ expression of p21 ⇒ potent Cdk inhibitor (CKI)
      • Binds Cyclin D-Cdk4/6 and Cyclin E-Cdk2 complexes
        • ⊗ transition through G1 checkpoint
      • Transcriptional repression of Cdc 25
        • Needed to pass through G2/M checkpoint
      • Binds and inhibits DNA pol sliding clamp ⇒ ⊗ DNA replication
    • Induction of apoptosis
      • Via caspase and Bcl2 pathways
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47
Q

G2/M Checkpoint

Overview

A

Controls entry into mitosis.

  • Evaluates:
    • Cell size
    • Protein reserves
    • Intact fully replicated genome
  • Problems in the DNA or genome triggers checkpoint ⇒ halts cell cycle until replication completed or damage repaired
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48
Q

G2/M Checkpoint

Regulation

A

Regulated by Cyclin B-Cdk1 complex.

  • Cyclin B cyclical expression
    • Low [Cyclin B] during G1 and S phase
    • ↑↑↑↑ [Cyclin B] through G2 phase and into M phase
    • Destroyed at the end of mitosis
  • During G2 phase:
    • Cyclin B accumulates
    • Cyclin B complexes with Cdk1 (aka “Cdc2”)
    • Cdk1 undergoes two distinct regulatory phosphorylation events
      • Cyclin H-Cdk7 activates Cdk1 via ℗ at Thr 161
      • Wee1 inactivates Cdk1 via ℗ at Thr 14 and Tyr 15
        • Allows inactive Cyclin B-Cdk1 to accumulate through G2 phase
  • Upon entry into mitosis:
    • Inhibitory ℗’s removed by Cdc25 ⇒ activation of Cyclin B-Cdk1 complex
    • Active Cyclin B-Cdk1 complex complex ℗’s downstream targets
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49
Q

Cyclin B-Cdk1

Actions

A

Elicits effects via ℗ of downstream targets:

  • Activates condensins
    • Helps condense chromosomes
  • ∆ histones
  • ℗ nuclear lamins
    • Promotes dissociation of nuclear envelop
  • ℗ microtubules triggering instability
    • Facilitates mitotic spindle formation
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50
Q

Cdc25

Regulation

A

DNA damage ⇒ p53 activation ⇒ p21 ⇒ ⊗ Cdc25

Cyclin B-Cdk1 remains inactive

Halts entry into mitosis

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51
Q

Wee1

Cancer Expression

A

Wee1 is an inhibitory kinase

  • Often overexpressed in many cancer cells
  • Compensates for cells that have lost G1 and S phase checkpoints
    • Due to loss of p53 or Rb function
  • G2/M checkpoint is the major stop point for DNA repair in many cancer cells
  • Inhibitors of Wee1 a target for therapeutic intervention
    • ↑ genomic instability ⇒ cancer cell damage/death
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52
Q

Cdk Regulation

Summary

A

Regulated at a minimum of 5 steps:

  1. Presence/absence of cyclin partner
    • Via cyclin transcription/synthesis and regulated degradation
  2. Enabling ℗ events ⇒ opens catalytic domain of Cdk
  3. Inhibiting ℗ events ⇒ block Cdk function
    • Until a phosphatase like Cdc25 triggers the start of S phase
  4. Binding of Cdk inhibitor proteins (CKIs)
  5. Ubiquitylation and destruction of specific regulatory proteins
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53
Q

Cdk Inhibitory Proteins

(CKIs)

A

Adds another level of regulation to the cell cycle.

  • Regulation and actions:
    • ∆ cell cycle by ⊗ cyclin-Cdk complexes
    • Transcription
    • Apoptosis
    • Migration
  • Examples:
    • p21
      • Transcriptional target of p53
    • p15
      • Mediates response to TGF-β
      • Binds to Cyclin D-Cdk4/6 complexes
      • Results in G1 cell cycle arrest
      • Inhibits proliferation of cells like T and B lymphocytes
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54
Q

M Phase Checkpoint

A

Controls start of anaphase.

  • Occurs near the end of metaphase
  • Ensures each pair of sister chromatid is appropriately attached to at least two spindle microtubules arising from opposite poles
  • Critical checkpoint ⇒ seperation of sister chromatids irreversible
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55
Q

Embryonic

Cell Cycle Regulation

A
  • Early embryonic cells constantly replicating
    • Do not enter G0
  • Cell cycle control depends exclusively on post-transcriptional mechanisms
    • Involves the regulation of Cdks and ubiquitin ligases
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56
Q

Cancer

Cell Cycle Regulation

A
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57
Q

Mitotic Index

A

Clinical tool that determines how fast a population of cells is proliferating.

# of cells actively in mitosis / total # of cells

  • Low mitotic index ⇒ cells dividing slowly
  • High mitotic index ⇒ cells dividing rapidly
  • Can be a prognostic factor
  • Used in clinical decision making to ∆ treatment
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58
Q

Cancer

Quantitative Flow Cytometry

A
  • Uses fluorescent DNA-binding dyes
  • Allows assessment of # of cells in the cell cycle
    • Look @ ratio of cells in G1 and S phase
  • Can assess chromosome instability and aneuploidy
    • Aneuploidy in cancer tissue seen as a predictor of a poor prognosis
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59
Q

Sensor Proteins

A
  • Detects DNA damage
  • Recruites other molecules to the damage site
  • “Mark” the damage
  • Ex:
    • p53 ⇒ upregulates inhibitory molecules
    • Cdc25 family ⇒ downregulates stimulatory molecules
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60
Q

Malignant Transformation

A

The overall sequential transition from a normal cell to a malignant one is called the multistep process of carcinogenesis.

Cells acquire cancer promoting mutations through spontaneous and environmentally-induced DNA damage.

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61
Q

Carcinogenic

Genes

A

Generally encode products which:

  • Directly regulate cell proliferation
  • Are involved in the repair of damaged DNA
  • Control programmed cell death or apoptosis

These “driver” mutations classified as:

  • Proto-oncogene ⇒ promotes growth
  • Tumor suppressor gene ⇒ inhibits growth
  • Landscaping genes ⇒ impacts the cellular microenvironment
    • Cell adhesion, susceptibility to apoptosis, etc

Many passenger mutations will also develop.

By definition have no phyotypic consequence on the cell.

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62
Q

Proto-oncogenes

A

The normal cellular form of genes that are involved in regulating cell proliferation.

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63
Q

Oncogenes

A

Mutated, cancer causing forms of proto-oncogenes.

  • Promotes cell growth
  • Gain-of-function mutation in most cases
  • ↑ function can be due to:
    • ↑ function of the gene product
    • ↓ degradation
    • ∆ gene expression pattern
    • ∆ in the gene product’s function
  • Mutation of a single allele required to contribute to tumor formation
    • Works in a dominant manner within the cell
  • Usually lethal and rarely inherited ⇒ do not show an inheritance pattern
  • Result from somatic mutations
  • Many different genes can encode oncoproteins such as:
    • Growth factors or mitogens
    • Growth factor receptors (HER2/neu)
    • Signal transducers (Ras)
    • Transcription factors (Myc)
    • Cell cycle regulators (cyclin D)
    • Pro-survival molecules (Bcl2)
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64
Q

RET Oncogene

A
  • Oncogene which can be inherited
  • Germline mutation results in constitutive activation of RET
  • Results in multiple endocrine neoplasia type 2 (MEN2)
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65
Q

HER2/neu

Mutations

A
  • Gene encodes receptor tyrosine kinase called human epidermal growth factor receptor (HER)
    • Closely related to EGF receptor
  • Overexpressed through gene amplification
  • Prompts ligand independent signaling via the Ras-MAPK pathway
    • Drives cellular proliferation
  • Enables constitutive activation of growth factor signaling pathways
  • Operates as an oncogenic driver in breast cancer
  • Acts as both a biomarker and target for therapy
66
Q

HER2 ⊕

Breast CA

A
  • Breast CA that overexpress HER2/neu
    • More clinically aggressive
    • Less responsive to hormonal therapy
  • Recommended that every invasive breast CA be tested for HER2 mutations
  • Also recommend retesting whenever CA recurs or spreas
    • Genome instability and selective pressures ⇒ ∆ tumor status
  • Herceptin
    • mAb that targets HER2
    • Has improved prognosis for HER2-positive breast CA significantly
67
Q

Ras

Mutations

A
  • Small GTPases activated by guanine nucleotide exchange factors (GEFs)
  • Ras turns on other proteins ⇒ transcription of genes involved in regulation of:
    • Cell growth
    • Proliferation
    • Differentiation
  • Mutations ⇒ production of activated Ras proteins permanently locked into active form
    • Continually activates MAP kinase pathway
    • Leads to cell proliferation
  • Represents the most common type of mutation in an oncogene
68
Q

Cyclin D

Mutations

A
  • Critical role in growth factor signaling
    • Cyclin D-Cdk4/6 complex
      • Initiates release of Rb-dependent cell cycle-inhibitory “brake” on G1 checkpoint
  • ↑ cyclin D function ⇒ ↓ Rb activity
  • Gain-of-function mutations via:
    • Gene amplification
    • Reciprocal translocation
      • Positions the gene near cis Ig heavy chain enhancer elements
    • Chromosomal inversion
      • Brings proto-oncogene close to a strong transcriptional control element
  • CKIs can still inhibit the kinase action
  • ↑ cyclin D expression drives the cell closer to growth factor independent function
69
Q

Myc

Mutations

A
  • Part of the early response genes transiently induced by RAS/MAPK path following GF stimulation
  • Myc protein promotes transcription of many genes driving cell growth and proliferation
    • Ex. cyclin D expression regulated by Myc
  • Converted to oncogene through amplification or translocation
    • Burkett lymphoma ⇒ most often caused by translocation t(8;14) (q24; q32)
  • Potential therapy target:
    • Inactivation of small ubiquitin-like proteins in Myc + cells ⇒ mitotic catastrophe
    • Pharm uncoupling of bioenergetic pathways involving glucose or glutamine metabolism from Myc-induced accumulation might stop tumor growth
70
Q

BCR-ABL

(Philadelphia Chromosome)

A
  • ABL1 proto-oncogene encodes cytoplasmic and nuclear protein tyrosine kinase involved in:
    • Cell differentiation
    • Cell division
    • Cell adhesion
    • Stress response
  • Loss of regulatory domain on ABL1 protein converts to oncogene
    • Can occur through reciprocal translocation
    • Results in the Philadelphia chromosome
  • New chromosome encodes a chimeric gene - BCR-ABL ⇒ exhibits unregulated TK activity
  • Found in:
    • Most patients with chronic myelogenous leukemia (CML)
    • Acute lymphoblastic leukemia (ALL)
    • Acute myelogenous leukemia (AML)
    • GI stromal tumors
71
Q

Bcl-2

Mutations

A
  • Proto-oncogene is an apoptotic regulator
  • Oncogene activated by chromosome translocation in human follicular lymphoma
  • Oncoprotein
    • Does not drive cell proliferation
    • Instead promotes cell survival
    • Can inhibit effectiveness of chemotherapy due to “to live” signal
72
Q

Tumor Suppressor Genes

Functions

A
  • Normally:
    • Inhibits cell proliferation
    • Act as brakes for the cell cycle
    • Inhibits formation of tumors
  • Encodes:
    • Transcription factors
    • Cell cycle inhibitors
    • Signal transduction molecules
    • Cell surface receptors
    • Regulators of cellular responses to damage
  • Cancer often results from a loss-of-function mutation
  • Only one functional copy needed to prevent cancinogenesis
    • Functions in a recessive fashion at cellular level
  • Mutations inherited in autosomal dominant fashion
73
Q

Tumor Suppressor Gene

Categories

A
  1. Gatekeeper genes
  2. Caretaker genes
  3. Landscaper genes
74
Q

Gatekeeper Genes

A

Directly controls cellular growth, differentiation, and apoptosis.

  • Normal genes:
    • ⊗ mitogenic signaling pathways
      • Adenomatous polyposis coli (APC)
      • NF1
      • p21
    • ⊗ cell cycle progession
      • Rb
    • Enable genome stability
      • p53
    • Provide proapoptotic functions ⇒ promote tumor suppressor function
      • p53, BAX
  • Mutations directly relieves normal controls
  • Promotes outgrowth of cancer cells
75
Q

Caretaker Genes

A

Involved in maintaining the genetic integrity of the cell.

  • Regulates:
    • DNA repair mechanisms
    • Chromosome segregation
    • Cell cycle checkpoints
  • Mutations result in genome instability
    • ↑ frequency of alterations to gatekeeper genes
  • Examples:
    • BRCA-1 and BRCA-2 ⇒ breast CA
    • MSH1, MLH1, and MSH6 ⇒ Hereditary nonpolyposis colon CA
76
Q

Landscaper genes

A

Impacts the intracellular and extracellular environment of the malignant cell.

  • Mutations lead to abnormal extracellular and intracellular environments
  • Contributes to carcinogenesis
  • Examples:
    • E-cadherin ⇒ promotes cell adhesion inhibiting invasion and metastasis
    • Inhibitors of pro-growth programs for metabolism and angiogenesis
      • Von-Hippel-Lindau tumor suppressor protein in hypoxic response
77
Q

Two-Hit Model

A
  • Mutation in both copies of a tumor suppressor gene needed for carcinogenesis
  • Only one functional copy needed to prevent cancers
  • Someone with an inherited deficit only needs one somatic mutation for carginogenesis
78
Q

Retinoblastoma

(RB1)

A

Rare childhood tumor of the retina caused by loss-of-function in both RB1 alleles.

  • Sporadic form
    • Spontaenous
    • Occurs unilaterally
  • Familial form
    • ~30-40% of cases
    • Inherits one bad copy of RB1
    • A single hit causes loss of heterozygosity
    • Tends to develop tumors at an earlier age
    • More likely to have multifocal unilateral or bilateral retinoblastoma
  • Loss of RB1 function results in loss of functional sequestration of transcription factor E2F
    • E2F able to bind and promote production of cyclin E
    • Allows cell to transition through G1 checkpoint in absence of growth factors
79
Q

p53

Mutations

A

Guardian of the Genome

  • p53 is the most common genetic mutation in human tumors
  • Loss-of-function mutations found in wide variety of cancers
  • > 50% of malignant cells have a p53 mutation
  • Other cancers have mutations that ∆ p53 function
    • ↑ Mdm2 expression ⇒ functional p53 deficiency
80
Q

Li-Fraumeni

Familial Cancer Syndrome

A
  • Individual inherits one abnormal copy of the TP53 gene
  • 25x greater chance of developing cancer by age 50
  • ↑ risk many cancers
    • Breast CA
    • ALL
    • Soft-tissue sarcomas
    • Osteosarcomas
    • Adrenocortical carcinoma
    • Some brain cancers
81
Q

BRCA-1 / BRCA-2

Mutations

A
  • BRCA proteins expressed in most cells
  • Role in maintaining genome stability through repair of double stranded breaks
  • Significant role in breast and ovarian cancer
    • BRCA-1/BRCA-2 mutation cause 90% of “single gene” breast CA
    • Penetrance between 30-90% depending on mutation type, genetic and environmental factors
  • Mutations to these genes rare in sporadic breast cancer
    • May be due to EMSY
      • Binds and inhibits BRCA-2
      • EMSY genes often amplified in sporadic breast cancer resulting in functional inhibition of BRCA-2
82
Q

Epigenetic

Effects

A

Many cancers have mutations in genes responsible for epigenetic regulation.

Can include changes in:

  • DNA methylation
  • Histone modifiers (writers and erasers)
  • Histone readers
  • Chromatin remodelers
  • MicroRNAs
  • Other components of chromatin

Intergenerational epigenetic inheritance may explain some aspects of cancer heritability.

83
Q

Epigenetic

Morphological Changes

A

Can visibly change the appearance of malignant cells:

  • Hyperchromasia
  • Chromatic clumping
  • Vesicular nuclear chromatin
84
Q

Decitabine

A
  • DNA methyltransferase inhibitor
  • ∆ cell epigenetic patterning through prevention of DNA methylation
  • Used to treat myeloproliferative disorders and ALL
85
Q

Environmental Risk Factors

A

Environmental exposures & host characteristics can significantly impact the likelihood of developing cancer.

86
Q

Carcinogens

A

Materials that are known to cause cancer.

Classified as:

  • Physical radiation
  • Chemical
  • Biological
87
Q

Radiation

A
  • Exposure ↑ risk of cancer
  • Non-ionizing radiation
    • UV radiation from sunlight
  • Ionizing radiation
    • Cosmic sources
    • Nuclear power plant generation
    • Medical uses like XR and CT
      • Accounts for 50% per capital radiation dose
  • Radon gas ⇒ greatest exposure to radiation for most people
    • Tasteless, colorless, odorless gas
    • Released during decay of uranium in rock and soil
    • Inhalation can occur during mining
    • Present in many homes
      • Seeps up from the ground
    • Estimated to be 2nd leading cause of lung CA
88
Q

Chemical Carcinogens

A

Two types:

  1. Direct-acting
    • Requires no metabolic conversion
  2. Indirect-acting
    • Requires metabolic conversion
    • Usually by CYP450 enzymes

Notable chemical carcinogens ⇒ tobacco smoke, aflatoxins, arsenic

89
Q

Tobacco Smoke

A
  • Contains > 7,000 chemicals
    • 250 known to be harmful
      • Cyanide, CO, ammonia
    • > 70 can cause cancer
  • Smoking is a leading cause of cancer and associated death
    • Lung, esophagus, larynx, mouth, throat, kidney, bladder, liver, pancreas, stomach, cervix, colon, rectum
  • Smoking 1 PPD ⇒ 150 extra mutations in each lung cell for each year smoked
90
Q

Aflatoxins

A
  • Exposure associated with ↑ risk of liver cancer
  • Family of toxins produced by certain fungi that grow on food products
    • Corn, peanuts, cottonseed, tree nuts
  • Crops can be contaminated
  • FDA w/ guidelines for safe levels
    • Routinely test levels in “higher risk” products
      • Peanuts and peanut butter
  • Estimated that 4.5 billion people worldwide chronically exposed through diet
91
Q

Arsenic

A
  • Found in water, soil, and air
  • Human exposure most common via cigarette smoke & contaminated food/water
  • Routinely tested for in public water supplies
    • Groundwater in West, Midwest, Texas, and Northeast exceed safe limits
92
Q

Biological Carcinogens

A

Pathogens that increase the likelihood of cancer.

Produces products that ∆ cell cycle and/or promote chronic inflammation.

93
Q

Human Papillomaviruses

(HPV)

A
  • High risk strains ⇒ HPV-16 and HPV-18
  • Make proteins that bind pRb, p53, and CKIs (p21, p27)
  • Linked to CA of cervix, penis, anus, vulva, and vagina
94
Q

Epstein-Barr Virus

A
  • Virus causes mononucleosis
  • Have proteins that function as oncogenes
    • Drive production of host genes including cyclin D
  • Encodes proteins that inhibit apoptosis
  • Linked to Burkett’s lymphoma & other CA’s
95
Q

Hepatitis B & C Viruses

A
  • Persistent infection w/ HBV or HCV associated with ↑ risk of liver CA
  • Might express proteins w/ direct role in carcinogenesis
  • Both induce long-term infections ⇒ chronic inflammation
    • ∆ cell death and proliferation
  • Genetic damage accumulates due to immune-mediated hepatic inflammation & oxidative stress
96
Q

Helicobacter pylori

A
  • Chronic infection linked to peptic ulcers
  • Induces chronic inflammation
  • Some genes thought to play a role in carcinogenesis
97
Q

Patient Characteristics

∆ carcinogenesis

A
  • Age
    • Most important risk factor
    • Accumulation of somatic mutations
    • ↓ immune function
  • Lifestyle choices
    • Dietary habits, tobacco/alcohol use, degree of physical activity, sexual and reproductive hx
    • ⅓ of all cancer deaths due to 5 leading behavioral and dietary risks
      • High BMI, low fruit and vegetable intake, lack of physical activity, tobacco use, alcohol use
  • Microbiota
    • ∆ homeostasis and immnunostasis
    • Upregulation of microbial components (dysbiosis) ⇒ impairment of gut barrier function ⇒ ↑ inflammation
    • Some bacteria can secrete substances that lead to DNA damage
      • Hydrogen sulfide, genotoxins, ROS
    • Can induce inflammatory responses ⇒ excessive ROS and NO production by immune cells
  • Infectious or inflammatory conditions
  • Immunodeficiencies
  • Certain medications
98
Q

Cellular Energetic

Changes

A

Rapidly dividing cells rely on glycolysis for energetic needs and anabolic products.

(Even when O2 plentiful)

99
Q

Cancer Cells

Metabolic Requirements

A

Derived from products of glycolysis:

  • NADPH
    • Electron donor in anabolic pathways
  • Ribose-5-phosphate
    • For nucleotide synthesis
    • Derived from PPP
  • DHAP
    • Lipid synthesis for new membranes
  • 3-phosphoglycerate
    • Precursor for synthesis of serine & glycine
    • Serine needed for entry of THF into carbon pool
  • THF & glycine
    • Required for purine synthesis
100
Q

mTOR

(Mechanistic target of Rapamycin)

A

Major nutrient sensor of the cell.

  • Stimulated by nutrient rich environments
  • Coordinates signals for anabolic cell growth and proliferation
  • Upregulates transcription factors
    • c-Myc
    • HIF-1α (hypoxia-inducible factor 1 alpha)
  • ∆ transcriptome of the cell
  • Leads to reprogramming of glycolysis
    • ↑ flux by 200x
101
Q

Reprogramming of Glycolysis

A

Relys on glycolysis for ATP and anabolic products.

Triggered by mTOR ⇒ c-Myc and HIF-1α:

  • ↑ glucose uptake and trapping
    • ⊕ GLUT-3
      • Highest affinity / Lowest Km for glucose
    • ⊕ Hexokinase (HK-2)
      • Highest affinity / Lowest Km for glucose
      • Embryonic isoform
  • ∆ flux through glycolysis
    • ⊕ Pyruvate kinase (PKM2)
      • Embryonic isoform
      • Rate of catalysis controls flux
      • Dynamically regulated between fast tetrameric form and slow dimeric form
    • ⊕ Pyruvate dehydrogenase kinase
      • Inhibits PDH complex
      • Diverts pyruvate away from TCA
      • Converted to lactate for ATP
102
Q

PKM2

A

Embryonic pyruvate kinase (PKM2) induced by mTOR.

  • Fast tetrametric form
    • Favored in the presence of:
      • Fructose-1,6-bisphosphate
      • Serine
      • Intermediates from purine synthetic pathway
    • Substrates indicates that anabolic substrates are plentiful
    • Glycolysis runs at full speed
  • Slow dimeric form
    • Favored in the absence of anabolic intermediates
    • Glycolysis backs up
    • Pushes glucose-6-P into other pathways:
      • PPP
        • Generate NADPH and ribose-5-P
      • Lipid synthesis
      • Amino acid synthesis
103
Q

Acetyl CoA

Regulation

A
  • ⊕ Pyruvate dehydrogenase kinase ⇒ ⊗ PDH complex
    • ↓ Acetyl CoA ⇒ TCA cycle
  • ⊕ acetyl-CoA synthetase-2
    • Catalyzes acetate → acetyl CoA
    • Compensates for ↓ [Acetyl CoA] from PDH complex
  • Acetyl Co-A needed for:
    • Lipid synthesis
    • As a substrate for TCA cycle
      • Used to generate anabolic substraits
      • Needed to sustain growth of the cell
104
Q

Glutamine

A

Cancer cells are addicted to glutamine.

  • Directly used in purine and pyrimidine synthesis
  • cMyc upregulates glutaminolysis proteins
    • Glutamine transporter
    • Glutaminase
  • Glutaminolysis provides:
    • Glutamate
    • Aspartate
    • CO2
    • Pyruvate
    • Lactate
    • Alanine
    • Citrate
  • Serves as anaplerotic substrates for TCA
  • Provide carbon skeletons for biosynthesis
105
Q

Immune Surveillance

A
  • Immune system patrols for invading pathogens & cells that turn cancerous
  • Abnormal cells detected and removed by healthy immmune system
  • Tumors can stimulate a protective specific, adpative immune response through tumor specific CD8+ T-cells
  • Malignant cells find ways to escape immune surveillance
106
Q

Immune Escape

Causes

A
  1. Weak immunogenicity of the tumor due to its host origins
  2. Rapid growth of the tumor overwhelms the immune system
  3. Selective pressures on tumor cells promotes the development of mechanisms for evading host immune responses
107
Q

Tumor-Specific Antigens

(TSAs)

A

Antigens that are uniquely expressed by tumor cells but not by normal cells.

Sometimes referred to as neoantigens.

Hypothetically, any of these Ag could be recognized by the immune system.

108
Q

Tumor-Associated Antigens

(TAAs)

A

Normal cellular antigens expressed at higher levels by tumors as compared to normal cells or at different stages of development or differentiation.

CA-125 ⇒ ovarian cancer

PSA ⇒ prostate cancer

109
Q

Biomarker

A

Protein or other component in the body that can be used as a measurable indicator to identify a disease state or assess the severity of the disease.

110
Q

Cancer Biomarker

A

A biological factor which can be quantitatively measured to yield cancer-related patient information including:

Cancer predisposition

Early detection

Monitoring cancerous growth

Selection of treatment

Overall prognosis

TAAs and TSAs can be used.

111
Q

CTLs

A
  • Recognize tumor antigens presented by class I MHC
  • If tumor isn’t cleared, cells may upregulate CTLA-4 ⇒ downgregulation of CTL response
112
Q

TH1 Cells

A
  • Specific for the tumor antigens
  • Important in initiation of CTL function
  • Generates IFN-γ and TNF-α ⇒ classically activated macrophages
113
Q

Classically Activated

Macrophages

A
  • Stimulated by IFN-γ
  • Kill tumor cells via ADCC
  • Recognize phospholipids ectopically expressed by malignant cells
  • Release lysosomal components and cytokines
    • Can lead to thrombosis in tumor blood vessels
    • Results in inhibition of tumor growth
114
Q

B-Cells

A
  • Formation of tumor specific antibodies
    • ⊕ ADCC by NK cells and macrophages
    • ⊕ complement-mediated tissue damage and inflammation
  • Passive Ab administration
    • Therapeutic effect shown
    • Was linked in some cases to tumor progression
115
Q

NK Cells

A
  • Down-regulation of MHC I by 50% of tumors
  • Loss of MHC I ligand for inhibitory receptor of NK cells ⇒ tumor killing and cytokine production
  • Can kill tumor cells by ADCC
  • Killing enhanced by IFN-γ, IL-12, and IL-15
116
Q

TH2 Cells

&

Alternatively Activated Macrophages

A
  • TH2 Cells
    • Produce IL-10 and IL-4
    • Leads to alternatively activated macrophages
  • TH2 Cells & M2 macrophages ⇒ microenvironment high in TGF-β and vascular endothelial growth factor (VEGF)
  • Downregulates the immune response
  • Promote tumor angiogenesis
  • Effects could contribute to tumor progression
117
Q

Tumor Microenvironment

A

The unique cellular composition surrounding the tumor.

Pro-tumor

  • TH2 cells and alternatively activated macrophages
  • Generates an immunosuppresive environment
  • Stimulation of Treg cells
  • Generation of a low level of chronic inflammation

Anti-tumor

  • TH1 cells and classically activated macrophages
  • CTLs
  • B-cells
  • NK cells
118
Q

Tumor

Decreased Immunogenicity Mechanisms

A
  • Derived from host cells
    • Do not express PAMPs
    • ↓ anti-tumor innate immune response
    • ↓ adaptive immune response
  • High mitotic index & genome instability ⇒ high rates of heritable somatic changes
    • Mutations that ↓ tumor immunogenicity have a selective advantage
  • Antigenic modulation
  • Low levels of MHC Class I expression
  • ↓ expression of adhesion molecules
  • Proteolytic shedding of MIC
    • MIC molecules ⇒ stress-induced “alterer” molecules
      • Binds NK cell activating receptor (NKG2D)
      • NK cells fail to get stimulatory signal
      • Lack of MHC class I will no longer trigger killing
  • Blocking antibodies
    • Anti-tumor Ab bound to tumor antigens
      • ⊗ CTL function
      • ⊗ ADCC by NK cells
119
Q

Tumor

Treated as Self

A

Tolerogenic state can be induced by:

  • Failure to induce a robust “danger signal”
    • “Danger signal” ⇒ ↑ B7 and MHC class I & II expression
      • Allows effective stimulation and activation of naive T-cells
      • T-cell activation in the absence of a “danger signal” is likely to result in tumor specific T-reg cells
      • If naive T-cells encounter tumor Ag without co-stimulation ⇒ anergy (peripheral tolerance)
  • Poor innate immune response
  • Prolonged antigenic exposure
    • If tumor cells are not promptly eliminated ⇒ downregulation of tumor specific T-cells by AICD and CTLA-4
120
Q

Activation Induced Cell Death

(AICD)

A

Programmed cell death caused by the interaction of Fas:FasL

  • Negative regulator of activated T lymphocytes
    • Results from repeated stimulation of TCR
  • Helps to maintain peripheral immune tolerance
  • Both activated T cells and B cells express Fas and undergo clonal deletion by the AICD mechanism
  • Activated T cells that express both Fas and FasL may be killed by themselves or by each other
121
Q

Tumor-Induced

Immune Suppression

A

Tumors can express or secrete factors that alter the immune response.

  • Inhibitory cytokines
    • TGF-β and/or IL-10 produced by many tumors
    • Combo ⊗ immune response
    • ↑ alternatively activated macrophage function
    • ↑ angiogenesis
  • FasL expressed by some tumors
    • Binds to Fas on leukocytes recruited to the tumor
    • Causes death of the attacking cells
  • Programmed Cell Death-ligand-1 (PD-L1) expressed by tumor cells
    • Binds to the PD-1 on activated T cells, B cells, and myeloid cells
    • Binds to B7 on APCs
    • Both PD-L1:PD-1 and PD-L1:B7 delivers an inhibitory signal to the immune cell
    • Fosters the development of Treg cells
    • Blocking this interaction is a major pharmaceutical target
122
Q

Immunoprivileged Sites

A
  • Classic anatomical sites protected from immune surveillance
    • CNS
    • Anterior chamber of the eye
    • Testis
    • Placenta and fetus
  • Usually maintained behind a barrier
  • Barrier either:
    • Inhibits the movement of immune cells
    • Express cell surface glycocalyx molecules that hide/cover tumor antigens
  • Acquired immunoprivileged sites
    • Healthy tissues may act as de facto privileged sites because they lack pro-inflammatory or ‘danger’ signals
123
Q

Passive Immunotherapy

A

Uses monoclonal antibodies (mAb) to tumor surface antigens.

  • Naked mAb
    • Rituximab (Rituxan) ⇒ mouse/human chimeric mAb
      • Binds CD20 on B-cell non-Hodgkin’s lymphoma
    • Herceptin ⇒ humanized mAb
      • Binds HER2/neu
    • Ipilimumab (Yervoy) ⇒ fully human mAb
      • Binds to CTLA-4
  • Conjugated mAb
    • Targets a drug, toxin, or radioactive substance directly to the cancer cells
    • Allows [drug] to be high @ site of malignancy while sparing the rest of the body
    • mAbs that target tumors can be labeled with radionuclides that emit gamma rays or nanodots to detect tumors and metastatic disease
124
Q

Administration of Cytokines

A
  • Remove tumor cells
  • Transfect cells with one or more cytokines
    • IFN-α, IFN-γ, TNF-α, IL-2, IL-12, GM-CSF
  • Return modified cells to the patient
  • Hopes of stimulating a targeted immune response against the tumor
125
Q

Therapeutic Vaccination

A
  • Vaccines given to patients who already have cancer in the hopes of using Ag from the tumor to mobilize the immune response against the malignant cells
  • Technique involves:
    • Removal of dendritic cells from the patient
    • Pulsing the cells with tumor lysates or peptides
    • Reinfusing cells back into the patient
126
Q

Preventative Vaccines

A
  • Vaccines that protect from known oncogenic viruses
  • ↓ incidence of cancers
  • ↓ morbidity and mortality
  • Ex. HPV and Hep B vaccines
127
Q

CTLA-4

Pathway

A

Cytotoxic T lymphocyte antigen-4 (CTLA-4) / B7 Pathway

  • During normal T-cell activation, TCR recognizes Ab bound to MHC class II on APC
    • Pathway requires a second signal often provided by CD28:B7
    • Results in activation and clonal proliferation of the T-cell
  • After several days of proliferation, CTLA-4 is up-regulated on the surface of T-cells
    • CTLA-4 has a higher affinity for B7 than CD28
    • Interaction of CTLA-4 and B7 inhibits the activation response
    • CTLA-4 blocks T cells from attacking tumor cells
  • Ipilimumab ⇒ mAb that targets CTLA-4
    • Disrupts its interaction with B7
    • Allows T-cells to attack tumor cells
128
Q

PD1 Pathway

(Programmed Cell Death-1)

A
  • Normally
    • PD-1 functions as an immune checkpoint
    • Prevents activation of T-cells
    • Reduces autoimmunity and promotes self-tolerance
    • PD-1 expressed on activated T cells, B cells, NK cells, and Mφ
    • Interacts with either PD-L1 or PD-L2
    • Tightly controlled through the microenvironment and cytokines
  • Some cancers overexpress PD-L1
    • Could prompt CTL exhaustion
    • Down regulation of the immune response
    • Induction of Treg cells
    • Overexpression of PD-1 on tumor-infiltrating lymphocytes correlates with poor outcomes
  • New drugs target PD-1
    • Can activate the immune system to attack tumor cells
    • Ex. Opdivo
129
Q

Treg Inhibition

A
  • Treatment options:
    • Selective Treg inhibitors
    • TGF-inhibiting mAb
  • Drugs are being explored to see if they can selectively deplete Treg cells without impacting other T-cell subclasses
  • Allows a more anti-tumor response
130
Q

Adoptive Cellular Therapy

A
  • Tansfusion of T-cells into a patient
  • Has been tested for treatment of cancer and chronic infections
  • Currently in various stages of clinical trials
131
Q

Graft-vs-tumor / Leukemia

Adoptive Cellular Therapy

A

Treatment for certain relapsed or refractory leukemias:

  • Infusion of alloreactive T cells following complete or partial hematopoietic stem cell transplant
  • Non-host T-cells attack non-donor targets including host tissue
    • Often causes graft-vs-host reactions
  • Goal for alloreactive donor T-cells to respond against residual tumor cells
  • Contributes to eradication of the tumor or graft-vs-tumor response
132
Q

Chimeric Antigen Receptors

(CARs)

A
  • Engineered receptors
    • Single polypeptide ligand binding domain grafted onto a T-cell signaling domain
  • Chimeric molecule:
    • Antibody-derived recognition moiety
    • CD3-Zeta (activation domain)
    • Costimulatory domain
  • CARs then integrated into a retroviral vector
  • Patient T-cells are harvested and transformed ex vivo
  • T-cells transferred back into the patient
  • CAR T therapy currently used to treat acute lymphoblastic leukemia (ALL) by targeting CD19
    • Marker of both normal and neoplastic B cells
133
Q

Cancer Preventative

Immune Functions

A
  1. Suppresion of viral infections
    • Infection can induce certain kinds of tumors
  2. Timely elimination of pathogens to reduce extent and duration of inflammation
    • Chronic inflammation can promote tumorigenesis
  3. Immunosurveillence
    • Identifies and destroys transformed cells before they can establish malignancy
134
Q

Immune Evasion

Summary

A
  • Selective pressures and genome instability promote decreased immunogenicity
    • Antigenic modulation
    • Low levels of MHC class I expression
    • Decreased expression of adhesion molecules
    • Proteolytic shedding of MIC
    • Blocking antibodies
  • Tumors can arise in healthy tissues without a “danger signal” ⇒ antigens often viewed as self
  • Tumors induce immune suppression
  • Tumors can arise in immunoprivileged sites or sites with decreased immunosurveillance such as adipose tissue and the CNS
135
Q

Benign Tumor

Characteristics

A
  • Localized overgrowth of tissue
  • No infiltration or metastasis
  • Neoplastic cells closely resemble orgin tissue ⇒ well-differentiated
136
Q

Benign Tumor

Architecture

A

Tissue architecture resembles adjacent normal tissue.

Parenchyma or stromal cells are usually not prominent.

137
Q

Benign Tumor

Nomenclature

A

Suffix “oma” preceded by tissue of origin

  • Mesenchymal origin ⇒ CT and derivatives
    • Fibroma ⇒ composed of fibroblasts and collagen matrix
    • Lipoma ⇒ composed of adipocytes and little stroma
      • Usually surrounded by a fibrous capsule
    • Chondroma ⇒ composed of chondrocytes
      • Also refers to benign tumor of the bone
  • Epithelial origin
    • Papilloma ⇒ contain finger-like projections of epithelial structures
    • Adenoma ⇒ forms glands
    • Cystadenoma ⇒ forms cyts in a glandular background
  • Muscle origin
    • Leiomyoma ⇒ made of smooth muscle
138
Q

Hamartoma

A

Benign tumor composed of disorganized tissue.

  • Formed by cells that belong in that tissue but are not arranged properly
  • Ex. Hamartoma in the lung
    • Composed of cartilage, respiratory epithelium, smooth muscle, and mucus glands
    • Mishapen lump of tissue
139
Q

Choristoma

A

“Heterotropic rest”

  • Nest of normal cells from a different tissue
  • Ex. pancreatic tissue in stomach
140
Q

Teratoma

A

Benign tumor made of cells that come from different germ cell layers.

141
Q

Tumor

Growth Rate

A

Dependent on many factors:

  • Rate of cell division vs rate of cell death
  • Growth rate generally inversely related to degree of cellular differentiation
    • Highly differentiated cells ⇒ slower growth rate
    • Undifferentiated cells ⇒ faster growth rate
      • Often comprised of small dark staining cells with little cytoplasm
        • High nuclear:cytoplasm ratio
142
Q

Malignant Tumor

Characteristics

A
  • Malignant cells infiltrate into surrounding tissue
  • Locally invasive
  • Capacity to metastasize
  • Shows genetic instability
  • Neoplastic cells appear different from tissue of origin
  • Normal cellular arragement may be disrupted
    • Nuclei tend not to be at basal side of epithelium
143
Q

Malignant Tumor

Architecture

A
  • Tissue architecture varies
    • Well or moderately differentiated ⇒ retains qualities of origin tissue
    • Poorly differentiated ⇒ has lost qualities of origin tissues
  • Stroma generally reactive
    • Local fibroblasts respond to tumor ⇒ desmoplastic response
      • ↑ collagen deposition
    • Fibroblasts can produce growth factors
      • Sustains growth/survival of malignant cells
    • Can be scirrhous
      • Firm, irregular texture
      • Gritty
144
Q

Malignant Epithelial Tumor

Nomenclature

A

Suffix “carcinoma” preceded by tissue of origin.

  • Tends to sprad to regional lymph nodes first
  • Can metastasize from there via bloodstream to distant sites
145
Q

Malignant Mesenchymal Tumor

Nomenclature

A

Suffix “scarcoma” preceded by tissue of origin.

  • Usually do not spread to lymph nodes
  • Goes right to hematogenous route
    • Look for metastasis in lungs
146
Q

Malignant Tumors

With Special Nomenclature

A

Do not follow the rules ⇒ end in “oma”

  • Glioblastoma
  • Neuroblastoma
  • Medulloblastoma
  • Multiple myeloma
  • Plasmacytoma
  • Lymphoma
  • Melanoma
  • Mesothelioma
147
Q

Malignant Cells

Features

A

Loss of normal function ⇒ loss of associated morphology

Common features of malignant cells:

  • Pleomorphism ⇒ ↑ variation in shape within population
  • Anisocytosis ⇒ ↑ variation in size within population
  • ↓ cell-cell adhesion
  • Loss of polarity
    • Sheets or masses of cells grow in a disorganized fashion
  • Mitoses
    • Can be atypical
    • Contain abnormal mitotic figures
      • Tripolar, quadripolar, or multipolar spindles
148
Q

Tumor Grading

A

Based on the degree of differentiation of the cells within a tumor.

  • Well-differentiated ⇒ low grade
    • Ex. squamous cell carcinoma that makes keratin
      • Retains its “squamous-ness”
  • Poorly-differentiated ⇒ high grade
    • Ex. Squamous cell carcinoma that does not make keratin
    • Often correlates with more aggressive tumor behavior
  • Completely undifferentiated ⇒ anaplastic
    • Sign of a highly malignant tumor
149
Q

TNM System

A

Based on the extent of invasion/metastasis.

TNM system:

  • T ⇒ Tumor characteristics
    • Size
    • Depth of invation into normal tissue
  • N ⇒ Number of lymph nodes involved
  • M ⇒ Metastasis
    • Presence of metastasis ⇒ M1
    • Absence of metastasis ⇒ M0

Any tumor that demonstrates distant metastasis is considered Stage IV cancer regardless of T and N values.

150
Q

Tumor Staging

A

Based on the clinical severity of the disease.

  • Extent of tumor
  • Spread
151
Q

Benign vs Malignant

Tumors

A
  • Benign tumor
    • Well-circumscribed, smooth interface between tumor and surrounding breast tissue
    • Glands distinguishable ⇒ adenoma
    • Embedded in stroma of fibroblasts and collagen ⇒ fibroma
    • Tumor known as a fibroadenoma
  • Malignant tumor
    • Poorly circumscribed
    • Has irregular extensions into surrounding breast tissue
    • Cells resemble glands but lack organization of normal mammary tissue
    • Tumor called an invasive adenocarcinoma
152
Q

Pre-neoplastic Lesions

A

Distinct changes that occur in tissues prior to the appearance of a malignant tumor.

153
Q

Epithelial Layer

Malignant Progression

A

Progression within an epithelial layer towards malignancy:

  • Metaplasia
    • A change in the epithelial layer to another epithelial cell type
  • Dysplasia
    • Disorganization within the epithelial layer
  • Carcinoma in situ
    • Clearly malignant cells are present in the epithelial layer
    • No malignant cells observed below the basement membrane
  • Invasive carcinoma
    • Cells invade the submucosa and spread into into the surrounding tissue
    • If left unchecked, malignant cells will invade further into the lymphatics and circulatory system
    • Forms metastatic lesions of tumor in distant tissues
154
Q

Dysplasia

A

Areas of abnormal tissue organization and higher frequencies of mitotic figures within a normal epithelial layer.

  • Ex. adenomatous polyp of the colon
    • Cells lose normal appearance
      • Dysplastic nucleus elongated and no longer sits on basement membrane
        • Appears stratified
      • Mucus vacuole may not be seen
155
Q

Local Invasion

A
  • Malignant cells invade local tissue
  • If epithelial cells, must acquire ability to migrate through the basement membrane
    • Requires production of new proteins
      • Proteases to degrade tissue matrix
      • Survival factors to allow survival outside of origin tissue
156
Q

Distant Metastasis

A

3 main routes for spread beyond local barriers:

  1. Direct seeding of body cavities
    • Tumor cells must have access to the area
    • Ex. ovarian carcinoma often seed the peritoneum once they have spread beyond the ovary
  2. Lymphatic spread
    • Most common path for carcinomas
    • Follows normal lymphatic drainage for origin tissue
    • Lymphadenopathy may be due to metastasis or a reactive immune reaction in response to tumor growth
  3. Hematogenous spread
    • Most common route for sarcomas
    • Venous more common than arterial spread

Within the blood or lymph, tumor cells must be able to survive without integrin attachment.

157
Q

Tumor

Host Effects

A
  • Local impingement of tissues/structures
    • Ex. glioblastomas in the brain
  • Pain
  • Compression
  • Bone fractures
  • Tumor cachexia
    • Caused by cytokines ⇒ TNF-α, IL-1, IFN-𝛾
  • Hormone effects
    • Produce effects not directly due to the physical tumor
    • Ex. hyponatremia 2/2 lung cancer secreting substance similar to ADH
    • Called a paraneoplastic syndrome
158
Q

Paraneoplastic Syndromes

A

Secretion of hormones by tumors.

159
Q

Tumor Detection

A

There is a minimum number of cells required for a tumor to be detected.

  • Ex. 1-gram tumor contains 1x109 cells
    • Assume clonality ⇒ arose from a single cell
    • Takes 30 generations to reach 1x109 cells
    • Could reach 1 kg size in 10 more doublings
160
Q

Tumor Markers

A
  • Important tool for tumor evaluation and diagnosis
  • Ideally:
    • Tumor marker detectable even when tumor is very small
      • Action can be take before tumor becomes clinically significant
      • Hopefully before it is capable of metastasis
161
Q

Prostate Specific Antigen

(PSA)

A
  • Protease secreted by the prostate
    • Cleaves binding protein for insulin-like growth factor
  • ↑ [PSA] with prostate cancer or hyperplasia
  • Biomarker for prostate cancer ⇒ a tumor associated antigen (TAA)
    • Useful to monitor cancer recurrence s/p prostatectomy
    • Lack of specificity ⇒ limited clinical impact
      • Could lead to un-needed interventions or anxiety
162
Q

Tumor Immunohistochemistry

A

Tumor markers used to help ID origin of malignant cells.

  • Ex. Patient w/ hx of prostate CA has new liver masses
    • Multiple masses more suggestive of metastasis
    • Mass removed via biopsy & sent to pathologist for evaluation
    • Stain tissue sections with Ab for various tumor Ag
      • PSA ⇒ prostate CA
      • CA19-9 ⇒ pancreatic CA
      • CEA ⇒ colon CA
    • If Ab to PSA stains tumor cells ⇒ dx with metastatic prostatic adenocarcinoma in the liver

Foundations of Disease (46 decks)

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