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Pathobiology > Block 2 > Flashcards

Block 2 Flashcards

Cancer

1
Q

What is cancer?

A

uncontrolled, clonal (arising from a single transformed progenitor cell) proliferation of cells uncoordinated with normal tissue proliferations that continues in the absence of stimuli

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2
Q

Benign vs. malignant tumors?

A

non-cancerous, slow growing, distinct borders (capsulated)
don’t invade surrounding tissue or spread
cells are normal
can still cause health issues

cancerous, grow quickly, irregular borders (non-capsulated)
invade surrounding tissue and spread
cells have large, dark nuclei, can have abnormal shape
often cause death

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3
Q

How can benign tumors cause health issues?

A
  1. compression of surrounding tissues and organs
    ex) pituitary adenoma pressing on optic nerve
  2. obstruction of passages (blood vessels, airways, digestive tracts)
  3. hormonal effects: tumors in endocrine glands can disrupt hormone levels
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4
Q

Tumor grade vs. stage?

A

appearance of cancer cells: nuclear atypia (high N:C ratio), cellular pleomorphism (variation in size and shape), polarity: poorly organized, loss of tissue architecture, tend to grow/spread faster (more mitosis), necrosis
poorly differentiated = higher grade = more abnormal looking

extent of tumor spread from the primary site
high stage = spread to distant parts of the body
TNM staging: tumor size (T1-T4), lymph node number/localization (N1-N3), metastasis (M0-M1)

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5
Q

How are cancers named?

A

tissue of origin and if they are malignant or benign

malignant: -carcinoma, -sarcoma
benign: -oma

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6
Q

How does cancer lead to death?

A
  1. local growth: space filling lesions that can impinge crucial structures and obstruct normal flow (nerves, blood vessels, GI) ; bleeding, infection
  2. metastasis: replacing normal, functioning tissue; most common = lungs, liver, bones (no immune cells), brain (LOF)
  3. secretion factors: secrete biological molecules that lead to physiologic dysfunction: pro-clotting factors (cut off blood supply), tumor necrosis factor (cachexia: muscle wasting, fat loss)
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7
Q

What are the three conditions associated with secretion of factors?

A

Trousseau’s Syndrome: secretion of tissue factor that lead to coagulation

Paraneoplastic Syndrome: secretion of hormones not normally made by those cells that leads to hypercalcemia, hypoglycemia

Cancer Cachexia: pro-inflammatory molecules (TNF) and catabolic factors produced by tumor suppresses appeptite; loss of skeletal muscle and adipose tissue from proteolysis, lipolysis, and futile cycling

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8
Q

What are the agents of mutation that initiate cancer development?

A
  1. chemicals: carcinogens can initiate cancer (mutagens) or promote its growth (stimulators): cigarette smoke, alcohol
  2. UV radiation: also mutagenic (pyrimidine dimers)
  3. Microbial: viruses (HPV), bacteria (H Pylori), parasites can encode oncogenes or proteins that disable tumor suppressors, can cause chronic inflammation with injury repair, cause immunosuppression
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9
Q

What are the two types of carcinogens?

A

initiators (mutagens) and promoters (stimulator of growth): need both

inflammation: ROS are mutagenic, growth factors, pro-angiogenic factors

consequences of proliferation
- DNA replication errors
- Telomere shortening

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10
Q

What are the Hallmarks of Cancer?

A

KEEP dividing/proliferating + avoid being killed
1. sustained proliferative signaling
2. evading growth suppressors
3. avoiding immune destruction
4. enabling replicative immortality
5. tumor-promoting inflammation
6. activating invasion & metastasis
7. inducing or accessing vasculature
8. genome instability and mutation
9. resisting cell death
10. deregulating cellular metabolism

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11
Q

Sustaining proliferative signaling

A

mutations in growth factor signal transduction cascade (oncogenes)

  1. Growth Factors: increased expression that permits autocrine signaling
    - TGF-alpha, FGF
  2. Receptors: activation without growth factors
    - EGF-R in lung
  3. Signal transduction
    - RAS: always active + GTP-bound
  4. Transcription Factors: activates cell cycle genes
    - MYC: amplifications in breast, colon
    translocations in Burkitt Lymphoma
  5. Cell cycle increases
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12
Q

Evading growth suppressors

A

Together with sustained proliferative signaling (oncogene mutations), you
need co-occurring evasion of growth suppressors (tumor suppressor mutations) to drive tumor development

dysfunction of various genes that arrest the cell cycle: Rb (blocks DNA synthesis) + p53 (regulates cell cycle, DNA repair, apoptosis)

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13
Q

What drives cancer growth?

A

genetic mishaps: translocation, mutation, amplification, deletion

epigenetic changes: histone modification, DNA methylation

genetic mutations can cause epigenetic changes

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14
Q

Tumor suppressor genes vs. oncogenes?

A

inhibit cell proliferation and promote apoptosis (p53, BRCA1, BRCA2, Rb); both need to be mutated to lose function

mutations promote cell growth and proliferation (GOF); one mutation required; MYC, RAS, Abl

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15
Q

What is loss of heterozygosity?

A

one copy of the tumor suppressor gene is lost (inherited or spontaneous); loss of the other copy via mutation or deletion results in inactivation

most common is p53: impaired cell cycle regulation, DNA repair, apoptosis

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16
Q

Resisting Cell Death

A

genetic changes in the intrinsic apoptosis pathway are very common in cancer
1. anti-apoptotic oncogenes (amplification): BCL2, BCL-xL, MCL-1
2. pro-apoptotic (mutations/decrease expression) tumor suppressor: Bax, Bak

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17
Q

Activating Invasion/Metastasis

A

tumors are most lethal when they spread

steps
1. epithelial-mesenchymal transition (EMT)
2. invade (leave current tissue)
3. intravasate (get into bloodstream)
4. circulate (move to another place)
5. extravasate (out of bloodstream)
6. colonize (start growing in new tissue)

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18
Q

Why do micrometastases stay dormant?

A
  1. anti-growth signals in normal tissue
  2. incapable of activating angiogenesis
  3. tumor-suppressing action of immune system
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19
Q

What is the key process of invasion/metastasis?

A

EMT: epithelial to mesenchymal transition = lose organization, cell-to-cell adhesion, and attachment to basement membrane and gain migratory and invasive properties

Marker epithelial cells: E-cadherin
Marker mesenchymal cells: N-cadherin, vimentin

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20
Q

Enabling Replicative Immortality

A

increased telomerase expression in cancer cells keeps telomeres long so they can keep dividing and avoid senescence

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21
Q

Tumor-promoting inflammation

A

not oncogenic itself but allow mutations in other genes during normal cell division
cancer cell can benefit from inflammation
inflammatory cells release ROS cause mutation, and they can also supply growth factors and other tumor survival factors

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22
Q

Deregulating cellular energetics

A

Warburg effect – cancer cells shift from oxidative phosphorylation to aerobic
glycolysis/lactic acid fermentation to gain biomass: use these breakdown products to make
building blocks for the cell to keep growing (nucleotides, amino acids, lipids)

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23
Q

Inducing Angiogenesis

A

Tumors need access to nutrients to survive/spread – get this from making new
blood vessels (angiogenesis) via vascular endothelial growth factor (VEGF)

neovasculature is aberrant
- excessive vessel branching
- distorted/enlarged vessels
- erratic blood flow
- leakiness

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24
Q

Genome instability/mutation

A

not oncogenic itself but allow mutations in other genes during normal cell division
Cancer cells often have mutations in DNA repair genes – cells develop more mutations, genetic diversity often helps them keep growing

ex) mismatch repair: hereditary non-polyposis colon cancer (HNPCC)
nucleotide excision: XP
recombination repair: breast, ovarian

25
Q

Avoiding Immune Response

A

T cells recognize neoantigens, tumor associated antigens, and unconventional tumor antigens
cancer cell needs to fend off the immune system’s attempt to kill it, so they suppress immune cell activation by increasing expression of checkpoint proteins PD-1,PD-L1, CTLA-4

26
Q

New Hallmarks of cancer?

A
  1. Unlocking phenotypic plasticity
  2. Nonmutational epigenetic programming
  3. Polymorphic microbiomes
  4. Senescent cells
27
Q

Unlocking phenotypic plasticity

A

cancer cells are able to evade terminal differentiation and keep dividing by
1. staying in an immature cell type (blocked differentiation)
2. reverting from a mature to a more immature cell type (de-differentiation)
3. reverting to a different cell type altogether (trans-differentiation)

28
Q

Nonmutational epigenetic programming

A

enabling, not oncogenic
components of the tumor microenvironment (hypoxia, interactions with surrounding cells) can induce epigenetic changes that affect gene transcription (oncogenes)

29
Q

Polymorphic microbiomes

A

enabling, not oncogenic
microbes can either prevent or promote tumor development (damage DNA directly)
can directly interact with cancer cells to enable them to sustain proliferative signaling or evade growth suppressors

30
Q

Senescent cells

A

cells in proliferative arrest secrete pro-proliferative factors, avoid apoptosis, promote angiogenesis, Senescence Associated Secretory Profile (SASP) promote inflammation

31
Q

Difference between driver and passenger mutations?

A

driver: mutation that is critical to and responsible for the development of cancer (cells without it die)
passenger: mutation that has no effect on tumor growth/fitness

32
Q

How many drivers do tumors have?

A

5-6 +/- 2 mutations: oncogenes, tumor suppressors, telomerase

therefore develops in older individuals who accumulate more mutations

Exception = chromothripsis: chromosome shattering in a single event

33
Q

Which tissues have higher risk of acquiring driver mutations?

A

organs with higher tissue/stem cell replacement will have higher risk of cancer because more cell divisions means higher likelihood of acquiring mutations + tumors forming

34
Q

Why is understanding the genetic basis of cancer critical?

A

diagnosis and treatment
1. precision medicine: prescribing patients a specific treatment regimen based on genetic make up of their tumor (driver can be targeted with drug or certain chemos)
2. cells with the same driver mutations respond to the same therapies even in different tissues (Gleevec = BCR-ABL inhibitor treats both chronic myelogenous leukemia and GI stromal tumors with 9:22 translocation)

35
Q

Why is tumor heterogeneity important?

A

the fact that tumors have multiple/diverse drivers makes it much harder to treat
- hetero within a tumor, across patients
- even if you target one driver, tumor can compensate

36
Q

What is the difference between intertumoral and intratumoral heterogeneity?

A

inter: variability between tumors across patients from environmental factors, germline genetic variation, somatic mutations

intra: variability within the cells of a tumor; picking up passenger mutations during clonal proliferation

37
Q

How does intratumoral heterogeneity manifest itself?

A

spatial: genetically diverse tumor cell subpopulations can be distributed across multiple sites or even at a single anatomical location in the same patient

temporal: genetic diversity can change over time

38
Q

How does exposure to cancer therapies increase the genomic complexity of tumors?

A
  1. genetic changes may develop in response to therapy (de novo)
    ex) ROS1 drug resistance
  2. genetic changes may be present before therapy

mutations acquired can be on-target (new mutation in oncogene that renders drug ineffective) or off-target (diff. oncogene)

cases also exist where different mutations are seen in different sites of metastatic disease

39
Q

How can we profile tumor heterogeneity?

A

Fluorescence in situ hybridization (FISH): DNA probes to hybridize to specific DNA regions to asses gene amplifications

Immunohistochemistry (IHC): antibodies to detect protein expression

DNA sequencing
Sanger: single region, very slow, one strand at a time, need 20% VAF for detection
NGS: many genes of interest examined in parallel, high throughput, can detect low frequency genetic variants

40
Q

Why calculate the VAF?

A

useful to determine the predicted abundance of a mutation within the tumor: higher VAF = more cells with the mutation

41
Q

What is the VAF?

A

variant allelic fraction: fraction of total sequencing reads at a specific genomic position that contain the variant

non-tumor tissue:
no variant: 0%
heterozygous: 50%

tumor tissue:
no variant: 0%
heterozygous variant: 50%
loss of heterozygosity: 100%

42
Q

What factors influence the VAF?

A
  1. ratio of malignant to normal cells in the sample
  2. whether variant is present in all malignant cells or only a subclone
  3. whether the gene has an abnormal number of copies in the malignant cells
43
Q

How do you treat cancer?

A
  1. surgery: physical removal
  2. radiation: induce DNA damage in cancer cells
  3. cytotoxic chemotherapy: drugs that cause DNA damage or inhibit mitosis
  4. molecularly targeted therapy: drugs that target mutant proteins in cancer cells
  5. immunotherapy: drugs that allow immune system to remove cancer cells
44
Q

How does targeted therapy work?

A

easier to turn off an oncogene than turn on a tumor suppressor
most targeted therapies are kinase inhibitors: small molecule binds to ATP pocket
ex) Gleevac binds in BCR-ABL pocket

45
Q

How does tumors avoid immune surveillance?

A

T-cells engage with target cells by binding to an antigen on the target cell via its T-cell receptor; checkpoints to prevent hyperactivation of T-cells
cancer overexpresses these so T-cells can’t induce death

46
Q

Which immune checkpoints are expressed on T-cells and tumor cells?

A

T-cells: PD-1, CTLA-4
Tumor: PD-L1

47
Q

How does immunotherapy work?

A

checkpoint inhibitors enable T-cells to become activated when they encounter cancer cells
checkpoints inhibitors are more effective when the cancers have a high mutational burden = more neoantigens (foreign), more T-cell infiltration, more tumor clearance

48
Q

What are TILs?

A

tumor infiltrating lymphocytes: increase abundance of immune cells that can get into the tumor and clear cancer cells
1. isolate T-cells from tumor
2. multiply T-cells + insert

49
Q

What are CAR T-Cells?

A
  1. get T-cells from patient’s blood, engineer them to produce chimeric antigen receptors (CARs) direct against antigens that are expression on cancer cells

chimeric = receptors both bind antigen and induce signaling to activate T-cell

used for blood cancers (CD19, B-cell marker)

50
Q

What is personalized medicine?

A

sequencing patients’ tumors to inform prognosis/treatment
- identify both driver and passenger mutations
- predict disease prognosis, therapies
- helps determine if therapies are working

51
Q

What are the main ways targeted therapies can work?

A
  1. directly turning off mutated oncogene (EGFR inhibitors in lung cancer)
  2. mutations in the tumor confer sensitivity to a non-direct therapy (patients with high mutational burden are more sensitive to immunotherapy)
52
Q

Germline vs. somatic mutations

A

Germline: passed down from parents, present in every cell
- present in normal and tumor tissue

Somatic: only present in specific tissues
- more common in tumors

53
Q

What is circulating tumor DNA?

A

– tumor-derived DNA released from cancer cells
- Less invasive/easier to obtain than solid tumor biopsies
- If more than one tumor (metastases), get information about multiple sites at once
(but harder to tell where the DNA is coming from)
- Potential to detect a new site of metastasis before it shows up on imaging

54
Q

Sporadic vs. hereditary vs. familial cancers?

A

cancer that occurs due to spontaneous mutations that accumulate over a person’s lifetime; typically diagnosed at an older age

caused by a single genetic change in the germline; pattern of specific, recurring cancer types across multiple generations; diagnosed at younger age

cancer that appears to occur more frequently in families than expected compared to rates in the general population (clustering); shared genetics/enivronment; no pattern of genetic transmission

55
Q

What are features suggestive of hereditary cancer?

A
  1. multiple primary tumors in the same organ (same breast)
  2. multiple primary tumors in different organs (breast + ovarian)
  3. bilateral primary tumors in paired organs (separate cancers in both breasts)
  4. multifocality within a single organ (multiple genetically-related tumors in the same breast)
  5. younger age at cancer diagnosis than others in the general population
  6. family history
56
Q

Which inheritance pattern is most common in hereditary cancer predisposition syndrome?

A

autosomal dominant: normally one hit in the tumor suppressor genes

incomplete penetrance is common (genotype doesn’t express phenotype) because other factors

variable expressivity: extent a genotype is expressed at the phenotypic level = type of cancer, age of onset in families because of other factors

57
Q

What are BRCA1 and BRCA2? What is their role in Hereditary Breast and Ovarian Cancer Syndrome?

A

tumor suppressor proteins in the homologous recombination (HR) DNA repair pathway
inactivation leads to defective repair of DSB

associated with breast, ovarian, prostate, and pancreatic cancer

58
Q

What is PARP?

A

enzyme in BER pathway that repairs single-stranded breaks

tumors with BRCA1/2 are sensitive to inhibitors because they cause apoptosis

59
Q

What is Lynch Syndrome?

A

caused by germline mutations in MLH1, MSH2, MSH6, PMS2 = genes involved in mismatch repair

associated with colorectal, uterine, stomach cancer

sensitive to immunotherapy (microsatellite instability-high): higher mutational burden, more neoantigens on tumor cells, more immune cell infiltration

Pathobiology (3 decks)

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