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Foundations Week 8 > Neoplasia II > Flashcards

Neoplasia II Flashcards

0
Q

What are targets of carcinogenic agents?

A

Growth promoting proto-oncogenes

Growth inhibiting tumor suppressor genes (anti-oncogenes)

Genes that regulate programmed cell death (apoptosis)

Genes involved in DNA repair

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1
Q

What is carcinogenesis?

A

normal cells are transformed into cancer cell

Requires mutation that is nonlethal - acquired (chemicals, viruses) or inherited (retinoblastoma)
Clonal expansion of single cell with genetic damage –> neoplasm

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2
Q

What are mutated proto-oncogenes?

Oncoproteins are constitutively ____

A

oncogenes

active - NOT dependent on growth signals/response to inhibitory signals

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3
Q

What are the functions in cell growth & proliferation of growth-promoting proto-oncogenes?

A 
GF - PDGF - glioblastoma
GF receptors - ERBB2 - breast
Signal transduction - RAS - pancreas
Nuclear transcription - Myc - lymphoma
Cyclins & CDKs - cyclin D1 - lymphoma
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4
Q

What is the process of normal cell division vs. cancer in growth-promoting proto-oncogenes?

A

Normal cell division - proto-oncogenes –stimulate–> cell growth & proliferation

Cancer - proto-oncogenes –activation–> oncogenes (mutation) –> increased rate of cell growth & proliferation –> malignant transformation

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5
Q

What are growth-inhibiting tumor suppressor genes (anti-oncogenes)?

A

part of network of regulatory factors that recognize genetic damage & shut down cell proliferation

mutation –> loss of function

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6
Q

What are examples of anti-oncogenes?

A

RB & p53

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7
Q

What is the process of normal cell division vs. cancer in growth-inhibiting tumor suppressor genes?

A

normal cell division - proto-oncogenes –stimulate–> cell growth & proliferation

cancer - proto-oncogenes –> cell growth & proliferation (due to loss of mutation of tumor suppressor genes) –> malignant transformation

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8
Q

What is the mechanism in which genes involved in DNA repair & apoptosis cause cancer?

A

normal cell –> DNA damage (due to DNA damaging agents - chemicals, radiation, viruses with UNSUCCESSFUL DNA repair) –> failure of DNA repair (genes affecting DNA repair or genes affecting cell growth/apoptosis–> mutations in genome of somatic cells –> activation of growth-promoting oncogenes OR inactivation of tumor suppressor genes OR alteration of genes that regulate apoptosis

Can get unregulated cell proliferation OR decreased apoptosis –> clonal expansion

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9
Q

What are the 7 fundamental changes that occur during development of neoplasm?

A 
self-sufficiency in growth signals
insensitivity to growth-inhibitory signals
evasion of apoptosis
limitless replication
defects in DNA repair
angiogenesis
invasion & metastasis
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10
Q

What are the 3 classes of carcinogenic agents?

A

chemicals, radiant energy & oncogenic microorganisms (viruses/bacteria)

Several agents may act together to produce multiple genetic abnormalities necessary to transform cells

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11
Q

What are the most important human carcinogens worldwide?

A

tobacco, asbestos, aflatoxin, UV light & HBV

80% of human cancers are preventable

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12
Q

What are the steps involved in chemical carcinogenesis?

A
  1. Tumor initiation - carcinogenic agent (initiator) causes mutation - irreversible. Not sufficient for tumor formation (need promoter)
  2. Tumor promotion - promoters cause cell proliferation. Endogenous (hormones)/exogenous. Induce tumors in initiated cells
  3. Progression - growth becomes autonomous when sufficient mutations have immortalized the cells
  4. Malignancy - end result; cells may acquire ability to invade & metastasize
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13
Q

What are chemical carcinogenesis initiators? What is the primary target? What are the 2 categories of initiators - give example?

A

include natural & synthetic substances
DNA is the primary target

Direct acting - don’t require metabolic activation; ex - alkylating chemotherapy agents

Indirect acting (procarcinogens) - require metabolism to be active (cyt P450); ex - substances in tobacco

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14
Q

How do alkylating agents work?

A

alkylate DNA –> alters DNA base pairing
used to TREAT certain cancers - breast cancer
known to CAUSE second cancers

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15
Q

What are specific examples of alkylating agents?

A

Cyclophosphamide - risk of bladder cancer & leukemia

Chloroambucil - risk of leukemia

Melphalan - risk of leukemia

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16
Q

What cancers are linked to tobacco? What is the most common cause of cancer death worldwide? Mainstream smoke contain ___ chemicals

A

lung (bronchial) larynx, kidney, bladder, oral cavity, esophagus, pancreas, leukemia

lung cancer

~4000; polycyclic aromatic hydrocarbons play major role in lung cancer

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17
Q

What is aflatoxin B1? What does it affect? What type of cancer does it cause?

A

toxin from fungus (aspergillus flavus) that contaminates grains & nuts; rarre in well-developed countries - seen in parts of Asia & Africa

Causes mutation in p53 - mechanism is intercalating agent

Most potent liver cancer causing chemical known

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18
Q

What type of point mutation is associated with Aflatoxin B1 exposure?

A

frameshift - presence of intercalating agent causes addition of single base during DNA replication/repair –> frameshift error

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19
Q

What is radiation carcinogenesis?

A

Radiation - energy that is transmitted in form of waves/particles

Any source of radiation has capacity to transform virtually all cell types into cancerous cells

Hallmark is a long latent period

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20
Q

What are the 2 main types of radiation?

A

UV & ionizing

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21
Q

What is UV radiation? How does it cause DNA damage? What type of malignancies are affected by UV?

A

UVB causes DNA damage by forming pyrimidine dimers

Implicated in skin malignancies - melanoma, squamous cell carcinoma & basal cell carcinoma

22
Q

Pyrimadine dimers can be repaired but excessive sun exposure overwhelms repair systems. What is a disease that affects DNA repair & is affected by UV exposure.

A

Xeroderma pigmentosum - DNA repair defects - have greatly increased risk of skin cancer

23
Q

What are exposures of ionizing radiation carcinogenesis?

A

Radon, X-rays, nuclear medicine, consumer products, etc.

24
Q

What is the risk of cancer with radiation therapy/exposure dependent on?

A

Type & dose, size of treatment field, sensitivity of tissue, age of patient.

25
Q

When is risk higher with ionizing radiation?

A

risk higher in children
bone marrow - most sensitive - risk for leukemia
skin, bone & GI - less sensitive
breast cancer XRT - risk for lung cancer & esophageal cancer

26
Q

What carcinogenesis are related to microorganissm?

A

~20% of cancers associated with infections

Hep viruses (HBV, HCV)
HPV
Helicobacter pylori

27
Q

HPV is the major cause of ___. What is it’s role in other cancers?

A

cervical squamous cell carcinoma
~85% of cervical SCC

role in other cancers - anus, vulva, vagina, base of tongue, tonsils & soft palate

28
Q

How does HPV cause cancer?

A

Produces viral proteins E6 (affects p53) & E7 (affects Rb) that promote cell proliferation via inhibition of tumor suppressors p53 & Rb

29
Q

Look at slide 29

A

do it!

30
Q

How is Hepatitis viruses related to cancer?

A

Implicated in 70-85% of hepatocellular carcinoma worldwide

Hep C virus & cancer pathogenesis

  • role of viral oncoproteins is unclear
  • recurring cycles of necrosis & regeneration –> accelerated cell turnover rate –> increased probability of mutations & less time for DNA repair
31
Q

How does helicobacter pylori related to cancer?

A

major cause of gastritis & ulcers

Chronic infection associated with gastric carcinoma, pancreatic carcinoma, gastric lymphoma of mucosa-associated lymphoid tissue (MALToma)

  • up to 80% of MALToma patients achieve remission after treatment with H. pylori eradicating antibiotics
    • this is contrary to idea of neoplasm as independent of initial trigger

Exception to autonomous -take away initiator –> can go away

32
Q

What is the local effect?

A

impingement on adjacent structures with obstruction

ex - superior vena cava syndrome (SVC) - neoplasm compresses SVC, thrombus in LSV; causes dilated veins & plethora of trunk & neck; 27 days after treatment - less dilated veins & capillaries

33
Q

Administration of what would dissolve the thrombus?

A

Tissue plasminogen activator - binds to plasminogen –> plasmin –> degrade fibrin

IF give:
FVIII concentrate - more clots
Antithrombin - help clot localize

34
Q

What are examples of local effects - impingement on adjacent structures?

A

meninngioma - benign tumor of meninges - small space (skull) pushes on brain & skull
‘

35
Q

What is an example of local effect - impaired organ function?

A

bone marrow replaced by leukemic blasts –> anemia, leukopenia & thrombocytopenia

36
Q

How does neoplasm cause hormonal effects?

A

Neoplasms arising in endocrine glands may be functional (secrete hormones) - thyroid, pituitary, ovary; secrete hormone normally produced in that organ; more typical of benign - well differentiated

Tumors arising in non-endocrine tissues (lung) may elaborate hormones = ectopic hormone production

  • paraneoplastic syndromes - ex -lung carcinoma produces a parathyroid hormone
37
Q

What is a paraneoplastic syndromes?

A

symptoms that can’t be readily explained by

local/distant spread of tumor OR elaboration of hormones native to tissue of origin

38
Q

Most common paraneoplastic syndrome is due to ____ of __ by tumor

A

ectopic production of hormone by the tumor.

Paraneoplastic syndromes - 10-15% of cancer patients; may be the earliest manifestation of an otherwise clinically silent neoplasm

39
Q

What are types of paraneoplastic syndromes NOT related to hormone production?

A

nerve & muscle syndromes - immune-mediated
dermatologic disorders - immune-mediated; GF
bone & soft tissue changes - mechanism unknown
vascular & hematologic changes

40
Q

What is a common symptom of widespread malignancy?

A

Cachexia - wasting syndrome - loss of body fat & lean body mass; profound weakness; anorexia & anemia

41
Q

What is the cause of cachexia?

A

tumor products, cytokines from inflammatory cells
- tumor necrosis factor (TNF), interleukin, interferon
altered sense of taste & smell
impaired absorption
catabolism of muscle & protein
depression

also seen in advanced AIDS & chronic infection

42
Q

What is tumor grading?

A

histologic criteria - degree of differentiation, pleomorphism, # of mitoses & necrosis?

compile criteria & apply numerical grade

43
Q

What are different grades?

A

Grade 1 - well differentiated - resemble normal tissue in architecture & cellular features

Grade 2 - moderately differentiated

Grade 3 - poorly-differentiated - minimal resemblance to normal, disorganized, high N:C ratio, many mitoses, often necrotic

Grading schemes & criteria vary with each type of neoplasm - breast, brain, kidney, prostate…

44
Q

What is tumor staging?

A

size of primary tumor OR depth of invasion (ex - colon cancer & melanoma)

Extent of spread beyond primary tumor - lymph nodes & other sites

TNM
Tumor (size, depth)
Nodes
Metastases

45
Q

____(grade/stage) determines prognosis

A

STAGE!!

46
Q

What are used in grading a neoplasm?

A

degree of pleomorphism, degree of differentiation, number of mitoses & presence of necrosis

Spread of lymph nodes –> stage!

47
Q

Carcinoma in situ is stage __

A

0

48
Q

What are sampling methods for neoplasm?

A

needle aspiration, Pap smear, endoscopic biopsy, core biopsy, excise skin lesion, open, excisional biopsy

49
Q

How does the pathologist evaluate neoplasm?

A

diagnosis - neoplasm (benign/malignant), infection, inflammation

If neoplasm, subtype, tissue of origin
- If not clear, need ancillary techniques - immuno-histochemistry, flow cytometry, molecular studies

Prognostic features - grade, stage & margins

50
Q

What do molecular studies evaluate?

A

evaluate for translocation & other genetic changes (deletions, inversions, etc) associated with malignancy

Increasing # of molecular studies are used for diagnosis, prognosis, & tx

51
Q

What is an example where molecular/genetic testing is used?

A

chronic myelogenous leukemia - tx with Gleevec block ATP binding site on bcr-abl fusion protein –> inhibits growth of cancer cells

t(9;22) –> bcr-abll fusion gene, for diagnosis, prognosis & tx

52
Q

What are the uses of tumor markers? What is used to measure it?

A

tumor screening
support of tumor diagnosis
prognostic indicators
monitoring for relapse disease status

measured in bloody, other body fluid or tissue

Foundations Week 8 (8 decks)

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