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
What is the risk of cancer with radiation therapy/exposure dependent on?
Type & dose, size of treatment field, sensitivity of tissue, age of patient.
25
When is risk higher with ionizing radiation?
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
What carcinogenesis are related to microorganissm?
~20% of cancers associated with infections Hep viruses (HBV, HCV) HPV Helicobacter pylori
27
HPV is the major cause of ___. What is it's role in other cancers?
cervical squamous cell carcinoma ~85% of cervical SCC role in other cancers - anus, vulva, vagina, base of tongue, tonsils & soft palate
28
How does HPV cause cancer?
Produces viral proteins E6 (affects p53) & E7 (affects Rb) that promote cell proliferation via inhibition of tumor suppressors p53 & Rb
29
Look at slide 29
do it!
30
How is Hepatitis viruses related to cancer?
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
How does helicobacter pylori related to cancer?
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
What is the local effect?
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
Administration of what would dissolve the thrombus?
Tissue plasminogen activator - binds to plasminogen --> plasmin --> degrade fibrin IF give: FVIII concentrate - more clots Antithrombin - help clot localize
34
What are examples of local effects - impingement on adjacent structures?
meninngioma - benign tumor of meninges - small space (skull) pushes on brain & skull '
35
What is an example of local effect - impaired organ function?
bone marrow replaced by leukemic blasts --> anemia, leukopenia & thrombocytopenia
36
How does neoplasm cause hormonal effects?
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
What is a paraneoplastic syndromes?
symptoms that can't be readily explained by local/distant spread of tumor OR elaboration of hormones native to tissue of origin
38
Most common paraneoplastic syndrome is due to ____ of __ by tumor
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
What are types of paraneoplastic syndromes NOT related to hormone production?
nerve & muscle syndromes - immune-mediated dermatologic disorders - immune-mediated; GF bone & soft tissue changes - mechanism unknown vascular & hematologic changes
40
What is a common symptom of widespread malignancy?
Cachexia - wasting syndrome - loss of body fat & lean body mass; profound weakness; anorexia & anemia
41
What is the cause of cachexia?
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
What is tumor grading?
histologic criteria - degree of differentiation, pleomorphism, # of mitoses & necrosis? compile criteria & apply numerical grade
43
What are different grades?
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
What is tumor staging?
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
____(grade/stage) determines prognosis
STAGE!!
46
What are used in grading a neoplasm?
degree of pleomorphism, degree of differentiation, number of mitoses & presence of necrosis Spread of lymph nodes --> stage!
47
Carcinoma in situ is stage __
0
48
What are sampling methods for neoplasm?
needle aspiration, Pap smear, endoscopic biopsy, core biopsy, excise skin lesion, open, excisional biopsy
49
How does the pathologist evaluate neoplasm?
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
What do molecular studies evaluate?
evaluate for translocation & other genetic changes (deletions, inversions, etc) associated with malignancy Increasing # of molecular studies are used for diagnosis, prognosis, & tx
51
What is an example where molecular/genetic testing is used?
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
What are the uses of tumor markers? What is used to measure it?
tumor screening support of tumor diagnosis prognostic indicators monitoring for relapse disease status measured in bloody, other body fluid or tissue