T28 - Carcinogenesis II Flashcards
What are the three categories of physical agents that play a role in carcinogenesis?
chemical carcinogens
radiant energy
microbial agents
What is immune surveillance?
immune system’s surveilling the body for premalignant and malignant cells
What are the two subdivisions of chemical carcinogens?
direct-acting agents
indirect-acting agents
Describe the difference between direct-acting and indirect-acting agents in chemical carcinogens.
direct-acting agents require no prior metabolic conversion = weak carcinogens
indirect-acting agents erquire metabolic conversion (e.g. hydrocarbons in fossil fuels or benzo-a-pyrene in cigarette smoke)
What is the relationship between indirect chemical agents and cancer susceptibility?
because indirect agents require metabolic activation, enzymatic pathways involved in activation can impact cancer susceptibility (e.g. everyone inherits different cytP450 enzymes, so different susceptibilities to cancer)
What is aflatoxin B1?
DNA mutagen produced by strains of Aspergillus flavus in improperly stored grains and nuts (i.e. peanuts)
Aflatoxin B1 causes
hepatocellular carcinoma
How is carcinogenicity commonly tested?
expose a rodent to the carcinogen and then monitor for tumor onset and growth
What is the mechanism of action for chemical carcinogens?
contain highly-reactive electrophiles that bind to DNA and cause mutations
What are the two types of radiation carcinogens?
ionizing radiation
UV rays
Ionizing radiation has what effect on DNA?
causes chromosomal breakage and aberrations
Give a historical example of ionizing radiation that led to increased cancer prevalence.
Chernobyl nuclear disaster led to higher rates of thyroid cancer
How do UV rays affect DNA?
induce formation of pyrimidine dimers
Give an example of a tumor that results from UV ray damage of DNA.
melanomas (skin cancers in general)
What is the only retrovirus that has been definitively shown to be directly carcinogenic?
HTLV-1
HTLV-1 is endemic to (2)
the Caribbean
Japan
HTLV-1 causes
T-cell leukemia, because it has a tropism for CD4+ T cells
Explain on a cellular level how HTLV-1 causes T-cell leukemia. (4)
HTLV-1 genome encodes TAX viral protein → TAX activates cytokine genes and associated receptors in T cells → autocrine and paracrine loops cause T cells to proliferate → polyclonol process
Give an example of an oncogenic RNA virus.
HTLV-1
Give four examples of oncogenic DNA viruses.
Epstein-Barr virus
human papilloma virus (HPV)
hepatitis B virus (HBV)
hepatitis C virus (HCV)
Epstein-Barr virus has been implicated in the pathogenesis of what human tumors? (4)
Burkitt lymphoma
B-cell lymphomas in AIDS patients
Hodgkin lymphoma
nasopharyngeal carcinoma
Explain, on a cellular leve, how the Epstein-Barr virus contributes to tumor pathogenesis. (2)
EBV gene products stimulate B-cell proliferation
EBV binds to and infects B cells through CD21, a type 2 complement receptor
What is a gross consequence of HPV?
benign squamous papillomas (warts)
What are the low risk subtypes of HPV? (2)
HPV-6
HPV-11
What are the high risk HPV subtypes? (2)
HPV-16
HPV-18
The oncogenic potential of HPV originates from what genes?
viral genes E6 and E7
Describe the roles of viral genes E6 and E7 in HPV oncogenesis.
E6 binds to and mediates degradation of p53
E7 binds to and mediates degradation of RB
What are the properties of hepatitis B virus (HBV)? (3)
does not directly make the cancer-causing genes (unlike HTLV)
associated with liver cancer due to inflammation
continued proliferation caused by HBV causes DNA damage and gene mutations that are oncogenic
What is the transcription factor associated with HBV?
HBV encodes transcription factor HBx, which can activate TGFb1 and IGF1 growth factors and inhibit p53
(T/F) HCV is a DNA virus.
False. Hepatitis C virus is not a DNA virus (it’s an RNA virus), but like HBV is strongly linked to liver cancer.
What are heliobacter pylori and where are they found?
gram-negative bacteria that reside between mucus layer of stomach and gastric epithelium
Why is heliobacter pylori unique in the context of carcinogenesis?
first bacterial organism to be classified as a carcinogen
H. pylori is responsible for causing what two tumors?
gastric adenocarcinoma
gastric lymphoma
What are the clinical symptoms of gastric adenocarcinoma caused by H. pylori?
chronic inflammation of gastric epithelium (i.e. chronic gastritis)
H. pylori-related lymphomas have what cellular origin?
B-cell origin
The B-cells implicated in H. pylori-induced gastric lymphoma reside where?
reside in marginal zones of gastric lymphoid follicles → hence the name MALT lymphomas
How does the H. pylori-induced infection of B cells lead to neoplastic transformation?
chronic inflammation and stimulation of marginal zone B cells leads to DNA damage and neoplastic transformation
How is MALT lymphoma treated?
assuming early detection, can be treated with antibiotics to cure H. pylori infection
Differentiate between tumor specific and tumor associated antigens.
tumor specific antigens are only found on tumor cells
tumor associated antigens are found on tumor cells and on some normal cells
What are oncofetal antigens?
antigens expressed during embryogenesis but disappear and are not normally expressed in adult tissues
Give two examples of oncofetal antigens.
carcinoembryonic antigen (CEA)
alpha-fetoprotein (AFP)
What is carcinoembryonic antigen?
luminal glycoprotein involved in cell adhesion
Carcinoembryonic antigen is associated with what malignancies? (2)
inflammatory and cancerous lesions of both the colon and pancreas
What is the clinical utility of the carcinoembryonic antigen?
because of its lack of specificity for cancer, it’s most useful for monitoring recurrence of carcinomas after surgery
What is alpha-fetoprotein?
glycoprotein globulin secreted by fetal liver and yolk sac
Alpha-fetoprotein is associated with what malignancies?
alpha-fetoprotein is expressed by:
hepatocellular carcinomas
testicular cancers/teratomas (i.e. germ cell tumors)
yolk sac tumors (i.e. endodermal sinus tumors)
Give two examples of glycoproteins (apart from oncofetal antigens) that can serve as tumor antigens.
gangliosides
mucins
Describe how gangliosides can serve as tumor antigens.
normal in composition, but overexpressed in melanomas and colon cancers
Describe how mucins can serve as tumor antigens.
under-glycosylated
As tumor antigens, mucin are associated with what malignancies? (4)
carcinomas:
breast
pancreatic
ovarian
colon
Differentiate between mucin CA-125 and mucin CA-19-9.
CA-125: blood marker expressed in ovarian cancers, but NOT specific
CA-19-9: blood marker sensitive but NOT specific to pancreatic cancer
How does Gleevec/Imatinib cure/treat CML?
it poisons the BCR-ABL fusion protein
Give three examples of oncogenes that, when mutated, produce peptides only found in tumor cells.
p53
RAS
CDK4
Give two examples of non-mutated proteins that can be overexpressed, conferring tumor immunity.
HER2/NEU (in breast cancer)
tyrosinase (in melanomas)
What is Herceptin?
anti-HER2/NEU antibody
What is the predominant anti-tumor mechanism?
cell-mediated immunity
What are the four classes of anti-tumor immune effector mechanisms?
cytotoxic T cells
natural killer (NK) cells
macrophages
humoral mechanisms
What is the role of cytotoxic T cells in antitumor effector mechanisms? (2)
protects against virus-associated neoplasms
requires prior exposure (i.e. immunization)
What is the role of natural killer cells in antitumor effector mechanisms? (3)
kill without prior sensitization (in contrast to cytotoxic T cells)
activated by IL-2
active against tumor cells with low MHC Class I expression
What is the role of macrophages in antitumor effector mechanisms? (2)
produce reactive oxygen species or TNF to kill tumor cells
What is the role of humoral mechanisms (antibodies) in antitumor therapy?
monoclonal antibodies against tumor markers used in therapy (i.e. anti-CD20)
Carcinogenesis obviously occurs in patients without immune deficiencies. What are three mechanisms by which tumors evade the host immune system?
selective outgrowth of antigens (disguise)
lost/reduced expression of histocompatibility molecules (hide)
spontaneous/pathogen/drug-induced immunosuppression of host (suppress)
What are the local effects of tumors on hosts? (3)
destruction of normal tissues
ulceration through natural boundaries, causing hemorrhage or infection
tumor rupture or infarction
Describe the hormonal effect of tumors on hosts. Give an example.
over-production of hormones native to tumor origin
for example:
insulinoma of pancreas
What is cancer cachexia?
progressive loss of fat + muscle leading to wasting, weakness, and anemia
What causes cancer cachexia?
caused by excess of cytokines, not just tumor metabolism
Define paraneoplastic syndrome.
symptoms not accounted for by local or distant spread of tumor
Give three examples of paraneoplastic syndromes.
endocrinopathies (lung tumor making ACTH)
neuromyopathies (lung tumor causing myasthenia gravis)
vascular/hematologic derangements (pancreatic carcinoma causing deep vein thrombosis)
What are four tools used in the diagnosis of cancer?
pathology
tumor markers
molecular cancer diagnostics
molecular profiling
What are the four substeps within pathology as a tool for the diagnosis of cancer?
histology
cytology
immunochemistry
flow cytometry
What is histology, in the context of diagnosing cancer?
microscopic examination of formalin-fixed tissue using H&E staining
What is cytology, in the context of diagnosing cancer?
microscopic examination of individual cells smeared on slide
What are the two types of cytologic specimens?
exfoliative = removal of cells from tissue/organ
fine needle aspiration = use a needle + syringe to suck out cells
What are two disadvantages of cytology?
limited specimen sample
no info about tissue architecture
What is the utility of tumor markers in diagnosing cancer?
can be used to screen for malignancies or monitor for cancer relapse
In what context is “minimal residual disease” detected?
PCR is used to detect presence of BCR-ABL transcripts in blood to monitor Philadelphia chromosome-positive CML
Describe how molecular profiling of tumor works. (4)
mRNA extracted from 2 tissue sources (normal + tumor) → complementary DNA samples made → cDNA hybridized to cDNA probes in a matrix → laser detects fluorescence from each spot, allowing comparison of genome between normal + tumor
Give three examples of techniques (and an associated malignancy) used in molecular cancer diagnostics.
flow cytometry = hematopoietic malignancies
FISH = CML
PCR = CML
How does Epstein-Barr virus cause Burkett lymphoma? (4)
EBV stimulates B-cell proliferation → secondary mutations accumulate → t(8;14) chromosomal translocation → constitutive expression of Myc gene fused to immunoglobulin heavy chain gene
(T/F) In HPV, E6 and E7 are sufficient to induce transformation.
False. RAS and other genes would be required to induce transformation — E6 or E7 on their own are not sufficient.
What is hepatitis C virus’ mode of action? (2)
induction of cirrhosis and parenchymal regeneration
