Neoplasia Part 3 Flashcards
what is a major etiology of cancers?
Carcinogens
Cancer results from accumulation of ______ including genes that regulate apoptosis and senescence
multiple mutations
what are 3 types of Carcinogenic Agents?
-Chemicals
-Radiant energy
-Microbial agents
T/F the different types of Carcinogenic Agents may act together or alone to elicit genetic alterations leading to neoplasia
true
what are the 3 groups of carcinogenic chemicals?
-direct acting
-indirect acting
-natural products
what occurs with direct acting carcinogenic chemicals?
No metabolic conversion to be
carcinogenic
what is an example of direct acting carcinogenic chemicals?
Chemotherapeutic drugs (alkylating agents- cyclophosphamide)
what occurs with indirect acting carcinogenic chemicals?
Require metabolic conversion to ultimate carcinogen by cytochrome p-450 enzymes (which are unique among individuals)
what are two examples of indirect acting carcinogenic chemicals?
-Polycyclic hydrocarbons: benzo[a]pyrene in smoked tobacco, smoked fish/meat
-Aromatic amines and azo dyes: β naphthylamine –> bladder cancer in aniline dye and rubber industry
what are some Natural Products that act as carcinogenic chemicals? (2)
-Aflatoxin B1: produced by Aspergillus on improperly stored grains/nuts→ hepatocellular CA
-Nitrites: preservatives-form nitrosamines
what is the Mechanism of Action for carcinogenic chemicals?
Chemical carcinogens are mutagenic (initiators):
- Contain highly reactive electrophile groups, which form adducts (covalently bound) with
nucleophiles (principally DNA)
- In subsequent transcription or DNA replication, if the adduct is not repaired, it predisposes to mutations, strand breaks etc.
what genes are common targets for the adduct formation that occurs with carcinogenic chemicals? (2)
-Oncogenes (RAS)
-tumor suppressor genes (p53)
T/F DNA adduct formation alone is sufficient for the carcinogenesis process to proceed.
FALSE (it is not, just an initiating event)
how do Promoters correlated with tumors?
-Do not cause mutations (not initiators), so alone are not tumorigenic
-INSTEAD: Induce cell proliferation of mutated cells → new mutations that can lead to cancer formation
what are examples of chemicals that are Promoters of cancer formation (not initiators)? (2)
-phorbol esters: used in cancer research
-estrogen: promoter in patients with breast and endometrial cancer
how does radiation cause cancer? (2)
-Causes double-stranded DNA breaks, translocations, point
mutations
-UV radiation forms pyrimidine dimers (thymine-thymine) which
normally are fixed by nucleotide excision repair pathways
what is the only RNA/retrovirus that can cause cancer in humans?
Human T-cell leukemia virus-1 (HTLV-1)
what are 4 DNA viruses that can cause cancer in humans?
-Human papilloma virus (HPV)
-Epstein-Barr virus (EBV)
-Kaposi sarcoma herpesvirus (HHV-8)
-Hepatitis B virus (HBV)
where is HTLV-1 endemic?
Japan and Caribbean
how does HTLV-1 cause cancer?
CD4+ T cell tropism
How is HTLV-1 transmitted?
through intercourse, blood and breast milk
what cancer is associated with HTLV-1?
leukemia (3-5% after long latency)
what protein in HTLV-1 drives cancer formation?
Tax protein
there are >150 types of HPV. how are the different types categorized?
-low-risk (e.g. 6,11)
-high risk (e.g. 16,18,31,33)
what can low-risk HPV (e.g. 6,11) cause?
-squamous papillomas
-genital warts, condyloma acuminatum
what can high risk HPV (e.g. 16,18,31,33) cause?
-cervical/anogenital cancer
-associated with ~70% of oropharyngeal cancers*
what are the 2 different proteins of HPV oncogenesis?
-Early viral protein E7
-Early viral protein E6
how does Early viral protein E7 work in HPV oncogenesis? (3)
-Binds RB protein and displaces E2F, promoting progression
-Inactivates CDKIs
-Activates cyclins
how does Early viral protein E6 work in HPV oncogenesis? (2)
-Binds and mediates degradation of p53 and BAX (pro-apoptotic factor)
-Activates telomerase
summarize what happens during HPV oncogenesis?
E6 and E7 activate growth, stimulate loss of growth inhibition, inhibit apoptosis, and combat senescence
what cancers is EBV implicated in? (4)
-Burkitt lymphoma (African type)
-B-cell lymphoma in
immunosuppressed pts
Hepatitis B and C and associated with 75-80% of what cancers?
hepatocellular carcinomas
describe how the HBV Pathogenesis that can lead to cancer (2)
-Chronic inflammation with hepatocyte death
→ regeneration and genomic damage
-Activated immune cells make ROS (mutagenic) → NF-κB pathway activation which blocks apoptosis and allows accumulation of mutations (no viral oncoproteins)
what is the Cause of peptic ulcers?
Helicobacter pylori
what was the First bacterium classified as a carcinogen?
Helicobacter pylori
what cancers is Helicobacter pylori implicated in? (2)
gastric adenocarcinomas and
gastric MALT lymphoma
what are some of the negative effects tumors that have on hosts? (4)
-prognosis depends on location (e.g. pituitary, bile duct)
-Hormone production: seen in endocrine gland tumors (pancreas, adrenal cortex)
-Bleeding and infection
-intestinal complications (intussusception or obstruction)
what is intussusception of the intestines?
“telescoping” of the intestines on itself = folds in on itself
what are Paraneoplastic Syndromes?
-Symptoms not related to tumor spread or hormone production
-group of conditions that happen next to/in parallel with a tumor that have physiological effects
T/F Paraneoplastic Syndromes are seen in 10-15% of cancer patients
true
Paraneoplastic Syndromes may indicate underlying ____
neoplasm
T/F Paraneoplastic Syndromes can be lethal
True
Paraneoplastic Syndromes can mimic ____
metastatic disease
T/F Paraneoplastic Syndromes are diverse and associated with many tumors
true
what are some examples of common Paraneoplastic Syndromes?
-Cachexia
-Hypercalcemia
-Cushing syndrome
-Hypercoagulability
the Progressive loss of body fat and lean body mass with weakness, anorexia and anemia
Cachexia
why does cancer cause Cachexia?
high metabolic rates caused by tumor and host cytokines (e.g. TNF- decreases appetite), not by tumor’s nutritional demand
why does cancer cause Hypercalcemia?
due to release of PTHrP,
TGF-α (activates osteoclasts and active Vit. D)
why does cancer cause Cushing syndrome?
ectopic ACTH production (small cell lung cancers)
why does cancer cause Hypercoagulability?
can cause venous thrombosis and nonbacterial thrombotic endocarditis
what is cancer grading?
-Estimates aggressiveness based on cytologic differentiation
-Grade I, II. III. IV (in order of increasing anaplasia)
what is cancer staging?
a greater clinical value based on how far the cancer has spread:
-Size of primary tumor and extent of regional and distant (metastasis) spread
what are the 2 systems that are used for cancer grading?
-TNM system: T= tumor size (1-4), N= regional nodal involvement (0-3); M= metastasis (0,1) (e.g. T4N3M1)
-AJC system: 0 to IV scale (overall stage)
Laboratory Diagnosis of Cancer requires what for greatest accuracy?
detailed clinical findings and the Specimen should be adequate,
representative and properly preserved
what are some sampling approaches when diagnosing tumors?
-Cytologic Smear (cells on a slide)
-biopsy/excision
-Flow Cytometry
-Liquid biopsy
-molecular diahgnosis
what are 2 types of Cytologic Smears (cells on a slide) and what are they used for?
-Direct scraping: superficial fungal and herpes infections, PAP smear
-Fine-needle aspiration (FNA): for readily palpable lesions (breast,
thyroid, lymph nodes and salivary glands)
what are the 2 types of biopsies? what are they used for?
-direct: accessible lesions
-core: internal organs
_____ ensures accurate sampling for
internal lesions: mammography-guided, CT- guided, ultrasound-guided when doing a biopsy or incision
Radiologic assistance
what type of biopsy is used for breast cancer?
Stereotactic Biopsy
(mammographically guided)
what should be used in conjunction with Fine-needle aspiration (FNA)?
CT or ultrasound guided
what are the difference between looking at a smear sample with a frozen smear vs a permanent H&E section?
-frozen sample: helpful for immediate results but not for specific types of cancers (cannot identify specific cell types)
-permanent H&E section: takes longer but is more specific and can be used to ID type of cells
what is Immunohistochemistry (IHC) useful for? (2)
-determining the cellular differentiation of poorly differentiated tumor cells (e.g. epithelial, mesenchymal)
-diagnosis of lymphomas to determine lineage (B or T cell), differentiation of stage and in treatment of B-cell lymphomas (CD20 inhibitors- rituximab)
what is Flow Cytometry? what is it useful for?
sampling approach using a laser that will laser and sort 1 cells at a time to separate different cell populations based on markers (i.e. what each lymphocyte is expressing)
-helps classify leukemias and lymphomas
what are some important tumor markers? (3)
-PSA
-carcinoembryonic antigen (CEA)
-α-fetoprotein
what are cons to the tumor marker, PSA?
low sensitivity and low specificity
what is the tumor marker, carcinoembryonic antigen (CEA), used to help diagnose? (4)
cancers of colon, pancreas, stomach and breast
what is the tumor marker, α-fetoprotein, used to help diagnose? (2)
-hepatocellular carcinomas
-yolk sac remnants
PSA, CEA and α-fetoprotein are not good for ______ but great for detecting _______
early detection; recurrences
what is a Liquid Biopsy?
uses body fluids (blood/saliva) that contain circulating tumor cells or their products (DNA/RNA fragments) to screen, detect, and monitor cancer
what are 2 types of Molecular Diagnoses for cancer?
-PCR
-FISH/PCR
what is PCR used for in the Molecular Diagnoses of cancer?
detect monoclonality in lymphoid malignancies (i.e. is it a tumor or not bc tumors are not polyclonal)
what is FISH/PCR used for in the Molecular Diagnoses of cancer?
to detect:
-translocations (Ewing sarcoma, lymphoma)
-gene amplification (HER-2/neu, N-MYC)
other than diagnosis, molecular techniques can be used in what other ways in regards to cancer? (4)
-prognostic and therapeutic monitoring
-residual disease (BCR-ABL transcripts)
-hereditary predisposition (BRCA1)
-Targeted therapy: tumors from different sites with similar mutations can be given similar drugs
Rapid sequencing of the entire genome
genomics
what can genomics help to identify?
driver and passenger mutations that helps target treatment
Epigenetic modifications genome-wide
epigenomics
Microarray quantifies all RNAs expressed
transcriptomics
Measure all proteins simultaneously
proteomics
Test all of the cell’s metabolites
metabolomics
in terms of using genomics, which is easier to work with and why? DNA or RNA?
DNA bc RNA is more fragile and more likely to degrade
what are the current trends in terms of genomic therapy? (3)
-to develop methods sequencing several hundred key genes to detect mutations in as few as 5% of tumor cells
-Use DNA arrays to identify changes in DNA copy number (amplifications, deletions)
-In the future, may use epigenomics to predict
drug efficacy
in the Future of Cancer Diagnostics, there is a Paradigm shift to what?
classify based on mutation (with plan for targeted treatment) rather than on morphology or cell of origin
(bc many cancers can share the same mutation even though they present very differently they can be treated the same)
in the Future of Cancer Diagnostics, , optimal diagnosis and management combines what techniques?
histopathology with relevant molecular diagnostic techniques (IHC, FISH, PCR, flow cytometry, all of the -omics etc.)
