7. Cancer IV Flashcards
(39 cards)
• Tumor starts as one clone, or a group of cells that have a specific mutation that allows the cell to transform to a malignant phenotype
○ Cancer is ____
• What causes transformation?
○ ____ mutation that occurs in division in absence of external stimulus
○ Causative agents
§ Chemical, radiation, viral, and microbial types
monoclonal
spontaneous
Carcinogenic Agents
- ____ Carcinogens
- Radiation
- ____ and Microbial
- May act alone or in concert
chemical
viral
Chemical Carcinogens
Direct-Acting
Do not require ____
Used as ____
Indirect-Acting
Metabolized by ____ dependent monooxygenase
____ vary among individuals – personalized medicine target
• Direct-acting ○ Alkylating agents - used to treat cancer because it causes \_\_\_\_ damage and causes cell to die ○ Used to treat cancer because they divide faster, so they're more sensitive to damage via AA ○ They're carcinogenic, but not strongly carcinogenic; the risk must be taken in order to remove the current cancer ○ \_\_\_\_, chlornambucil, \_\_\_\_ are examples of anticancer drugs • Indirect-acting ○ Once \_\_\_\_ it becomes carcinogenic ○ Enzymes can differ in \_\_\_\_ form one person to another - variability - due to certain AA having slight differences, no change in structure only in activity § If one person has slightly higher activity, will convert the chemical faster/higher amount > higher chance to develop \_\_\_\_ § Personalized medicine - your risk is higher if exposed to this potential carcinogen
metabolism
chemotherapeutics
p450
alleles
irreversible
cyclophosphamide
nitrosurea
metabolized
activity
cancer
Indirect-acting Carcinogens
Polycyclic hydrocarbons
____
Cigarette smoke
____ in meat
Aromatic Amines
____ dye industry
– ____ – bladder cancer
• Polycyclic hydrocarbons ○ Benzopyrenes come from fossil fuels and cigarette smoke • Aromatic amines ○ Dyes that have been used in last 200 years to produce the color blue, yellow § Workers that were exposed - higher rates of cancers • These both require \_\_\_\_ activation
fossil fuels
broiled fat
analine
b-naphtylamine
metabolism
Natural Indirect Carcinogens and others
____ – produced by Aspergillis strains found on poorly stored nuts
* Consumption of these nuts has led to increase incidence \_\_\_\_ cancer * \_\_\_\_ plants can be a source of carcinogens * Betel nuts - chewed that can lead to oral cancer * Pesticides/home compounds can also lead to cancer
aflatoxin B1
hepatocellular
natural
Mechanisms of Chemical Carcinogens
Initiators: DNA \_\_\_\_ agents Some target specific gene more often \_\_\_\_ TP53 – “\_\_\_\_”
Promoters Induce cell \_\_\_\_ Non \_\_\_\_ Induce cell proliferation make mutations in initial clone cell \_\_\_\_ Accumulation of additional mutations e.g \_\_\_\_, hormones, phenols
damaging
Ras
signature mutation
cell growth
tumorigenic
permanent
phorbol esters
Radiation Carcinogenesis
Induces DNA damage UV rays \_\_\_\_ dimers Nucleotide Excision Repair Skin cancers -- Squamous and Basal cell carcinoma– \_\_\_\_ sun exposure -- Melanoma - Intense \_\_\_\_ sun exposure -- \_\_\_\_ Carcinogenesis
Radionuclides, Ionizing radiation - \_\_\_\_ DNA breaks \_\_\_\_ repair Non-homologous End joining Used in therapy with \_\_\_\_ consequences to adjacent tissues
pyrimidine
accumulated
intermittent
field
double stranded
recombination
secondary
• Damage type differs between UV exposure and ionizing radiation
• UV exposure
○ Dimerized of pyrimidines that are ____ bound leading to an error
§ The nt will have to be excised via ____
□ If you have deficiencies - ____ - very sensitive to UV damage
○ Too much damage will overcome the capability of NER > carcinogenic process occurring
○ The more sunlight you’re exposed to, the more likely you’ll develop squamous/basal cell carcinoma
§ ____ people are more susceptible to sun cancer formation
○ The whole area is exposed to UV light, there will be mutations, but won’t be the same in all ____ > but the whole field has a higher chance of cancer development
§ Field carcinogenesis, also occurs in the oral cavity
• Ionizing radiation ○ Can lead to \_\_\_\_, translocations and sometimes mutations (but less likely), leading to \_\_\_\_ to repair the break; or \_\_\_\_ (resulting in genomic instability) ○ Thyroid cancer - a secondary tumor down the line can occur from treatment; can be in the same or adjacent tissue
covalently
NER
XP
fair-skinned cells deletions recombination non-homologous end joining
Host Defense against Tumors: Tumor Immunity
Tumors must evade ____ surveillance
Immune ____ increases risk for tumors
Challenge is finding tumor specific antigens
Targeting cytotoxic T-cells against Tumor specific antigens \_\_\_\_ and mutant tumor suppressors Viral antigens \_\_\_\_ proteins Other mutated cellular proteins
• If person is immunocompromised, risk of cancer is increased ○ In \_\_\_\_ immunocompromised and \_\_\_\_ patients it is evident ○ Immune suppression by \_\_\_\_ can also increase the risk for tumors • Before we can train immune system to attack tumor, we need to train it to recognize tumor-specific antigens ○ Categorized into these fours • Most important cell-type in tumor immunity is \_\_\_\_ ○ Recognize antigens
immune
suppression
oncoproteins
overexpressed
congenital
transplant
drugs
CTL
Oncogenes and mutant tumor suppressors
Mutations in protooncogenes and tumorsuppressors induce new antigens
E.g. ____, ras, ____, and CDK4, her2/neu
So far only ____ antibodies appear to be protective for breast cancer
• Normally endogenously expressed due to mutations, and now they are new: ○ B-cat, ras, p53 and CDK4 • Her2/neu - GFR ○ Not mutated, but it's \_\_\_\_ in breast cancers ○ Already on the \_\_\_\_, and targeted therapy can shut down the signaling mechanism and kill the cells
b-catenin
p53
her2/neu
overexpressed
surface
Other Mutated Proteins
Genomic instability leads to mutation in numerous genes
Altered protein products would be ____ to the cancer cells
Diverse and varied targets, perhaps unique to each tumor
Chemical and radiation induced changes may have “____” like p53 for aflatoxin B1
• Any gene can be mutated, so it is extremely diverse, and it would trigger an immune response • Can be helpful: when carcinogens can induce \_\_\_\_ mutations ○ P53, aflatoxin B1 produces a toxin that induces a mutation which can link the cancer to aflotoxin exposure
unique
signature mutation
specific
Overexpression of normal proteins
Select cell expression at low level perhaps does not induce “____”
Now target for tumors that have deregulated these gene products
\_\_\_\_ in melanocytes Cancer-Testis antigens -- Sperm do not express \_\_\_\_ -- e.g. Melanoma Antigen 1 (MAGE1) === 37% of melanomas === Also found in subset of lung, liver, stomach an esophageal tumors
• Sometimes genes that are usually repressed, but they become activated and express their products ○ Initially at such a low level/not expressed, so immune system was not trained so there's no \_\_\_\_ ○ An immune response is induced § Tyrosinase □ Expressed, but in very \_\_\_\_ levels □ Immune system doesn't normally detect it - untrained to recognize as self □ Malignant melanoma - \_\_\_\_ levels increase - triggers an immune response § Cancer-testis antigens □ Only expressed in sperm, and because it doesn't express MHCI (need it to present antigen to cell surface); the immune system has not been exposed to antigens □ In cancers they're not repressed, and expressed by other cells (which have MHCI) and the immune system recognizes it as foreign and targets it □ \_\_\_\_ and RAGE are examples
self-tolerance
tyrosinase
MHC class I
self-tolerance
low
tyrosinase
MAGE
Viral antigens
____ and EBV produce viral product kept in check by immune surveillance
Effectiveness of Vaccine against HPV supports the role of the ____
• Immune system can be used to protect against cancer ○ Person has a vaccine against HPV - immune surveillance set to look for HPV antigens ○ If a cell that is transforming to cancer due to HPV > you have trained the immune system to go and kill the transforming cell § Decreases incidence of HPV induced \_\_\_\_ cancer
HPV
immune system
cervical
Other Targets
Oncofetal proteins
— ____ protein re-expressed in tumors
glycolipids and glycoproteins
- – ____ specific glycolipids/proteins would be sequestered
- – Seen on non-____ tumors
Differentiation specific antigens
— ____ tissue of origin for tumor
• Oncofetal proteins ○ Initially shut down following fetus is born, and then the repression is lifted during carcinogenesis ○ \_\_\_\_ § Expressed in colon/stomach cancer ○ \_\_\_\_ § Expressed in liver cancer ○ Both antigens are detected in serum, and supports the diagnosis (not the \_\_\_\_ itself!) • Glycolipids/glycoproteins ○ Normally not exposed to immune system due to location § \_\_\_\_ - found on apical side of ductal side of breast epithelium □ No exposure to immune cells, and they don't know that it's endogenous protein □ Upon cancer losing contact and \_\_\_\_, the apical membrane becomes exposed to the immune system • Differentiation specific antigens (CD#) ○ Expressed on B cells, T cells and blood cells § Based on the antigen expression - can categorize the \_\_\_\_ § In lymphoma, can deduce the cell type using this mechanism
fetal
ductal
polarized
delineate
carcinoembryonic antigen (CEA) alfofetal protein (AFP)
diagnosis
mucin-1
polarity
cell type
Anti-tumor mechanisms
Cell mediated immunity
Cytotoxic T-cells
— ____ cells respond to viral tumors
Natural Killer cells
— Target tumors that downregulate ____
— Diverse receptors, including ____ induced antigens
Macrophages
____ produced by Cytotoxic T cells and NK cells activates Macrophages
Humoral immunity
Anti CD20 AB treats ____
• NK cells ○ Downregulate MHCI so the cancer cells become more susceptible to NK cells (because they're killing CTL) ○ Cancer cells under stress express antigens that are targeted by the NK ○ Less selective than \_\_\_\_ • Macrophages ○ Produce \_\_\_\_, other cytokines and cause death ○ Inflammation that is seen in tumors - while it is there to control growth, it can lead to \_\_\_\_ itself - precipitating more damage § Double-edged sword • Humoral immunity ○ NHL - cancer cells overexpress CD20 - can use ab against the CD20 antigen leading to a burst of the tumor cell
CD8+
MHC class I
stress
INFg
non-hodgkin lymphoma
CTL
ROS
DNA damage
Immune Surveillance and Immune Evasion
Immunodeficiency increases risk 200 fold
____ Immunodeficiency
____ patients
____-infection
Immune competent host develop cancer
Tumors must evade the immune system
congenital
transplant
HIV
Mechanisms of Immune evasion
____ of immune system eliminate highly antigenic tumor cells
Reduction/loss of ____ markers
Antigen Masking – Thicker coat of ____ hides antigens
Induction of immunosuppression
— Expression of ____
— Engagement of T-cell inhibitory receptor, ____
— Expression of ____ – apoptosis
Downregulation of co-stimulatory molecules needed for strong ____ response
• Cancer cells will try to lose their MHC, so the immune system will not recognize the cancer cells • Induction of immunosuppression ○ Growth inhibition by TGF-b > the expression of TGF-b can lead to immunosuppression as well ○ Can utilize CTLA4 that will dampen the immune response ○ Tumor cells can express and secrete FasL, which will bind to Fas receptor and will induce apoptosis of the \_\_\_\_ cell
selective pressure
histocompatability
glycolipids
TGFb
CTLA4
FasL
T cell
immune
Clinical Aspects of Cancer
Effects of tumor on Host
____ of Cancer
____ Diagnosis
How do we recognize cancer?
grading and staging
laboratory
Effects of Tumor on Host - Location
Mass effects
- - ____ or malignant tumors
- - Block flow in ____, duct, bowel etc
- – e.g ____ artery, liver, intestine
- - Compress/damage normal tissue
- – e.g ____ adenoma compression of gland
Produce hormones -- e.g Pancreatic b-cell tumors – \_\_\_\_ Ulcerate surface -- \_\_\_\_ -- Secondary infection Intussusception -- Tumor protruding into gut lumen caught in \_\_\_\_
benign
vessel
renal
pituitary
hyperinsulinemia
bleeding
peristaltic pull
• Mass effects
○ Based on ____
§ Pituitary adenoma - very small location, and the tumor is very small, but it has significant outcome:
□ Compresses the gland, and the hormones will not be secreted
§ Growth in the brain - even if small can have fatal outcomes
§ Growth in vessel wall of renal artery - and blocks flow - renal issues
§ In the liver, blocking flow of ____ will lead to digestion of liver
○ Intussusception
§ Blocking intestinal lumen > tumor protruding into the gut will interrupt the peristaltic movement leading to blockage and then ____ of local tissue
○ Production of hormones
§ Pancreatic b-cell tumor - if well differentiated > will retain some of normal function > insulin production
□ Manifest as hyperinsulinemia (low levels of blood ____)
§ Pituitary adenoma can also produce certain hormones
○ Ulcerate surface (because the vasculature is ____ in cancer)
§ More likely to occur in GI tumors, stomach tumors and colon cancer
□ Bleeding can be massive
□ Bleeding can be small, but ____ - so subtle to not be detectable by patient > can lead to ____
location bile gangrene glucose occult anemia
Effects of Tumor on Host - paraneoplastic syndromes
Paraneoplastic syndromes May precede tumor \_\_\_\_ Differ based on tumor \_\_\_\_ Several mechanisms
Most Common \_\_\_\_ Cushing Syndrome \_\_\_\_ Nonbacterial thrombotic endocarditis
• Paraneoplastic syndrome ○ Any symptom that is not directly to the \_\_\_\_, or the \_\_\_\_ that may be acquired by cancer (invasion of tumor into surrounding tissue) ○ May precede tumor ID, can help the clinician diagnose the cancer ○ Certain cancers produce certain \_\_\_\_ in paraneoplastic syndromes that can help diagnose the cancer • Hypercalcemia ○ If breast tumor goes to bone: § Bone resorption § Increase levels of Ca++ in blood □ These are due to \_\_\_\_ of cancer into blood, not paraneoplastic! ○ Paraneoplastic syndrome: § Production of \_\_\_\_ that will lead to increased levels of Ca++ • Cachexia ○ Wasting
identification
origin
cachexia
hypercalcemia
mass effect
function
hormones
invasion
hormones
Miscellaneous (non-specific syndrome)
Non-specific syndrome \_\_\_\_ Dysgeusia \_\_\_\_ cachexia
Cachexia
Loss of ____ and ____, Weakness, Anorexia,
Anemia
Wasting ____ than reduced food intake dictates
Metabolism is ____, not lower
Due to cytokines like ____ from Macrophages or tumor cells
Only treatment is to remove ____
• Dysgeusia - fowl smelling breath • Cachexia - very thin, very fast weight loss ○ Non-specific ○ Not due to \_\_\_\_, or because the tumor is using up the calories ○ It's because of the \_\_\_\_ released by the tumor cells or the macrophages § TNFa ○ Patient may not be eating - starvation; however, metabolic rate increases (it would usually decrease)
fever
anorexia
fat lean mass faster higher TNFa tumor
tumor size
cytokines
Paraneoplastic syndromes
Clinically important because 10-15% of cases Often \_\_\_\_ manifestation May cause significant morbidity/mortality May \_\_\_\_ treatment
Hypercalcemia
____
Most common cause is production of ____ by tumor
• Hypercalcemia ○ Multifactorial due to production of hormones ○ PTHrP leads to release of \_\_\_\_
early confound multifactorial parathyroid hormone-related protein (PTHrP) Ca++
Paraneoplastic lesions
Cushing syndrome
____ disorder
One cause may be ____
Increase ____- like peptides by tumor
Constellation of effects due to ____
Neurologic, cardiovascular ,immunosuppression, metabolic changes (obesity/____), musculoskeletal changes, etc
• Cushing syndrome ○ Many reasons for the disorder, cancer is one of them § By itself, Cushing syndrome does not mean the patient has a \_\_\_\_ ○ Hypercortisolism § Immunosuppression exacerbates the conditions in cancer patients
endocrine tumor ACTH or ACTH hypercortisolism moonface tumor
