Neoplasia Flashcards
what are the 8 fundamental changes in cell physiology which are considered the hallmarks of cancer?*****
1) self-sufficiency in growth signals –> proliferate without external stimuli
2) evading growth suppressors
3) altered cell metabolism –> switch to aerobic glycolysis to use more energy for more growth (WARBURG)
4) Evading apoptosis
5) unlimited replication
6) inducing angiogenesis
7) ability to invade and metastasize
8) evade host immune response
What gene rearrangements revolve around the tyrosine kinase ALK receptor?
deletion on chromosome 5 fuses part of the ALK gene with another gene called EML4 –> this is in a subset of lung adenocardinoma!
What differentiates the rate of growth between benign and malignant tumors?
Benign: usually progressive and slow; may come to a standstill; mitotic figures are rare but normal if present.
Malignant: erratic, may be slow to rapid; mitotic figures may be numerous and abnormal.
What is Carcinoma in situ and what makes it different than carcinoma?
what is the best example of this
a pre-invasive neoplasm… when dysplastic changes involve the full thickness BUT DOES NOT penetrate the basement membrane.
once the tumor breaches the basement membrane, it’s “carcinoma” or invasive.
how many alleles do we have to change in proto-oncogenes to make it cancerous?
what about tumor suppressor and the promoting of neoplasms?
1
2
follicular lymphoma translocation?
(14;18)(q32;q21)
most carcinogens are metabolized by what?
cytochrome P-450 dependent mono-oxygenases
On the worldwide distribution of prostate and breast, where is it most frequent?
what are the reasons for the differing incidences? (6 things)
developed countries have the highest levels of people suffering from these
1) infectious disease
2) smoking + alcohol consumption
3) Diet
4) obesity
5) reproductive history (exposure to estrogen stimulation)
6) environmental carcinogens
When might you see migratory thrombophlebitis?
(trousseau syndrome) –> encountered with deep-seated cancers, most often carcinomas of the pancreas or lung.
What is the one unequivocal criterion of malignancy? what is its definition?
Metastasis… benign do NOT metastasize.
spread of a tumor to sites that are PHYSICALLY DISCONTINUOUS with the primary tumor.
ERBB1 problems are found in a subset of what cancer? how is it happening?
what about ERBB2? what does it encode and what happens?
lung adenocarcinomas –> POINT MUTATIONS lead to constitutive activation of EGFR tyrosine kinase (since ERBB1 encodes it)
Encodes HER2 –> breast carcinomas –> AMPLIFICATION (not mutations) leading to over expression of HER2 receptor and constitutive tyrosine kinase activity
What is TP53?
GUARDIAN OF THE GENOME
it’s a tumor suppressor protein that regulates cell cycle progression, DNA repair, cellular senescence, apoptosis
MOST FREQUENT MUTATED GENE IN HUMAN CANCER
why are benign tumors generally considered well-differentiated? (2 things)
how do we know a benign tumor of a endocrine gland is well-differentiation and what’s the implication behind this?
How does this differentiate from anaplastic tumors?
pretty much retains its functional ability
1) it so easily resembles the normal tissue that it can be impossible to recognize it as a neoplasm.
2) mitoses are rare and usually are of normal configuration
– they secrete hormones characteristic of their origins, so we would see increased levels of hormones in the blood.
***anaplastic tumors will instead have new and unanticipated functions
TP53 is found where?
17p13.1
Asbestos:
1) what types of human cancers are associated with this?
2) when might someone be exposed to this?
lung, esophageal, gastric, and colon carcinoma; mesothelioma
used to be part of fire, heat, and friction resistant materials. underlayment and roofing papers/roof tiles.
NF2
1) what does it encode?
2) lack of this product means what?
3) what disease is a complication?
creates neurofibromin 2 or MERLIN
lacking merlin means no stable cell-to-cell junctions, and are insensitive to normal growth arrest signals generated by cell-to-cell contact
neurofibromatosis type 2
What’s said to cause the induction of cutaneous cancers?
why is this carcinogenic?
nonmelanoma vs melanoma?
UVB light
it forms pyrimidine dimers
total cumulative exposure to UV –> nonmelanoma (low and slow exposure)
intense intermittent exposure –> melanoma (high and fast exposure)
What is tumor differentiation?
what if there is lack of differentiation? what does this mean?
what tumor is considered to have this lack of differentiation, typically?
extent to which neoplastic PARENCHYMAL cells resemble the corresponding NORMAL parenchymal cell morphologically and functionally.
this is called anaplasia –> “to form backward” implying a reversal of differentiation to a more primitive level.
malignant neoplasms are considered to be anaplastic in nature.
Hypercalcemia can be seen in what cancers?
squamous cell carcinoma of the lung.
what is a promoter?
what are indirect-acting carcinogens? what’s the product called?
what’s an example?
chemical agents that increase in proliferation, but that are not mutagenic UNLESS an initiator has screwed up the DNA.
these REQUIRE metabolic conversion to become active –> called an “ULTIMATE CARCINOGEN”
Polycyclic hydrocarbons
Radon
1) what types of human cancers are associated with this?
2) when might someone be exposed to this?
Lung carcinoma
decay of mineral containing uranium; quarries and underground mines
What’s to note about genetic predispositions and the relevance of inherited factors and environmental factors in neoplasia?
include 2 diseases
well defined inherited components that lead to cancer can be greatly influenced by non genetic factors
ex) breast cancer (BRCA1 and BRCA2) –> enhanced 3x after 1940 because change in reproductive history
strongly environmental diseases can conversely be upregulated by genetic problems
ex) cytochrome p-450 problem’s increases susceptibility in lung cancer caused by smoking.
What is metaplasia?
what is dysplasia? what features can you see that tell it’s not metaplasia?
what features of anaplasticity can be seen in dysplasia?
replacement of one type of cell with another type, often in association with tissue damage, repair, regeneration. –> the replacement is always better suited for the new environment.
“disordered growth” –> metaplasia that has gone awry… loss of uniformity, loss of architectural orientation.
pleomorphism, abnormal nuclear morphology (1:1 cytoplasm:nucleus), mitotic figures
Arsenic and arsenic compounds:
1) what types of human cancers are associated with this?
2) when might someone be exposed to this?
Lung carcinoma + skin carcinoma
metal smelting, food and water contamination
antibodies specific for intermediate filaments tell us what?
solid tumor cells often contain intermediate filaments characteristic of their cell of origin
Carcinoembryonic antigen (CEA) markers are good for what?
colon, pancreas, stomach, and breast
What is the influence of age on the likelihood of being afflicted with cancer?
why is it that after 80 cancer deaths decline?
most carcinomas occur in the later years of life (>55)
lower number of people who actually reach this age.
what do Long Intervening Noncoding RNA do? (linc-RNA)
regulate the activity of chromatin “writers”, the factors that modify histones and thereby control gene expression
WT1
1) what does it create and what does it do
creates WT1 protein (tumor suppressor) –> transcriptional activator of genes involving renal/gonadal differentiation
Wilms tumor –> pediatric kidney cancer
What is a polyp?
what is an adenoma? example?
when a neoplasm (benign or malignant) produces a macroscopically visible projection above a mucosal surface
benign EPITHELIAL neoplasms derived from glands, although they may or may not form glandular tissue.
VHL?
1) what does it encode?
2) germline loss-of-function causes what? what chromosome? what do they have a high risk for? 2
3) biallelic loss-of-mutations are common in what?
encodes ubiquitin ligase responsible for degradation of hypoxia-induced factors (HIFs) (things that alter gene expression in response to hypoxia)
germline loss-of-function mutations of VHL cause Hippel Lindau syndrome on chromosome 3p –>
pheochromocytomas, renal cell carcinoma
sporadic renal cell carcinoma
HH signalling
what about hemihypertrohy syndrome of beck with wiedemann syndrome?
this is a feature that allows humans to differentiate into a complex segmented body plan –> segmentation and bilaterally can be achieved
HH (hedgehog) is affected
What does MYC do? 3 things
activates expression of genes involved in cell growth
upregulates expression of telomerase
can reprogram somatic cells into pluripotent stem cells.
What is RB?
what is it called?
what is it doing?
tumor suppressor protein
“GOVERNER OF PROLIFERATION”
key negative regulator of the G1/S cell cycle transition
Vinyl chloride
1) what types of human cancers are associated with this?
2) when might someone be exposed to this?
hepatic angiosarcoma
refrigerant; adhesive for plastics; used to be used in aerosols.
What happens once we have lost p53 function?
DNA damage goes unrepaired, allowing driver mutations to accumulate in oncogenes and leads to malignant transformation.
what DNA virus binds to p53 and degrades it? this also happens with RB*
E6 protein of high risk HPV
all signal transaction pathways converge where?
what are the two major genes to talk about?
nucleus
RAS and BRAF
Li-fraumeni syndrome?
associated with TP53 –> 25x greater chance of developing a malignant tumor by age 50
Explain Sentinel Nodes and its clinical role in staging cancer.
what is the definition of a sentinel node?
how do we know where it is?
should we be worried about an enlargement of a lymph node next to the cancer?
biopsy of sentinel nodes is used to assess the presence or absence of metastatic lesions in the lymph nodes.
“the first node in a regional lymphatic basin that receives lymph flow from the primary tumor”
radio labeled tracers or colored dyes
it doesn’t necessarily equate with dissemination of the primary lesion.
what is the molecular basis of multistep carcinogenesis?
3 stages:
Colon epithelial hyperplasia –> formation of adenomas –> enlarge and ultimately undergo malignant transformation
PTCH
1) what does it create?
2) what does it usually do?
3) what happens if this protein is not made?
4) what do germline loss of function mutations result in?
5) what 2 major diseases are associated with this?
creates the protein PATCHED
negative regulators of hedgehog signaling pathway.
absence of these proteins (due to a mutation) –> unopposed hedgehog signaling –> increases pro-growth genes (including NMYC and D cyclins)
loss of function –> Gerlin Syndrome
medulloblastoma / basal cell carcinoma of the skin
1) What is lymphatic spread? what is this most characteristic in?
2) what provides the opportunity to spread?
3) how are the lymph nodes involved?
transport through lymphatics.. CHARACTERISTIC OF CARCINOMAS
metastasis
follows the natural route of lymphatic drainage.
in 2008, the incidence of new cancer is what and what is the projection for 2030?
12.7 million new cancer cases worldwide, leading to 7.6 million deaths
estimated to increase to 21.4 million and 13.2 respectively.
PSA marker is for what?
Prostatic adenocarcinoma
Xeroderma pigmentosum?
lack proteins responsible for nucleotide excision repair that deals with pyrimidine dimers, so will easily get cancer
NF1
1) what does it make?
2) what happens if you have a mutation?
3) what diseases/cancers are common?
creates Neurofibromin –> acts as a brake on RAS signaling.
RAS tends to become trapped in an active, signal-emitting state
develop numerous benign neurofibromas and optic nerve gliomas –> neurofibromatosis type 1
(GTP BINDING PROTEINS)
What are the 3 RAS mutations to know?
what does each correspond with cancer wise?
What does this mutation do?
KRAS –>Colon, lung, pancreatic
HRAS –> Bladder and kidney
NRAS –> melanoma, hematologic malignancies
RAS that is activated is deactivated through GAP.. but in cancers this GAP is mutated, keeping the GTP on and not allowing it to turn off its pro-growth signals
What’s to note about BCL2 in the apoptosis pathway?
in more than 85% of B cell lymphomas it’s over expressed due to a 14;18 translocation.
DIC (disseminated intravascular coagulation) is most commonly associated with what?
acute promyelocytic leukemia
Gerlin Syndrome?
increased risk of what 2 things
caused by germline loss of function mutation –> also called nevoid basal cell carcinoma syndrome
increased risk of basal cell carcinoma of the skin and medulloblastoma
follicular lymphoma translocation?
(14;18)(q32;q21)
Warburg Effect
1) what is it?
2) why is it a part of cancer?
3) why use this and not mitochondrial oxidative phosphorylation?
even in the presence of oxygen, cancer cells use high levels of glucose uptake and conversion of that glucose to LACTOSE via the glycolytic pathway
this provides rapidly dividing tumor cells with metabolic intermediates that areneeded for synthesis of cellular components
mitochondrial oxidative phosphorylation does not… nothing of it goes to production of components for growth.
