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.
What 5 criteria were mentioned that help show anaplasia?
what is to know about each one?
Pleomorphism –> variation in size and shape (including some tumor giant cells)
2) abnormal nuclear morphology (usually the nuclei are disproportionately large for the cell –> 1:1 instead of 1:4 or 1:6
3) Mitoses –> many cells are undergoing mitosis.. and the presence of ATYPICAL, BIZARRE MITOTIC FIGURES
4) loss of polarity –> orientation is disturbed
5) areas of ischemic necrosis –> vascular stroma is insufficient to supply the growing tumor.
What epigenetic modifications contribute to the malignant properties of cancer cells?
DNA methylation in cancer cells –> silences tumor suppressor genes
histone modification
Hepatitis B and C virus can lead to what?
it hurts the liver cells, causing regeneration –> higher chance for hepatocellulr carcinoma
What is the hematogenous spread of cancer?
what are the major cancer types that tend to spread in this fashion?
what are specific examples that we must know? (4 of them)
penetration of arteries and veins and spreading through the blood
characteristic of sarcomas (and some carcinomas)
blood borne cells often come to rest in the first capillary bed they encounter… most often the LIVER and LUNG.
1) renal cell carcinoma –> invades the renal vein
2) Hepatocellular carcinoma –> invades hepatic vein
3) Follicular carcinoma of the thyroid
4) Choriocarcinoma
people with acanthosis nigricans?
50% of cases can form some sort of cancer over 40 years old
What’s the TNM system?
what would carcinoma in situ be?
T for tumor (1-4 for primary lesion, 0 for lesion in situ)
N for nodal (0 meaning no node, 3 would denote increasing number and range of nodes
M for metastases –> 0 is no distant, M1 or M2 indicates presence of some
T0N0M0
How is a mixed tumor of the salivary gland different form an adenoma of the colon?
Mixed tumor of the salivary gland contains epithelial components scattered within a myxoid stroma that can have cartilage or bone –> all come from a single clone that produces BOTH EPITHELIAL AND MYOEPITHELIAL cells –> so it’s a PLEOMORPHIC ADENOMA
anemia is only epithelial cells.
why utilize tumor markers?
THEY ARE FOR MONITORING POST CANCER TREATMENT SUCCESS
why are some cells in ALL cancers stem-cell like?
where do they come from?
what can help them have limitless replicative potential?
this is needed to allow self-renewing capacity in cancer
they come from proliferating cells that acquire a mutation that confers “stemless”
cancer cells acquire lesions that inactivate senescence signals and reactivate telomerase.
deficiency of hedgehog gives you what?
hemihypertrophy
cyclopia
holoprosencephaly.
infiltrating cancers provoke what?
what 3 things can result?
what about the microenvironemtn?
chronic inflammatoryy reactions
it can be coextensive that can cause anemia (due to inflammation induced sequestering of iron and downreg of erythropoietin), fatigue, and cachexia
they modify the local tumor microenvironment to enable many of the hallmarks of cancer
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
Hypertrophic osteoarthropathy?
what characterizes this?
small portion of people with lung carcinoma have this
1) periosteal new bone formation,
2) arthritis of the adjacent joints
3) clubbing of the digits.
What is the two hit hypothesis surrounding retinoblastoma?
what about familial? inheritance pattern?
sporadic?
if there are two “hits” involving both alleles of RB at chromosome 13q14… you get retinoblastoma.
familial, children inherit one defective copy (the first hit), then the normal is mutated with regards to sporadic –> end up more likely getting bilateral retinoblastoma. (AUTOSOMAL DOMINANT)
sporadic cases –> both normal ones need to undergo somatic mutation –> so the probability is low so bilateral is low, but unilateral is more common (still sporadic cases are SUPER rare)
Explain what happens when p53 is putting cells in arrest.. what’s doing this job?
it arrests it in G1 and has it repaired by GADD45
if not, it apoptosis.
what method is widely used for cervical cancer?
cytologic smears (Pap smear)
Cadmium
1) what types of human cancers are associated with this?
2) when might someone be exposed to this?
Prostate carcinoma
yellow pigments and phosphors, battery making, soldering.
what do we target in cancers?
PD-1 or PD-L1 or CTLA4
Evasion of Apoptosis:
1) how is it initiated?
2) cancers have abnormalities in which pathways?
3) what about antiapoptotic family member of BCL2, MCL-1?
intrinsic or extrinsic.
both pathways are present, but more commonly in intrinsic pathway
over expression is linked to cancer cell survival and drug resistance
the growth of cancers is accompanied by what 3 things?
what’s the most reliable feature of these three that differentiates cancers from benign tumors?
what about in benign tumors?
progressive infiltration, invasion, and destruction of the surrounding tissues
invasiveness
cohesive expansile masses that remain localized and CANNOT infiltrate, invade, or metastasize.
How does cancer evade host defenses?
1) what cells are usually AGAINST tumors?
CD8 CTLS
they can lose or reduce the expression of MHCs, or immunosuppression mediated by PD-1 ligand, TGF-b, or galectins by the tumor cells.
chemotherapy and radiation do what with TP53?
what are examples of the types of each
they are more likely to kill wild type TP53 than mutated alleles
wild type –> testicular teratocarcinomas / childhood lymphoblastic leukemia
mutated –> lung and colorectal cancers (can’t be killed)
Li-Fraumeni syndrome:
what’s affected
what is their likelihood of tumors?
what type of tumors
inherited mutation of 1 copy of TP53.
25x greater chance of developing a malignant tumor by age 50 than the general population
syndrome –> so think multiple primary tumors of varying types.
What are the most associated radiation-induced cancers?
myeloid leukemias
cancers of the thyroid (but only in the young)
“blast” means what?
familial cancer seen in babies or very young infants.
What’s the difference between the local expansion of benign tumors and the localized invasion of malignant tumors?
how can malignant tumors be misleading?
Benign –> usually cohesive, expansive, well-demarcated masses that DO NOT INVADE or infiltrate surrounding normal tissues
Malignant –> locally invasive, infiltrating surrounding tissue.
some can be cohesive and expansive, similar to benign
Genes that promote autonomous cell growth in cancer cells are called what?
what are the unmutated counterparts called?
what pathway seems to be the most frequently mutated oncogenic pathway in human neoplasms?
what are oncoproteins
oncogenes
protooncogenes
receptor tyrosine kinase pathways
protein encoded by an oncogene that drives increased cell proliferation
Tumor Suppressor Genes
what are the two big ones? what are their proteins?
these are genes that apply the brakes to cell proliferations, and abnormalities lead to failure of growth INHIBITION.
RB and TP53
Rb and p53!!
What three things activate p53?
once activated, what 3 things does it do.
DNA damage
hypoxia,
oncogenic stress (like RAS activated becasuse of increased MAPK or PI3K/AKT pathways.
induces transient cell cycle arrest, senescence, or programmed cell death
How is a cystic teratoma of the ovary fundamentally different from a mixed tumor of the salivary gland?
mixed tumor of the salivary gland –> all coming from a single clone that produces both epithelial and myoepithelial cells (which means bone/cartilage in there)
cystic teratoma of the ovary –> teratomas come from totipotential germ cells that can differentiate into ANY type of cell in the body… cystic teratoma is on the ectodermal lines –> skin with hair, sebaceous gland, teeth.
Rb (NOT RB)
P53
tumor suppressor “pocket” protein that binds E2F transcription factors, preventing G1/S transition
in the majority of cancers –> causes cell cycle arrest and apoptosis
What do Cyclin dependent kinases do?
what do these have to bind to in order to do this?
helps cells go through the cell cycle
Cyclins
growth promoting, or growth inhibiting port-oncogenes
are the genes themselves related to the function of cancer?
no this is what the normal function is before mutation.
medulloblastoma is what?
what is it related to?
most common brain tumor in kids
related to WNT and SHH pathways.
Beryllium
1) what types of human cancers are associated with this?
2) when might someone be exposed to this?
Lung carcinoma
missile fuel and space vehicles; hardener for lightweight metal alloys
one of the most profound selective pressures that cancer cells face is what?
years later what happens
chemotherapy or radiotherapy.
tumors that come back are often resistant to the same treatment that was given earlier.
constitutively active means what?
synthesis of a protein or enzyme at a constant rate regardless of what’s going on constitutively.
What is Cancer?
What is Neoplasia?
Tumor?
Oncology?
Clonal?
Malignant tumors are collectively referred to as cancers.
“new growth” that is unregulated, irreversible, and monoclonal (derived from a single mother cell)
Tumor is synonymous with neoplasm.
study of tumors or neoplasms
H. Pylori infections are implicated in what?
gastric adenocarcinomas: inflammation –> proliferatation –> adenoma
gastric lymphomas: B cell origin –> there is some Peyers patches that are called MALTomas, so lymphoma.
Explain the stepwise acquisition of mutations in the development of cancer:
1) what’s the first step? what does this typically require?
2) how does cancer progress from here? what does this increase the likelihood of?
3) from this point forward, what do we acquire? what 3 things are these?
**more in other slides
1) the first driver mutation that starts a cell on the path to malignancy is the INITIATING MUTATION –> this typically requires additional driver mutations
2) these mutations lead to GENOMIC INSTABILITY –> increases the likelihood of more driver mutations, but also passenger mutations (no phenotypic consequences)
acquire the cancer hallmarks (excessive growth, local invasiveness, ability to metastasize.
MYC
prototypical nuclear regulatory protein
can up regulate telomerse
NMYC (neuroblastoma related) LMYC (lymphoma related – burkitt’s lymphoma)
Benzene
1) what types of human cancers are associated with this?
2) when might someone be exposed to this?
Acute Myeloid Leukemia
principal component of light oil; rubber, dry cleaning, adhesives too.
Where are mutations in TP53 found?
how many?
what if they are inherited?
chromosome 17p13.1
usually both alleles are affected.
Li-Fraumeni Syndrome
Flow cytometry is good for what?
malignant cells in liquid like lymphomas
What pathways are found in all human cancers?
RTK –> RAS –> operates through MAPK/AKT
BCR-ABL.. explain it
what cancers have this problem?
ABL gene translocated and fuses with BCR gene.
chronic myelogenous leukemia (CML) and some acute lymphoblastic anemia
What is APC?
what does it do?
what chromosome is it and loss of function mutations result in what?
how many mutations for adenoma to appear?
gatekeeper of COLONIC NEOPLASIA
tumor suppressor that functions by down regulating growth promoting signaling pathways.
5, adenomatous polyposis –> thousands of polyps in the colon during teens or 20s (ADENOMA)
both copies
Quick frozen section is used for what?
what about fine-needle aspiration?
nature of the mass of a lesion or margins
aspirating cell and examination –> used for readily palpable lesions in breast, thyroid, lymph nodes
Alpha Feto-protein (AFP) is a marker in what disease?
what about HCG?
CA-125?
hepatocellular carcinoma, gonads, teratomas
testicular tumors
ovarian tumors
what do miRNAs do?
they mediate sequence-specific INHIBITION of messenger RNA through RNA-induced silencing complex (RISC)
when cells get a sufficient dose of a carcinogenic agent, what happens
direct-acting carcinogens
why are some important?
initiation results –> permanent DNA damage and is thus irreversible
direct acting carcinogens require NO metabolic conversion to become arcinogenic… most are WEAK carcinogens.
some are cancer chemotherapeutic drugs –> i.e. after treating someone, they can have a second form of cancer… usually acute myeloid leukemia
hedgehog problems are associated with what cancer?
basal cell carcinoma
medulloblastoma too
EBV leads to what?
Burkitt Lymphoma
HTLV-1
what does it cause
what does it have a tropism for?
causes adult T-cell leukemia/lymphoma (ATLL)
has a tropism for CD4 T cell
What’s the general definition of Benign?
what about malignant?
“innocent” –> remains localized, will not spread to other sites, and can be surgically removed
also called cancer –> can invade and destroy adjacent structures and spread to distant sites (metastasize) to cause death
in general, benign tumors are designated by what suffix?
in general, malignant are designated by what suffixes?
- oma
- sarcoma (if mesenchymal tissues) or Carcinoma (if epithelial cell origin and ANY layer)
What are some malignant neoplasms that have inappropriate benign terminology? (4)
Lymphoma, melanoma, mesothelioma, and seminoma have -oma at the end of it, however they are all malignant.
Cushing syndrome-type symptoms can be seen in patients with what?
small cell carcinoma of the lung –> produces a steroid like substrate
considering the 8 hallmarks of cancer, how can these hallmarks be accelerated?two things
genomic instability and cancer-promoting inflammation
1) What are the two basic components of all benign and malignant neoplasms?
2) which helps with the classification of tumors and their biological behavior?
3) which is dependent for growth and spread
1) they all have neoplastic cells that constitute the tumor PARENCHYMA
2) all have a reactive stroma made up of CT, blood vessels, cells of adaptive and innate immune system.
Parenchyma
Stroma
What is a precursor lesion? why are they important?
where do ALL precursor lesions arise from? what process?
what are three processes that correlate?
what is Leukoplakia?
rarely a benign tumor turns malignant, but what benign neoplasm is particularly at high risk for cancer and hence is a precursor lesion?
localized morphologic changes that are associated with a high risk of cancer (specifically various forms of carcinoma). we can screen for them.
epithelial surfaces. chronic inflammation
endometrial hyperplasia, Barrett Esophagus, Squamous Metaplasia
another frequent precursor lesion –> thickening of squamous epithelium on the oral cavity, penis, vulva –> gives rise to squamous carcinoma.
Colonic Villous Adenoma
Once we have the acquisition of cancer hallmarks, how does this get to our diagnosis? 2 big things
what are these tumors often genetically?
we get additional mutations and the emergence of sub clones
sub clones are tumor cells that “win” when competing with other tumor cells for resources. this is what leads to tumor progression.
heterogeneous
What are the two main cell cycle checkpoints?
G1/S and G2/M
What can happen in the evolution of dysplasia in squamous epithelium?
the normal maturation of tall cells in the basal layer to to flattened squames fails –> replaced with basal-appearing cells with HYPERCHROMATIC nuclei
more abundant mitotic figures than normal in these cells, but not confined to the basal layer!
In 2014, what are the highest Cancer incidences in Males and Females respectively?
what about mortality?
Males: Prostate, lung, colon, rectum
Females: Breast, lung, and colon/rectum
Males: Lung, Prostate, colon/rectum, Pancreas
Females: Lung, Breast, Colon/rectum, Pancreas
bulky tumor in the abdomen, what are the two possibility
neuroblastoma and wilms tumor
Nickel
1) what types of human cancers are associated with this?
2) when might someone be exposed to this?
Lung and oropharyngeal carcinoma
nickel plating, batteries, ceramics
chemical initiating agents target what?
what about Aflatoxin B1? what does it lead to and where does it come from?
DNA
in mold and aspergillus –> improper grains and nuts and leads to Hepatocellular carcinoma
Retinoblastoma gene (RB)
familial type –> mutation in the GERM cell line and need 1 more sporadic. (so it’s easier to get) –> more likely to have bilateral issues and maybe multicentric.
sporadic –> both of the hits are sporadic, not in the germ line.
What are the growth factor oncogenes to know?
1) glioblastoma (2)
2) many sarcomas (2)
express both PDGF and PDGF receptor
TGF-a and EGFR (epidermal growth factor receptor)
How does chronic inflammation help modify the local tumor microenvironment to enable hallmarks of cancer?
1) what does it release to promote proliferation?
2) is there something that prevents it from happening?
3) anoikis?
4) inflammation leads to the growth of what?
5) what might the release of TGF-b do
6) immunosuppression?
releasing factors that promote proliferation (EGF)
removal of growth suppressors
enhanced resistance to death
inducing angiogenesis
promote epithelial-mesenchymal transitions –> key event in invasion and metastasis
remember that inflammation leads to immunosuppression, so makes sense.
Warburg Effect:
1) what triggers this to happen?
PI3K/AKT pathways –> stimulates lipid production and protein syntehsis
RTK –> influences metabolism
MYC –> changes gene expression to support anabolic metabolism / cell growth
Gain of function in the CDK4 and D cyclin genes leads to what?
promote G1/S progression
What is BRAF?
what does a mutation stimulate?
what three things is it often seen in?
serine/threonine protein kinase that sits on other serine/threonine kinases of the MAPK pathway.
mutations stimulate each of these downstream kinases and activate their transcription factors.
in 100% of hairy cell leukemia, melanoma, and colon carcinoma
Paralog?
gene that is related to another gene by descent form a single ancestral gene that as duplicated and that may have a different DNA sequence and biological function
like an isoenzyme but with genes
Cachexia:
1) what three things are associated with?
2) what specific factor is associated with it?
equal loss of fat and lean muscle
elevated basal metabolic rate
systemic inflammation
TNF-a
loss-of-function in tumor suppressor genes does what?
stops the ability to inhibit G1/S progression. so allows it to move on.
TP53
APC
VHL
guardian of the genome, most frequently mutated gene in human cancers
gatekeeper of colonic neoplasia
related to CNS tumors, renal cysts, neuroendocrine tumors, and renal cell carcinoma
what is HPV a problem to RB and P53?
E7 –> prevents RB from binding to E2F transcription factors, so E2F can go through the cell cycle unchecked
E6 –> degrades P53
What is CDH1?
what does it encode for?
what does it lead to if deficient? what is lost?
encodes E-Cadherin gene
E-Cadherin is a CAM that has a role in contact-mediated growth inhibition of epithelial cells…
associated with autosomal dominant familial gastric carcinoma –> loss of cohesiveness, increased invasiveness, increased WNT signalling
what are the 5 paraneoplastic syndromes?
Endocrinopathies Hypercalcemia neuromyopathic acanthosis nicrigans hypertrophic osteoarthropathy
