BOD exam 4 disorders of growth and genetic basis of disease Flashcards
1
Q
Describe factors involved in maintaining appropriate cell mass in tissue
A
balance between proliferation, differentiation, and cell death.
2
Q
agenesis
A
something did not form
3
Q
aplasia
A
something did not develop
4
Q
hypoplasia
A
formed little
5
Q
anomaly
A
formed weird
6
Q
atresia
A
closed tube that should have been left open
7
Q
atrophy
A
body tissue or organ wasting away.
8
Q
hamartoma
A
abnormal amounts of tissue native to a location
9
Q
choristoma
A
normal mature tissue in a abnormal location
10
Q
ectopic tissue
A
an anatomic abnormality where tissue develops in an area outside its normal location.
11
Q
metaplasia
A
transformation from one differentiated cell type to another.
stem cell reprogramming
12
Q
hypertrophy
A
increased cell number
13
Q
dysplasia
A
abnormal pattern of tissue growth
14
Q
disorders of growth can be either
A
Developmental or Acquired
15
Q
causes of hyperplasia
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increased functional demand
endocrine stimulation
increased nutrition
chronic irritation
chemical and physical agents
16
Q
types of mataplasia
A
epithelial - squamous, glandular (mucous
mesenchymal - chrondroid, osseous, myxoid
17
Q
dystrophy
A
faulty development or tissue maintenance
18
Q
alterations in cellular physiology in tumors
A
-self sufficient growth
-evasion of apoptosis
- sustained angiogenesis
- tissue invasion and metastasis
19
Q
self sufficient growth
A
insensitivity to antigrowth signals
unlimited ability to divide - constant “on” signal
20
Q
evasion of apoptosis
A
progression through cycle with abnormal DBNA
fixation of defect in progeny cells
21
Q
sustained angiogenesis
A
tumor induced microvasculature supports increased tissue mass
22
Q
tissue invasion and metastasis
A
loss of inhibition by normlal tissue barriers - matrix enzymes to destroy normal barriers
cell surface molecules to attach to new tumor bed
23
Q
2 components of all tumors
A
- neoplastic cells that constitute the tumor PARENCHYMA
- reactive STROMA made of connective tissue, blood vessels, and variable numbers of cells of the adaptive and innate immune system.
24
Q
what determines classification and biologic behavior of tumor
A
parenchyma
25
what determines growth pattern and spread of tumor
reactive stroma
26
differentiation
progressive acquisition of specialized characteristics (structural and functional) as cells mature
27
what does deffierentiation involve:
altered/restricted gene expression
the progressive loss of capacity to divide
28
characteristics of benign and malignant neoplasms
Anaplasia
- lack of differentiation
- feature of malignancy
29
features of malignant neoplasms
-pleomorphism
- abnormal nuclear morphology
- bizarre mitotic figures
- loss of polarity
30
pleomorphism
variation in size and shape
31
multistep nature of carcinogenesis
initiation
promotion
progression
31
abnormal nuclear morphology
-N:C ratio of 1:1 (normal is 1:4 or 1:6)
-abnormal shape
- abnormally large nucleoli
- clumped of hyperchromatic chomatin
32
carcinogenesis
the process by which nomral cells are transformed into cancer cells
multistep process
33
initiation
introduction of IRIVERSIBLE genetic change.
they are physical or chemical carcinogens that damage DNA.
- need DNA replication with an altered complementary DNA strand to follow so that the mutation becomes "fixed"
may appear normal and remain quiescent for years
34
Progression
conversion of a benign tumor to an increasingly malignant tumor
IRREVERSIBLE
genetic and epigenetic changes in tumor cells and their environment
often leads to metastatic tumor
appearance of more aggressive subclones - population becomes more heterogenous)
acquire genetic instability
35
promotion
outgrowth of initiated cells in response to selective stimuli (promoting agents or promoters)
are not themselves mutagenic
alter gene expression in initiators (and uninitiated)
- this creates an environment where the initiated cells happen to have a growth advantage
REVERSIBLE
36
hallmarks of progression
karyotypic instability
increasing tumor cell heterogeneity
37
in progression, cells are selected for:
rapid growth
invasion
metastasis
38
Basic nature of neoplasia
irreversible abnormalities
cellular immortality
malfunction of growth control genes
39
irreversible abnormalities
increased cell proliferation
arrested differentiation
decreased cell turnover (apoptosis)
40
cellular immortality
lack normal senescence turnover
41
malfunction of growth control genes
growth factors/receptors
cell cycle factors
42
4 genomic themes relevant to most cancers
1. nonlethal genetic damage
2. a tumor is formed by clonal expansion of a single mutated precursor cell
3. four classes of normal regulatory genes are the principal targets of cancer causing mutation
4. carcinogenesis results from the accumulation of complementary mutation in a stepwise fashion over time
43
genetic damage - initial mutation caused by:
environmental exposure
any acquired mutation caused by exogenous agents
viruses
environmental chemicals
endogenous products of cellular metabolism
mutation inherited in germ-line
spontaneous mutation
43
four classes of normal regulatory genes are the principal targets of cancer causing mutation
1. proto oncogenes
2. tumor suppressor genes
3. apoptosis related genes
4. DNA repair genes
44
proto-oncognes
normal cellular genes involved in cell growth/division
mutation in them activate them, causing excessive increase in the normal functions of the gene product
mutations can impart a new function on the gene product
mutations in these genes cause these genes to be constitutively active = excessive proliferation
44
clonal expansion of single mutated precursor cell
DNA alterations are heritable, passed on to daughter cells
all daughter cells will contain the SAME initial mutation, and may accumulate additional mutation over time
45
gain of function mutation in regard to proto-oncogenes
still transform cell even if a normal allele is present
46
normal signaling pathways which drive cell proliferation that proto-oncogenes may be
growth factors
growth factor receptors
signal transducers
transcription factors
cell cycle components
47
tumor suppressor genes
form a network of CHECKPOINTS to prevent uncontrolled growth/propagation of damaged DNA
mutations generally cause a LOSS OF FUNCTION in tumor suppressors
usually BOTH alleles must be mutated before transformation occurs
P53, PTEN, RB are some of the frequently mutated tumor suppressors
48
frequently mutated tumor suppressors
P53
PTEN
RB
49
Two Hit Hypothesis
two mutations (hits) involving both alleles of a tumor suppressor gene are required to produce a tumor
50
triggers for apoptosis
DNA damage
deregulation of proto-oncogenes (proliferative signals)
loss of adhesion of cells to basement membrane
51
evasion of apoptosis as a mechanism of cancer development
can have abnormalities in both intrinsic (mitochondrial) and extrinsic pathways (death receptor)
intrinsic abnormalities are more common in cancer
51
mechanism used to evade apoptotic cell death
1. loss of P53 causes reduced function of pro-apoptotic factors such as BAX
2. reduced egress of cytochrome C from mitochondria due to upregulation of anti-apoptotic factors
3. loss of APAF1
4. up-regulation of inhibitors of apoptosis (IAP)
5. Reduced CD95 level
6. inactivation of death-induced signaling complex
52
anti-apoptotic factors
BCL2
BCL-XL
MCL-1
53
chemotherapy implication of BCL-2 overexpression
chemotherapy and radiation kill cancer cells via the intrinsic apoptosis pathway
over-expression of anti-apoptotic BCL-2 proteins allows tumor cells to resist these therapies
53
dysregulation of cancer associated genes
chromosomal abnormalities
epigenetic changes
noncoding RNAs
54
mutations in DNA Repair Genes as a mechanism of cancer development
loss of function mutation
impair the cells ability to recognize and repair nonlethal genetic damage in other genes
affected cells acquire mutation at an alarming rate
55
chromosomal translocations can activate proto-oncogenes via
promotor or enhancer substitution --> over expression of proto-oncogene
formation of a fusion gene --> fusion protein with oncogenic properties
56
deletions
associated with a loss of tumor suppressor genes
57
amplifications
duplications of the DNA sequences encoding oncogenes
58
epigenetic changes in cancer
factors other than the sequence of DNA that regulate gene expression (alter ability for genes to be expressed)
- Dna methylation --> silencing of tumor suppressor genes
- histone modifications
59
characteristics of neoplastic cells
immortality
loss of anchorage dependence
decreased cell adhesion
loss of contact inhibition
altered intracellular communication
decreased requirement for growth factors
altered or new cell surface antigens
abnormal karyotype
60
telomeres
specialized DNA protein complexes which cap ends of linear chromosomes
maintain genetic stability -
protect DNA ends from being recognized as damaged DNA leading to recombination, fusion, etc.
implicated in aging process - cell senescence
telomeres shortened with each cell replication
shortening to critical length triggers cell growth arrest
61
telomerase enzyme and cancer
telomerase is found in fetal tissues, adult germ cells, and also tumor cells
some normal cells can circumvent telomeric senescence
telomerase enzyme adds telomeric base repeats back into chromosomes ends
most immortalized cells cultured cell lines, neoplastic cells express telomerase
thought to play a critical role in immortality of neoplastic cells
most canine neoplasms express telomerase
62
steps in tumor invasion
loosening of intracellular junctions
degradation of basement membrane
attachment of cell to extracellular matrix components
migration of tumor cells
63
altered interaction with neighboring cells
dissociation of cancer cells from each other
due to alterations in intercellular adhesion molecules : E-cadherin in epithelia
facilitates cell detachment from primary tumor to allow for invasion of surrounding tissues
64
altered interaction with basement membrane
tumor cells secrete proteases to degrade basement membrane
OR
tumor cells stimulate stromal cells to secrete proteases
matrix metalloproteinases
cathepsin D
urokinase plasminogen activator
65
increased motility
slow process
extend lamellipodia
all controlled by cytoskeleton
direction of motility controlled by autocrine growth factors and cleavage products of extracellular matrix components
66
altered or new cell surface antigens
proteins, glycoproteins, lipids, or carbohydrates
tumor specific antigens
tumor associated antigens
targets for diagnostics
targets for therapy
67
lymphocyte hematopoietic neoplasm
lymphoma
lymphocytic
leukemia
68
plasma cell hematopoietic neoplasm
extramedullary plasmcytoma
myeloma
plasmacytoid
lymphoma
granulocytic myeloid leukemia
granulocytic sarcoma
69
monocyte hematopoietic neoplasm
monocytic leukemia
70
erythroid hematopoietic neoplasm
erythroid leukemia
71
epithelial neoplasms - stratified squamous benign
squamous papilloma
basal cell tumor
72
epithelial neoplasms - stratified squamous malignant
squamous cell carcinoma
basal cell carcinoma
73
epithelial neoplasms - glandular, LIVER, benign
hepaticadenoma
74
epithelial neoplasms - glandular, LIVER, malignant
hepatocellular carcinoma
75
epithelial neoplasms - glandular, RENAL tubules, benign
renal cell adenoma
76
epithelial neoplasms - glandular, RENAL tubules, malignant
renal cell carcinoma
77
epithelial neoplasms - glandular, MAMMARY gland, benign
mammary adenoma
78
epithelial neoplasms - glandular, MAMMARY gland, malignant
mammary adenocarcinoma
79
loss of tissue organization in tumors
tumor cells breach the basement membrane
tumor cells infiltrate adjacent tissue
tumor cells replace or compress adjacent normal structures
80
loss of differentation
can dedifferentiate to a more stem--like cell
or can take on new morphological characteristics not normally seen in a particular tissue
81
what to do with the most poorly differentiated tumors?
immumohistochemistry
in situ hybridization
82
immunohistochemistry
antibodies label proteins within cells to identify cell type
83
in situ hybridization
identify which genes are being expressed as an indicator of cell type of origin
84
IHC (immunohistochemistry) markers
Vimentin - mesenchymal cells
cytokeratin - epithelial cells
CD3 - T cells
CD79 - B cells
desmin - smooth/striated muscle
85
histological features of malignancy
rate of growth - necrosis, hemorrhage
stromal response - variable, tumor dependent
invasiveness - demarcation
metastasis - distant spread
86
dissemination of cancers
lymphatic spread
carcinomoas --> regional lymph node --> sentinel lymph node
lymph node enlargement--> tumor cells, tumor debris, reactive hyperplasia
hematogenous spread --> cells come to rest in first capillary bed they encounter (liver, lung, paravertebral plexus (thyroid and prostate cancers))
seeding of body cavities and surfaces --> peritoneal cavity, pleural cavity
87
sentinel lymph node
first node in a regional lymphatic basin that receives lymph flow from the primary tumor
88
bronchogenic carcinoma
here, cells had cilia
in cats this type of lung tumor often metastasizes to the toes
89
growth of neoplasm
monoclonal = DOGMA--> all neoplastic cells arise from a SINGLE mutated cell
polyclonal --> multiple clones arise from multiple mutated cells
can arise from hyperplasia
somatic mutation are rare
90
somatic mutation
A somatic mutation is a genetic mutation that occurs in a somatic (non-germline) cell — meaning it is not inherited, and it only affects the individual, not their offspring.
In the context of neoplasia, a somatic mutation is a DNA alteration that happens during the life of the animal (or person), often due to:
Environmental exposure (e.g., UV light, chemicals)
Replication errors
Spontaneous DNA damage
91
drug (chemotherapy) resistance
gene amplification
increased expression of proteins that can pump drug out of cell (P-glycoprotein)
cells with membrane transport proteins that stop working (stop taking in drug)
cells that develop improved ability to fix DNA breaks caused by drugs
need combination therapy as tumors evolve mechanisms to evade effects of each drug
92
limitless replicative potential: stem-cell like properties of cancer cells
how do cancer cells become seemingly immortal?
evasion of senescence
evasion of mitotic crisis - reactivation of telomerase
capacity for self-renewal
93
cancer stem cell theory
Cancer stem cell theory proposes that a subset of cells within a tumor — called cancer stem cells (CSCs) — are responsible for:
Initiating the tumor
Driving growth
Causing recurrence
And resisting therapy
These CSCs behave like normal stem cells, but in a malignant way.
94
teratoma
classically defined as having two of the three embryonic layers (endoderm, mesoderm, ectoderm)
totipotent primordial germ cells can differentiate along some somatic lines to form these.
95
ectoderm derivatives
epidermis of skin + (sweat glands, etc)
lining of mouth and anus
cornea and lens of eye
nervous system
adrenal medulla
tooth enamel
epithelium of pineal and pituitary glands
96
mesoderm derivatives
notochord
musculoskeletal system
muscular layer of stomach and intestine
excretory system
circulation and lymph. systems
reproductive system - NOT germ cells tho
dermis of skin
adrenal cortex
97
endoderm derivatives
epithelial linings of GI, resp, urethra, bladder, and repro
liver
pancreas
thymus
thyroid and parathyroid glands
98
tumor angiogenesis
linked to tumor progression
a malignant tumor cannot grow larger than 1-2mm diameter unless it can induce angiogenesis.
need delivery of oxygen, nutrients, and removal of waste
growing tumors stimulate neoangiogenesis --> vessels sprout from previously existing capillaries
99
phases of tumor growth
avascular phase - nutrition solely from diffusion
vascularized phase -- diffusion alone is not enough to support tumor mass
100
neoangiogenesis
new vessels sprout from existing ones
new endothelium secretes growth factor like PDGF that stimulate growth of adjacent tumor cells
new vessels are leaky, dilated, haphazardly arranged and connected --> tumor cells can easily climb in --> vessel arrangement can affect anticancer drug deliver
101
what happens if angiogenesis is insufficient
tumor necrosis will occur
102
mechanisims of angiogenesis
1. adventitial cells and pericytes retract
2. basal membrane of pre-existing cells are degraded by proteases
3. endothelial cells migrate from pre-existing vessels toward the angiogenic stimuli and proliferate
4. migration of endothelial cells
5. endothelial cells that have migrated are structured into tubes to form capillary structures
6. structures mature into functional capillaries
7. blood flow initiated
103
stabilization of new vessels
E- Selectin - controls endo-endo interactions
mesenchymal cells --> express angiopoetin -1 --> binds to Tie-2 receptors on endos -->binding recruites more pericytes --> vessel sprouting and stabilization
104
initiation of angiogenesis
increased local production of angiogenic factors and/or loss of angiogenic inhibitors
factors produced by neoplastic cells or inflammatory cells (macrophages)
proteases produced by tumor cells or stromal cells regulate balance between pro- and anti- angiogenic factors--> can release proangiogenic factors like bFGF from extracellular matrix
105
initiation of angiogenesis
1. hypoxia leads to stabilization of HIF-alpha (oxygen sensitive transcription factor)
2. HIFalpha activates transcription of proangiogenic VEGF and bFGF --> they create an angiogenic gradient that stimulates proliferation of endos and growth of new vessels toward tumor. --> VEGF increases ligand expression that stimulate Notch signaling pathway which controls branching and density of new vessels
3. mutations in tumor suppressors and oncogenes can drive angiogenesis --> P53 normally stimulates expression of angiogenic factors --> gain of function mutation sin RAS or MYC upregulate the production of VEGF
106
tumor cell endothelial mimicry
aggressive, but NOT non-aggressive tumor cells can "mimic" other cell types in the expression of specific genes and in biological function --> epithelial to mesenchymal transition
can form vascular channels lined by tumor cells, without endothelium
107
anti angiogenic cancer therapy
target anti-angiogenesis therapy
targeting multiple angiogeneic apthways due to potential compensatory upregulation
--> VEGFr inhibitor
--> PDGFr inhibitor
--> MMP inhibitors (TIMP)
--> IFN gamma-inhibitor endothelial migration
--> thalidomide - inhibitor FGF, VEGF, TNFalpha
--> anti-VEGF abs
108
effects of neoplasm on host
space occupying
pressure atrophy
occlusion of passages
local tissue destruction
interference with vital function
109
diffuse intestinal lymphoma
malabsorption
protein- losing enteropathy
cancer associated cachexia
anemia of chronic disease
110
effects of neoplasm on host
infection
metabolic disturbances
paraneoplastic syndromes
cachexia
hyper coagulability
pain
anemia
111
metabolic distubances
pituitary adenoma --> ACTH secreting pituitary adenoma
chronic ACTH secretion causes bilateral hypertrophy/hyperplasia of adrenal cortical cells
112
metabolic distubances/paraneoplastic syndrom
apocrine gland adenocarcinoma --> hypercalcemia of malignancy
113
paraneoplastic syndromes
signs and symptoms that cannot readily be explained by the anatomic distribution of the tumor or the elaboration of hormones indigenous to the tissue from which the tumor arose
abnormal secretion of biological mediators --> both normal and abnormal to cell of origin
can be first manifestation of occult neoplasm
114
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