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biology of disease I > exam 3 > Flashcards

exam 3 Flashcards

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1
Q

Neoplasia nature

A

Irreversible abnormalities of:
-increased cell proliferation, arrested differentiation, decreased cell turnover (apoptosis)

Cellular immortality: cells lack normal senescence/turnover

malfunction of growth control genes: growth factors/receptors, cell cycle factors, apoptosis genes

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2
Q

How are neoplastic cell’s physiology altered

A

1) Self-sufficient growth- insensitivity to antigrowth signals, unlimited ability to divide: constant “on” signal

2) Evasion of apoptosis- progression thru cycle with abnormal DNA; fixation of the mutation

3) Sustained angiogenesis- tumor induced microvasculature supports increased tissue mass

4) Tissue invasion and metastasis- loss of inhibition by normal tissue barriers, cell surface molecules to attach and recognize new tumor bed, matrix enzymes to destroy normal barriers

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3
Q

Order of carcinogenesis

A

1) Initiation 2) Promotion 3) Progression

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4
Q

Initiation of carcinogenesis

A

DNA alteration- nonlethal, heritable to cell progeny, irreversible to change, produces no permanent morphologic change

through a single cell and there is a fixation of a lesion by a round of proliferation
*cell cycle checkpoints for checking the stability and integrity of cells

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5
Q

Promotion of carcinogenesis

A

a reversible step that follows initiation, clonal expansion of initiated cells, epigenetic changes (altered gene expression without altered DNA) and abnormal regulation and differentiation
-methylation of DNA and histone packaging, not DNA changed but how it is managed

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6
Q

Progression of carcinogenesis

A

the evolution of the malignant phenotype where there is a sequential appearance of more successful subclones; the population becomes heterogenous

acquire genetic instability- abnormalities of repair genes allows accumulation of genetic abnormalities

Tumor cells are selected for rapid growth, invasion, and metastasis

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7
Q

Is promotion reversible?

A

Yes, just remove the promoter and the tumor will regress

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8
Q

What is the only step in carcinogen initiation that is reversible?

A

Promotion

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9
Q

What steps in carcinogenesis development is there DNA mutation?

A

Initiation and Progression

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10
Q

What steps in carcinogenesis development is there a morphologic change in tissue?

A

Promotion and Progression

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11
Q

Proto-oncogenes

A

Mutations in these, cancer development is possible due to increased cell development
-Growth factors (stimulate cell surface receptors)
-Growth factor receptors/transmembrane proteins (initiate intracellular signaling through the cell membrane)
-Signal transducing proteins (inner membrane leaflet: start signal pathway to nucleus)
-Nuclear regulatory proteins (nuclear transcription factors - regulators of gene expression)
-Cyclins and cyclin dependent kinases- entry of quiescent cells into cell cycle

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12
Q

Chronic Myelogenous leukemia

A

abnormal fusion gene, called BCR-ABL which directs the production of abnormal tyrosine kinase, results in a philadelphia chromosome

Leads to dysfunctional regulation of cell growth and survival, ie drives proliferation of myeloid cells and longer cell survival.

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13
Q

Tumor suppressor genes

A

genes for slow proliferation and that suppress tumor development (normal cell proliferation control)
Loss of functional mutation (anti-oncogene)
Usually recessive alleles- must lose both for loss of control, double hit
Ex:
Retinoblastoma gene (Rb)-DNA binding protein, control of cell cycle
p53 gene- DNA proofreading, delay for repair or induction of apoptosis

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14
Q

Characteristics of Neoplastic cells

A
  • Immortality- lack of senescence,
    -Loss of anchorage dependence,
    -Decreased cell-cell adhesion,
    -Loss of contact inhibition
    -Altered intercellular communication
    -Increased motility
    -Decreased requirement for growth factors
    -Altered or new cell surface antigens
    -Abnormal karyotype
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15
Q

Telomeres

A

telomeres- specialized DNA protein complexes
cap ends of linear chromosomes. maintain genetic stability- protect DNA ends from being recognized as damaged thus preventing recombination or fusion

Play a role in aging and cell senescence: telomeres shortened with each cell replication, shortening is critical length triggers cell growth arrest

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16
Q

What normal cells circumvent telomeric senescence

A

male germ cells, activated lymphocytes, stem cells
telomerase adds telomeric base repeats back to the chromosome ends
immortalized cells express telomerase, thought to play a critical role in immortality of neoplastic cells
most canine neoplasms express telomerase

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17
Q

What characteristics of neoplastic cells change the arrangement of of cells

A

-Loss of anchorage dependence
-Decreased cell adhesion
-Loss of contact inhibition
-Altered intercellular communication

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18
Q

How do neoplastic cells have increased motility and mobility

A

through cytoskeleton activation

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19
Q

How do neoplastic cells have a decreased requirement for growth factors?

A

-Promotion of growth factors by other cells (Paracrine) that trigger signal transduction for cell proliferation

-Autoproduction of activated proto-oncogene coding for growth factor leading to the auto production of growth factors (autocine)

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20
Q

Route of spread

A

Direct local invasion
Blood vascular system
Lymphatics
Implantation
Transplantation

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21
Q

Lymphatic spread of tumor

A

-Dissemination to regional lymph node (typically localize in subscapular sinus, tumor cells may not establish metastasis in the node “skip metastasis”

-Regional lymph node (serves as a barrier/filter)

-Lymphatic involvement can precede systemic blood vascular involvement (ie via thoracic duct)

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22
Q

Stages of invasion and metastasis

A

-Invade extracellular matrix
-Penetrate vascular basement membrane and endothelium
-Move into/through blood or lymphatic stream
-Embolize/adhere at new site
-Penetrate vascular wall
-Grow at new site (only a few achieve this early on)

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23
Q

Monoclonality

A

a cell line that originates from a single progenitor (single cell) - and is therefore monoclonal
most tumors are monoclonal but some do have polyclonal origin

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24
Q

Regional transformation-polyclonal

A

exception to monoclonality where there is regional transformation
ofte polyclonal
-urinary bladder from the excretion of toxic metabolites
-Bronchial epithelium from inhalation of aerosolized toxic agents
-Type B leukemogenic virus (TBLV) lymphomas in mice
-Some Helicobacter induced enteric lymphomas of people

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25
Differentiation Arrest
-Cancer cell differentiation pathways do not function normally and tumor cells never fulyl mature -The level of arrest determines the degree of malignancy -Early arrest- malignant Late arrest- benign
26
Stem cells
long life span -allows accumulation of multiple genetic and epigenetic changes Extensive proliferation capacity Inherent ability to mobilize to remote sites, suggesting metastatic ability is acquired early in the tumor development Identification of small numbers of embryonic stem cells in canine neoplasms
27
What are the origins of neoplastic cells
1) Partially differentiated cell becomes differentiated and then immortalized 2) Stem cells- maturation arrest, tumor arises out of stem cells in a population
28
Latency
the period of time between initiation and the appearance of a clinically recognizable lesion -ex: it takes a long time for initiated cells to accumulate errors and present clinically
29
Tumor angiogenesis stages
avascular growth phase: a tumor where size is limited by diffusion vascular growth phase: growth dependent on adequate nutrients beyond what can diffuse --> avascular tumor necrosis
30
Tumor angiogenesis
the growth of new vessels from pre-existing vessels very closely linked essential for metastasis *vascular supply vessel formation is abnormal.
31
What are the two major mechanisms for angiogenesis?
1) Activation 2) Formation
32
Activation phase of angiogenesis
the first step of angiogenesis where 1)adventitial cells and pericytes retract 2) Basal membrane of pre-existing vessels is degraded by proteases from activated endothelial cells 3) Endothelial cells migrate from pre-existing vessels towards the angiogenic stimuli and proliferate 4) Migration of endothelial cells is based on cell-extracellular interaction mediated by vascular cell-adhesion molecules
33
Formation phase of angiogenesis
the second step of angiogenesis where: 1) endothelial cells form into tubal capillary-like structure and mature into function capillaries where blood flow is initiated 2) Dependent on E-selectin, transmembrane cell-adhesion glycoprotein; mediates endothelial cell-cell adhesion 3) Mesenchymal cells play a decisive role in the formation of mature blood vessels 4) After recruitment mesenchymal cells differentiate into smooth-muscle like pericytes, which cover the vascular tree
34
What are the regulators of angiogenesis?
-VEGF -bFGF -TGFalpha -EGF -TGFbeta -PDGF -IL-8 -TNFalpha
35
What are the three categories of carcinogens
1) Physical agents 2) Chemical gents 3) Biological (viruses, bacteria, hormones)
36
Actions of Chemical carcinogens
-Genotoxic: directly damage DNA -Non-genotoxic 1) Cytotoxic: induce cell necrosis with regenerative proliferation 2) Mitogenic: increased cell proliferation without necrosis
37
Incomplete carcinogens
only involve initiation (initial genetic error) -Promoter not involved
38
Complete carcinogens
involve both the initiation and promotion
39
Direct acting chemical carcinogens
do not require metabolism -Ex: alkylating agents
40
Indirect acting chemical carcinogens
metabolites are carcinogenic -Ex: polycyclic aromatic hydrocarbons, aromatic amines/Azo dyes/ alfatoxins, nitrosamines, metals
41
Genotoxic Alkylating agents
direct acting chemical carcinogens producing reactions with guanine in DNA (methyl or other alkyl groups are added, this inhibits base pairing and causes miscoding of DNA formation of cross-bridges/bonds in DNA (2 bases are cross-linked together by alkylating agent, this prevents DNA from being separated for synthesis or transcription) this causes mispairing of nucleotides, leading to mutations
42
Aflatoxins
toxic chemical produced by some fungal organisms (moldy corn, peanuts, grains, can have high aflatoxin content) the amount of aflatoxins correlates with the risk for liver disease and liver cancer
43
Prolactin link with mammary cancer
Prolactin regulates mammary gland differentiation and growth, in human breast cancer, there are increased prolactin receptors, circulating prolactin levels correlate with disease incidence High fat diet significantly increases serum prolactin levels in young bitches and high fat diet is also associated with early onset of first estrus. early onset of estrus is the best predictor of mammary neoplasia risk in dogs, dietary fat levels during reproductive development may be important in canine mammary tumorigenesis
44
Physical carcinogens
ionizing radiation -free radical-induced DNA injury, a complete carcinogen, cancer of virtually any tissue/organ radiation sources: nuclear weapons, medical diagnosis/therapy, industry occupational exposure, natural exposure
45
physical carcinogens- ultraviolet radiation
ultraviolet radiation leading pyrimidine cross-link formation in DNA developing skin cancer in humans/animals squamous cell carcinomas (white cats, hereford cattle, beagles)
46
Retinoblastoma gene product
interaction with viral protein inactivates pRb and is equivalent to mutation or loss of Rb gene as seen in retinoblastoma *Adenovirus EIA and protein, simian virus 40 large timor antigen and human papilloma virus E7 protein form a complex with pRb
47
Marek's disease
caused by an alphaherpesvirus (viral carcinogenesis) -Lymphoma in nerves and solid organs, vaccine is preventative, but in the face of infection can create carriers, newborn chicks are protected by maternal antibodies for a few weeks, virus is spread by inhalation of feather follicle dander
48
Feline sarcoma viruses
FeSV -arise through recombination of FeLV with parts of the host cell genome, no natural cat to cat transmission, tumors appear as multiple ulcerated or nodular non-healing lesions, metastasis may occur late in the course of the disease
49
What are examples of viral carcinogenesis?
-Papilloma viruses: Benign epithelial papillomas and squamous carcinomas, high tissue and species specificity, immunosuppression plays a role. Ex: Bovine papillomovirus (equine sarcoid) . oncogenic DNA virus -Herpes: Lymphoma in monkeys, Marecks (lymphoma in fowls), Lucke's renal carcinoma of frogs, Epstein-Barr virus in humans, oncogenic -Adenovirus: oncogenic virus -Polyomavirus: oncogenic virus -Retroviruses Acute transforming- sarcomas, rapid, efficient transformation, short latent period, contain viral oncogene, often replication deficient virus) (FeLV) (Chronic transforming- hematpoeitic neoplasms, leukemias and lymphomas, inefficient transformation; long latent period and no viral oncogenes) Include: Bovine leukosis, -Hepnavirus
50
Helicobacter pylori
a spirochere that causes gastric carcinoma in rodents, ferrets, cheetahs, and humans, gastric lymphoma in humans
51
Spirocerca lupi
a biological agent that causes esophageal fibrosarcomas in dogs
52
Inflammation associated sarcomas
Vaccine associated sarcoma/ trauma associated ocular sarcoma risk of cats developing sarcomas after administration of vaccine was approx 50% higher than in cats not receiving vaccines no single manufacturer or vaccine brand within an adjuvant class was found to be associated with sarcoma formation -Methylprednisolone acetate aqueous suspension, lufenuron flea control medication, and long acting penicillin
53
Direct effects of neoplasms on the host
-Occupying space -Pressure atrophy -Occlusion of passages -Local tissue destruction -Interference with vital function -Hemorrhage
54
Paraneoplastic syndromes
-infection- immune and inflammatory suppressions -Hormonal: Abnormal secretion of biological mediators (can be normal or abnormal to the cell of origin) -Cachexia- wasting effect of neoplastic tumors -Metabolic disturbances -Hematopoietic (hypercoagulability, Anemia) -Neuropathy
55
Cachexia (paraneoplastic syndrome)
characterized by marked weight loss, caused by IL-1, IL-6, and TNFa, nonspecific
56
`Nodular dermatofibrosis
Multifocal proliferation of fibrous tissue common in the german shepard common on the head and limbs *secondary and a marker for renal carcinoma because it has tumor derived growth factors
57
Hypertrophic osteopathy
a paraneoplastic syndrome where there is formation of periosteal new bone on the cortical region secondary and a marker to throacic masses (Inflammatory/infectious) and neoplastic Pathogenesis: -Vagus nerve compression -Increased blood flow to limbs -Stimulation of periosteal proliferation
58
Anemia (Paraneoplastic syndrome)
from erythrophagocytosis or bone marrow depletion
59
Eosinophilia (Paraneoplastic syndrome)
increased number of circulating eosinophils in response to mast cell tumor of T cell lymphoma Mediated by IL-5
60
Paraneoplastic disease for canine mast cell tumor
stomach ulcers, vomiting, and melena local swelling and bleeding, poor healing shock and death due to acute degranulation of the mast cell tumor
61
Paraneoplastic hypercalcemia
tumor that results in the release of PTHrP by tumor cells leading to increased calcium reabsorption in the gut and kidney, leading to bone resorption -Lymphoma, parathyroid gland tumors, anal sac gland adenocarcinoma
62
Insulinoma
a tumor of the islet in the pancreas that leads to hyperinsulinemia leading to hypoglycermia which results in death, collapse, nervousness, confusion, seizures, and coma
63
Adrenocortical adenoma
common in ferrets causing chronic estrogenic stimulation leading to alopecia, weakness, erythroid aplasia, vulvar swelling, and prostatic squamous metaplasia
64
Feline lung digit syndrome
a marker of lung tumors in cats that metastasize to the digit. Upon biopsy you would view pseudostratified columnar epithelim
65
Point of tumor grading and staging
Provides information beyond generalization about behavior and addresses heterogeneity of behavior (all tumors act different) Augments clinical decisions on therapeutic approach, permits comparison of therapeutic results across studies
66
What might tumor grade correlate with?
survival, metastatic rate, disease-free interval, frequency and or speed of local reoccurence
67
Pros/Cons of Tumor Grading
Pros: -Prognostically significant -Alter treatment decisions -Efficient -Cost effective -Traditional methods, no new tech needed Cons: -Tendency to drift to middle grades, small sample size, time consuming
68
Tumor staging
assessment of disease based on features of the primary lesion and the extent of disease in the body Describes extent of disease and also predictive of tumor behavior Along with grading is used to make treatment decisions
69
Canine Lymphoma Staging
I: single lymph node or group of nodes in one anatomic region II: many lymph nodes, but limited to one side of the diaphragm III: generalized involvement of lymphoid tissues beyond the lymph nodes IV: involvement of any non-lymphoid tissue (ex: liver)
70
Tumor grading criteria
-Degree of differentiation (does it look like normal tissue) -Mitotic index (cyclins,kinases, PCNA, Ki67) (number of mitotic index in 10 high powered fields) -Nuclear/cellular pleomorphism -Percent necrosis (eicoisanoids, cytokines) -Invasiveness (MMps, plasminogen activators, integrin expression) -Stromal reaction (growth factors) -Nucleolar size (RNA transcriptional activity, AgNORs) -Overall cellularity (growth fraction, apoptosis, tumor doubling time) -Inflammatory response (TNFa, IFNy, IL-2, MHCII, ICAM) *qualitative primarily
71
Survival (Increases/decreases) with advancing grade
Decreases
72
Canine Cutaneous Mast Tumors
Grade I: Confined to the dermis, lower cellularity, well-differentiated cells, monomorphic nuclei, no mitoses, minimal necrosis, ample granulated cytoplasm) Grade II: Dermis and subcutaneous, moderate cellularity, moderately pleomorphic cells, some nuclear pleomorphism, single nucleoli, 0-2 mitoses/HPF, some edema and necrosis, variable granulated cytoplasm Grade III: Deeply invasive, high cellularity, increased cellular pleomorphism, giant nuclear forms, multinucleated cells, prominenet nucleoli, 3-6 mitoses/HPF, common edema and necrosis, indistinct poorly granulated cytoplasm
73
What common mutation is present in grade II and III mast cell tumors?
tandem duplications with elongation of mutated c-kit dysregulation with ongoing activation of receptor without ligand binding
74
DNA microarrays
Tumor behavior is dictated by the expression of thousands of genes which allow clinical consequences to be predicted DNA microarray is a way to create a gene expression profile based on total cellular/tissue mRNA
75
VEGF
Vascular endothelial growth factor potent angiogenic factor and was first described as an essential growth factor for vascular endothelial cells. VEGF is up-regulated in many tumors and its contribution to tumor angiogenesis is well defined.
76
What are the classes of stromal cells of the tumor micro-environment?
1) Cancer-associated fibroblasts (CAFs) - mesenchymal lineage cells, likely abundant in non-malignant tumor ME. Recruited fibroblasts are in a chronic state of activation. activation associated with growth factors/cytokines, hypoxia, and reactive oxygen species 2) Angiogenic vascular cells (Endothelial cells and pericytes) 3) Infiltrating immune cells
77
How are CAFs positive regulators of cancer progression
1. Induction of angiogenesis- secrete chemokines to recruit bone marrow derived endothelial progenitor cells 2. Promotion of cancer cell migration and invasion- produce MMPs to degrade extracellular matrix (physical barrier to tumor migration), promote epithelial-mesenchymal trnasition (EMT) 3. help maintain cancer stem cell niches 4. metabol
78
What molecule is most important for recruitment of monocytes into the tumor bed
CCL2
79
All of the following are considered major non-malignant stromal cells of the tumor microenvironment except: a. Endothelial cells b. Macrophages c. Fibroblasts d. Squamous epithelial cells
d. Squamous epithelial cells
80
Exosomes
a mediator released by tumor cells that immunologically prime resident cells of metastatic sites to generate tumor permissive environments prior to arrival of tumor cells
81
Tumor neoantigens
after apoptosis, there is a release of anti-inflammatory mediators, dendritic cells still present antigen to CD8+ T cells since these are novoel protein sequences from non-synonymous protein coding they are not subjected to central T cell tolerance Can be recognized by both CD+ and CD8+ T cell subsets and are patient/tumor specific Clinically important as it might be a biomarker for clinical response to immunotherapy
82
Dendritic cells can acquire and present antigen and T cells on
both MHC class II (CD4) and class I (CD8)
83
CTLA-4
Cytotoxic t lymphocyte associated antigen 4: coinhibitory immune checkpoint molecule high in T cells of patients
84
Tumor elimination
transformed cells eliminated by the immune system; highly antigenic and result of the innate and adaptive immune systems working together
85
Tumor equilibrium
tumor cells incompletely eliminated by the immune system, continue to slowly divide, under strong immune pressure leading to the immune system selecting for poorly/non-antigenic tumor cells
86
Tumor escape
one or several tumor cell populations completely escape the immune response and begin to grow unchecked - clinically detectable through immunoselection (poor antigen tumor cells left, evades immune system) silenecing of tumor antigen expression (epigenetic after chronic T cell inflammation)
87
PD-L1
immune checkpoint molecule essential for preventing autoimmunity, (suppresses anti-tumor T cell responses) can be highly expressed by tumor cells and tumor associated antigen presenting cells (PD, macrophages)

biology of disease I (3 decks)

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