Cancer Biology, Block 6

Front 1

Benign vs Malignant tumors

Back 1

BASED ON POTENTIAL
Benign: microscopic and gross characteristics are innocent. It is localized, doesn't spread and treatable with surgical intervention

Malignant = can invade and destroy adjacent structures. Can spread to distant sites. May cause death

Front 2

Two components of tumors

Back 2

Parenchyma (transformed cells)
Non-neoplastic Stroma (supporting cells that tumor needs for growth and survival such as connective tissue, blood vessels and inflammatory cells)

Front 3

Naming of benign tumors

Back 3

-oma
except for:
hepatoma
seminoma
melanoma
lymphoma
mesothelioma
myeloma
sarcoma
carcinoma

Front 4

What is an adenoma?

Back 4

benign tumor of the glands (from glands or in glandular pattern

Front 5

What is a papilloma?

Back 5

benign epithelial neoplasm, finger like projections
WARTS

Front 6

What is a polyp?

Back 6

mass that projects above the mucosal surface

Front 7

What is a cystaderoma?

Back 7

hollow cystic mass

Front 8

Sarcomas

Back 8

cancers of cells with mesenchymal origin (bone, cartilage, fat, connective tissue, and muscle)

Front 9

Carcinoma

Back 9

From epithelia, most common type of malignant tumor. Cancers can thus be in all three germ layers

Front 10

Lymphoma

Back 10

cancer arising from lymph nodes and tissues

Front 11

Leukemias

Back 11

cancer of immature blood cells that grown in the marrow and accumulate in the blood stream

Front 12

Benign vs Malignant: 4 things that separate them

Back 12

1) Degree of differentiation (malignant can be anywhere on differentiation scale but benign tumors are always well differentiated)
2) Rate of Tumor Growth (malignant is faster)
3) Presence of local invasion (malignant)
4) Ability to metastasize (only malignant)

Front 13

Better differentiated cells retain?

Back 13

functional capabilities or gain unintended functions

Front 14

Name two unintended functions gained by well differentiated tumors

Back 14

1) AFP ---> secrete fetal protein

ECTOPIC HORMONE SECRETION:
2) Small Cell Lung Carcinoma ---> ADH secretion causing hypernatremia
3) Squamous lung cancer ---> PTH causing hypercalcemia

Front 15

What is Anaplasia?

Back 15

malignant neoplasms of undifferentiated cells. It is a hallmark of malignancy

Front 16

Tissue and Cellular characteristics of Anaplasia

Back 16

Tissue: Loss of polarity, anarchic growth
Cellular: Pleumorphism (variation in size and shape), Hyperchromic and large nuclei (N:C ration increases); Chromatin clumping; Large nucleoli, and large # of mitoses with multiple spindles

Front 17

Grading is used to measure?

Back 17

differenciation

Front 18

Scaling is used to measure

Back 18

spread of primary tumor

Front 19

What is dysplasia? How is it different from malignancy?

Back 19

Disorderly but non-neoplastic proliferation normally in epithelium. Unlike malignancy it can be unchanged for long periods, regress spontaneously, progress to malignancy

Front 20

Cervical dysplasia and carcinoma

Back 20

Mild Dysplasia (CIN1) = failure of proper maturation lowest 1/3 of mucosa
Moderate Dysplasia (CIN II) = failure of maturation in cell in lower 2/3 of mucosa
Severe displasia (CIN III) = abnormality affects >2/3 of epithelia; mitoses at all levels
Carcinoma in situ = entire thickness replaced by atypical dysplastic cells, no orderly differentiation. Basement membrane NOT crossed

Front 21

Top three causes of cancer death in men and women

Back 21

Men: Lung/Bronchus, Prostate, Colon/Rectum
Women: Lung/Bronchus, Breast, Colon/Rectum

Front 22

Has lung cancer begun to decrease in men or women

Back 22

In men but in women it has only plateaued

Front 23

Death vs incidence for following cancers: Lung, Prostate

Back 23

Lung: new case=deaths
Prostate: new cases> deaths
Pancreatic: new cases = deaths
Breast: new cases> deaths

Front 24

Cancers and stages

Back 24

Early: Breast, colorectal, melanoma, prostate
Late: Lung, ovary pancrease

Front 25

What cancer peaks at middle age?

Back 25

Testicular

Front 26

What cancer has a bimodal distribution?

Back 26

Hodgekins

Front 27

Oncogenes are?
Tumor Supressor Genes are?

Back 27

Oncogenes are growth factors: prepare cells to divide, stimulate proliferation
Tumor Supressor Genes are Growth Inhibiting Factors: CDK inhibitors (CIP/INK 4a) which inhibit cyclin D/cdk4 and cyclin E/cdk2; Also RB which is a cell cycle regulator at G1-S transitions

Front 28

What cyclin is over expressed in B Cell lymphomas, carcinomas?

Back 28

Cyclin D

Front 29

Cyclins and their CDK

Back 29

D - 4
E - 2
A - 2
B - 1

Front 30

CDK inhibitors regulating G1, G2

Back 30

p21 and p27 (CIP and INK) -->induced by p53 in response to DNA damage, slowing cell cycle
p16 (INK4a): inhibits cyclin D/cdk4, inactive in cancers

Front 31

How many alleles need to be altered in protooncogenes?

Back 31

only 1 confers gain of function mutation

Front 32

Oncogene point mutations

Back 32

K-Ras (colon, lung, pancreas), H-Ras (bladder, kidney), N-Ras (melanoma)

Front 33

What is the most frequently activated oncogene?

Back 33

RAS

Front 34

What is RAS

Back 34

a G protein stimulated by growth factors that activates the MAP kinase pathways, activating transcription and helping cell cycle progression

Front 35

RAS mutation

Back 35

Gain of function mutation at codon 12 or 61. Alters GTPase activity, can't hydrolyze GTP and RAS is always turned on

Front 36

What does MYC Proto-Oncogene do?

Back 36

It is a transcription factor. Its over expression has the same functional consequence as RAS

Front 37

Translocations causing oncogenes

Back 37

ABL proto-oncogene translocation resulting in chronic myelogenous leukemia (slow progressing, enlarged spleen, fatigue);

Front 38

What is the diagnostic marker for chronic myelogenous leukemia?

Back 38

Philadelphia Chromosome

Front 39

What is used to cure CML?

Back 39

Drugs that target BCR-ABL fusion kinase (which insert into the catalytic cleft)

Front 40

How to diagnose CML?

Back 40

Lots of leukocytes seen in blood smear; Diagnostic Hallmark of CML is the Philadelphia Chromosome

Front 41

What is the philadelphia chromosome?

Back 41

a translocation between a portion of chromosome 9 and chromosome 22, forming a BCR-ABL Oncogene with unregulated tyrosine kinase activity. The fusion gene has self sufficiency of growth signals, insensitivity to growth-inhibitory signals, evasion of apoptosis.

Front 42

Example of Gene Amplificaiton

Back 42

L-MYC oncogene is amplified with some types of tobacco smoking;
N-MYC amplification in neuroblastoma

Front 43

How can gene amplification be present?

Back 43

Double minutes (pieces of genes)
OR
Homogenous-staining regions (HSR) ---> when copies integrated into chromosome

Front 44

Overexpression of growth factor receptors, two examples

Back 44

1) EGF-R in some lung cancers
2) HER2/NEU oncogene in 30% of patients with invasive breast cancer.

Front 45

A subset of non-smoking women develop adenocarcinomas of the lung as a consequence of?

Back 45

Overexpression of EGF-R. Can be treated with drugs that inhibit EGF-R signaling such as Cetuximab (binds EGF receptor), Trastuzumab (binds EGF) Erlotininb and Gefitinin (blocks activity of EGF receptor)

Front 46

What is the gene that is a prognostic marker in breast cancer?

Back 46

HER2/NEU...overexpressed in cancers...can see using FISH or Immunohistochemistry

Front 47

What is a therapeutic target in breast cancer?

Back 47

HER2/NEU...Antibodies (Herceptin) block extracellular domain of HER2/NEU and prolong survival of this subset of women with breast cancer.

Front 48

Transformation of what causes cancer?

Back 48

A single progenitor cell that incurred genetic damage and undergoes clonal expansion ---> monoclonal nature of tumors

Front 49

When tumor is clinically detectable, what portion of its life cycle has occurred?

Back 49

30 doublings before it's detectable and 10 doublings afterward.

Front 50

What is tumor heterogeneity?

Back 50

A tumor becomes heterogenous over time although it begins monoclonal in origin ----> result of multiple mutations that accumulate independently of different cells. Subclones that beat the odds become cancer genes.

Front 51

Four classes of normal regulatory genes

Back 51

1) growth promoting proto-oncogenes
2) growth inhibiting tumor suppressor genes
3) genes that regulate apoptosis
4) Genes involved in DNA repair

Front 52

How do cancer cells develop limitless replication potential?

Back 52

Telomerase activation in cancer cells void the telomere time clock which usually limits the proliferative capability of normal somatic cells. You first have shortened telomeres, which, in the absence of p53, form dicentric chromosomes which replicate to form new double stranded breaks. These cells can survive and be cancerous if telomerase activity is present.

Front 53

What is tumor heterogeneity?

Back 53

A tumor becomes heterogenous over time although it begins monoclonal in origin ----> result of multiple mutations that accumulate independently of different cells. Subclones that beat the odds become cancer genes.

Front 54

Four classes of normal regulatory genes

Back 54

1) growth promoting proto-oncogenes
2) growth inhibiting tumor suppressor genes
3) genes that regulate apoptosis
4) Genes involved in DNA repair

Front 55

How do cancer cells develop limitless replication potential?

Back 55

Telomerase activation in cancer cells void the telomere time clock which usually limits the proliferative capability of normal somatic cells. You first have shortened telomeres, which, in the absence of p53, form dicentric chromosomes which replicate to form new double stranded breaks. These cells can survive and be cancerous if telomerase activity is present.

Front 56

How do tumors sustain angiogenesis?

Back 56

Induced by hypoxia; Normally VHL (Von Hipple Lindan Factor) binds to HIF-1alpha and is destroyed. However in hypoxia, HIF-1alpha cannot bind (a process that requires oxygen), translocates to the nucleus and activates VEGF.
In addition, FGF is released by stroma and tumor cells in ECF

Front 57

What type of cancer invades but rarely metastasizes?

Back 57

Basel Cell Carcinoma

Front 58

In general, the more anapestic the more likely to metastasize. There is one exception, what is it?

Back 58

Small cell lung carcinoma

Front 59

What are the steps in tumor invasion?

Back 59

1) Detachment of tumor cells from each other via loss of E-cadherin function. B Catenin are part of this complex, and allow for the transmition of antigrowth signals.
2) Local degradation of basement membrane and interstitial connective tissue via secretion of proteolytic enzymes (MMPS, Cathesin, Urokinase Plasminogen Activator)
3) Activation of tumor cells to ECM proteins via fibronectin and lamin receptor
4) Migration that involves many receptors and signal transmit ion pathways that converge on actin skeleto; Tumor derived cytokines cleave products of matrix and growth factors; Stromal cells produce growth factors like HGF, SCF

Front 60

What are the three pathways of metastasis and what types of cancers take them

Back 60

1) direct seeding (neoplasm invades body cavity) in ovarian cancer
2) Hematogenous spread (lung and liver) favored for sarcomas, usually venous
3) Lymphatic system, favored for carcinomas

Front 61

What is the Knudson Hypothesis?

Back 61

Retinoblastoma results from 2 mutations in the following senarios:
1) Hereditary: 1st mutation is germinal, present in all cells. Second mutation is only in retinoblast. Tumor is in both eyes.
Non-hereditary: Two somatic mutations, usually only one eye

Front 62

Is retinoblastomas a autosomal dominant or recessive condition

Back 62

dominant; these individuals are also susceptible to bone tumors, soft tissue sarcomas.

Front 63

How is RB lost?

Back 63

Deletion, point mutation, functional inactivation by viral oncoprotein, epigenetic silencing via methylation

Front 64

How do microRNAs play a role in cancer?

Back 64

Function is to control cell growth, differentiation, and cell survival.
MicroRNAs can increase expression of oncogenes or reduce expression of tumor suppressor genes.

Front 65

What is the normal function of RB

Back 65

Rb is normally hypophosphorylated in a complex with E2F in GI. It prevents cell cycle progression by sequestering E2F and by recruiting histone deacetylases and methyltransferases which bind to promoters of E2F-resposive genes on Cyclin E--->
However, mitogenic signaling leads to cyclin D expression and activation of Cyclin D Cdk4/6 complexes. Cyclins complexes phosphorylate E2F/RB resulting in release of EF2 which activates transcription of S phase genes

Front 66

What controls cyclins?

Back 66

Growth inhibitors such as TGF-B and p53 activate CDK inhibitors (p16, INK4a)----> inactivate cyclins
Growth factors EGF and PDGF----> activate cyclin

Front 67

An epigenetic point mutation in CDK inhibitors results in what?

Back 67

lack of CDK inactivation and thus growth (melanoma, pancreatic, esophageal, breast

Front 68

What would mimic RB loss?

Back 68

CDK4 overexpression
Cyclin D overexpression, amplification, translocation
CDK21 (p16) inactivation

Front 69

where is p53 located

Back 69

On chromosome 17, it is a tumor suppressor gene

Front 70

There is homozygous loss of ___ in almost all cancers

Back 70

p53

Front 71

mutations of p53 are usually inherited or somatic?

Back 71

somatic

Front 72

What is an example of an inherited p53 mutation?

Back 72

Li-Frauremi Syndrome (younger age, multiple sites)

Front 73

What is normal p53 function?

Back 73

- Arrests cell cycle in G1 to repair damaged DNA via p21 (CDKI)
- Repairs DNA via GADD45
- Transcribes BAX leading to apoptosis

Front 74

p16 inactivates?
p21 activates

Back 74

cyclins (tumor supressor)
CDKIs (leading to G1 arrest)

Front 75

What senses DNA damage

Back 75

ATM/ATR "sensors" which are protein kinases ----> phosporylate various targets (incl. p53 and DNA-repair proteins) and pause cell cycle and stimulation of DNA repair problems.

Front 76

what's p53's relationship with microRNA?

Back 76

p53 activates transcription of mir34 microRNA, which binds to cognate 3' untranslated regions. This 1) inhibits translation of growth promoting genes like MYC and CDK4 and inhibits translation of anti-apoptotic genes like BCL-2

Front 77

What is the role of MDM2?

Back 77

In non-stressed cells, p53 has a short half life, associating with MDM2 makes it inactive and undergoes degradation.
Under conditions of stress, p53 undergoes post-transcriptional modifications that release it from MDM2, prolonging its half life

Front 78

Binding of MDM2 to ARF does what?

Back 78

MDM2 can no longer interact with p53, activating it

Front 79

If you lose ARF, you lose or gain p53 function

Back 79

Lose it

Front 80

What does TNM stand for?

Back 80

----system of staging-----
T = size of Tumor
N = Nodal involvement
M - Metastases

Front 81

Functional loss of p53 can be due to what?

Back 81

1) mutation of p53
2) binding to viral oncoproteins (HPV viral oncoprotein E6)
3) Increase in MDM2
4) Deletion of p14ARF indirectly inactivates tumor suppressor pathway

Front 82

What is APC? What is it's function?

Back 82

Its a member of another class of growth suppressor genes and is part of the WNT signaling pathway. It's function is to down regulate B-Catenin. In resting cells, B-Catenin is bound to APC and destroyed. When cells are stimulated by WNT molecules, the destruction complex is deactivated, and degradation does not occur and cytoplasmic levels increase. B-Catenin translocated to nucleus and activates genes involved in Cell cycle progression. When APC is mutated, destruction of B catenin cannot occur---->cells under constant stimulation.

Front 83

What happens if there is a germ-line mutation of APC

Back 83

You can get the disorder "Familial Adenomatous Polyposis" in which individuals who inherit a single mutant APC allele develop thousands of adenomatous colon polyps in teens or early twenties....colon cancer is inevitable by 50.

Front 84

Relationship between APC and Colon cancer

Back 84

Normal APC but activating mutations in B-Catenin so that it is not destroyed.

Front 85

What is the progression of mutations for colon cancer?

Back 85

1) loss of one normal APC gene occurs early followed by inactivation of second APC gene later in life.
2) K-Ras mutation
3) p53 mutation, LOH, SMAD 2 and 4 (TGF-B)
4) Telomerase

Order is irrelevant. It's their accumulation that matters

Front 86

Mechanisms for Self sufficiency in growth signals?

Back 86

RAS mutation, MYC amplification, BCR-ABL translocation, EGF-R activation

Front 87

Mechanisms for Insensitivity to growth inhibitory signals

Back 87

BCR-ABL oncogene, pRb inactivation, p16 or INK4a, inactivation of APC

Front 88

Evasion of Apoptosis - mechanisms

Back 88

p53 mutations, BCR-ABL

Front 89

Limitless replication potential mechanisms

Back 89

activation of telomerase, inactivation of p53

Front 90

mechanisms for development of sustained angiogenesis

Back 90

overexpression of angiogenic factors, activation of HIF-1alpha

Front 91

mechanisms for ability to invade and metastasize

Back 91

inactivation of E-cadherin and cell-cell contact, activation of proteases, enhanced motility

Front 92

What is Cowden Syndrome?

Back 92

PTEN mutations, which is a tumor suppressor gene
Presents: Big head, autism
Facial and bucal lesions

Front 93

What is Li Fraumeni Syndrome?

Back 93

Inherited p53 mutation
Early onset sarcome, leukemia, Brain cancer,
Adrenocortical cancer
Breast Cancer

Front 94

What is Peutz Jeghers syndrome?

Back 94

Autosomal dominant mutation in tumor supressor gene.
Presentation:
Childhood GI heratomas
Pigmentation of lips, freckles on lips and fingertips

Front 95

Prophylactic mastectomy reduces risk by how much? What about oophorectomy?

Back 95

Decrease BC by 90%.
Decrease BC by 50% and Ovarian by 90%

Front 96

Evolutionary theory of aging

Back 96

aging confers a evolutionary advantage
selection pressure based on older individual being less useful

Front 97

Mutation accumulation theory

Back 97

mutation that kills late in life will not be selected against.
Aging is NON-Adaptive

Front 98

Disposable Soma Theory

Back 98

longevity, reproduction, and antagonistic pleiotrophy
1) Sexual reproduction may be at the expense of longevity (Bamboo)
2) gene or gene product has two effect: beneficial and detrimental (Antagonistic pleiotrophy (e.g., high testosterone)

Front 99

R selection

Back 99

density independent
selects for high reproductive rate
hazardous environment
rapid development, small body size, short life span (mice)

Front 100

K Selection

Back 100

Density dependent
selects for survival at max density.
Non hazardous environment
Delayed development, larger body size, longer lifespan

Front 101

mitochondrial DNA damage in comparison to nuclear?

Back 101

Mt DNA is more susceptible to ROS and it has worse repair mechanisms but the impact is less because it is redundant

Front 102

What is cellular senescence?

Back 102

loss of cell's ability to replicate.
senescent cells are larger than proliferating cells;
most common cause is telomeres shortening

Front 103

Hutchinson-Gilford Progeria syndrome is the result of what?

Back 103

Point mutation in LMNA gene (truncated form called progerin) which results in problems with Lamin A (nuclear envelope) making it hard for cells to divide

Front 104

What are some examples of changes in gene expression as we age

Back 104

decreased transcription of growth and stress related genes.
Increased transcription of inflammatory cytokines and matrix mellaloproteinases

Front 105

longevity is related to what?

Back 105

insulin and IGF-1
Decreased daf-2 expression in worms
size and height
caloric intake

Front 106

How does one tell you got the whole tumor when excising?

Back 106

You ink the margins and see if it has positive or negative margins. H and E most often used.

Front 107

What is the most common dye used in surgical pathology?

Back 107

H and E (Hematoxylin --basic, blue; Eocin - Acidic, red)

Front 108

what is the gross appearance of colonic adenoma

Back 108

strawberry

Front 109

Tumor staging is done how?

Back 109

Tumor (primary) --- 1 (mucosa) and 2 (musularis propria)
N (Node) - 3 (lymph node)
M (Metastasis) -4 (distant site)

Front 110

what the benefit of freezing pathological sections

Back 110

rapid, but lower quality, labor intensive

Front 111

Prussian blue dye stains?

Back 111

Iron

Front 112

Trichrome dye stains?

Back 112

Collagen (Fibrosis)

Front 113

Verhoeff dye stains?

Back 113

Elastin

Front 114

Ziehl Nielsen dye stains?

Back 114

Mycobacteria

Front 115

Silver Methanamine stains

Back 115

Fungi

Front 116

Why to use immunohistochemistry

Back 116

- identify origin of poorly differentiated or undifferentiated cells
- subclassify lymphomas, identify metastases, prognostic information

Front 117

What receptors can be identified using immunohistochemistry

Back 117

estrogen (TOMAXIPHAN)
progesterone
Her2/NEU (HERCEPTIN)

Front 118

Colorectal cancers over express?

Back 118

EGF-R

Front 119

EGF-R therapy can be given to which patients?

Back 119

Patients without K-Ras mutation.

Front 120

Lynch Syndrome

Back 120

MLH-1 mutations leading to bad DNA repair.

Front 121

What is used to stain astrocytomas?

Back 121

GFAP stains intermediate filaments of astrocytes

Front 122

What are the specialized cells of the CNS that line the ventricular system?

Back 122

Ependymal cells

Front 123

What produces CSF

Back 123

Choroid Plexus

Front 124

tumor of the neurons

Back 124

ganglioctyoma

Front 125

how do you stage brain tumors?

Back 125

You can't:
1) no CNS lymphatic drainage
2) No concept of margins (bc infiltration is the rule)
3) Rarely metastasize to lower origins

Front 126

What is the only proven environmental factor for brain tumors?

Back 126

Radiation:
given for TInia Capitis, brian tumors, acute lymphoma leukemia. Most come type of cancer is Meningioma 10 years post exposure

Front 127

Grading Brain Tumors

Back 127

1+ AMEN factor (1=Pilocytotic Astrocytoma, 2=Astrocytoma, 3=Anaplastic Astrocytoma, 4=Glioblastoma)
Atypia (of nucleus)
Mitoses
Endothelial proliferation of capillaries
Necrosis

Front 128

Genetic characteristics of primary and secondary glioblastomas

Back 128

Primary is usually EGF-R over expression
Secondary is usually Tp53 gene mutation

Front 129

When do you have a duty to warn?

Back 129

Special relationship
identifiable victim
harm in the forceable future and its serious

Front 130

When do you test children

Back 130

- with risk for genetic disease that has preventative measures (YES)
- If there are no available treatments but onset is in childhood, parent has discretion
- If onset is in adulthood and there are no preventable measures, then recommended NO
- discouraged for benefit of other family members

Front 131

GINA Act

Back 131

Can't discriminate based on genetic conditions.