Block V, Week Viii

Front 1

what is the difference between a neoplasm and a tumor?

Back 1

neoplasm: uncontrolled tissue growth
tumor: space occupying neoplasm

Front 2

what are the two basic components in all neoplasms that are both benign and malignant?

Back 2

1. Parenchyma (neoplastic cell population)
2. Stroma (supporting connective tissue - NOT NEOPLASTIC)

Front 3

1. a desmoplastic tumor means...
2. a scirrhous tumor means...

Back 3

1. neoplasm stimulates formation of collagen in stroma (generally agressive)
2. neoplasm is hard (and slow growing)

Front 4

1. a neoplasm that does not penetrate or invade surrounding tissues is known as?
2. a tumor that has the ability to invade surrounding tissues and metastasize is known as?

Back 4

1. benign
2. malignant

Front 5

do benign tumors ever metastasize?

Back 5

NO - NEVER

Front 6

1. nomenclature (suffix) for a benign neoplasm?
2. nomenclature (suffix) for a malignant neoplasm derived from any one of the three germ layers?
3. nomenclature for a malignant neoplasm derived from mesenchymal origins?

Back 6

1. -oma
2. -carcinoma
3. -sarcoma

Front 7

Prefixes:
1. adeno-
2. squamous-
3. transitional, urothelial

Back 7

1. an epithelial neoplasm often forming glandular structures
2. an epithelial neoplasm resembling squamous epithelium
3. neoplasm arising from urothelium

Front 8

what does the prefix "terato" mean?

Back 8

a neoplasm made up of parenchymal cells derived from more than one germ cell layer. (most often all three)

Front 9

Prefixes:
1. lipo-
2. rhabdomyo-
3. leiomy-

Back 9

1. a mesenchymal neoplasm arising from adipocytes
2. a mesenchymal neoplasm arising from skeletal muscle cells
3. a mesenchymal neoplasm derived from smooth muscle cells

Front 10

Prefixes:
1. angio-
2. fibro-

Back 10

1. a mesenchymal neoplasm derived from endothelial or vascular cells
2. a mesenchymal neoplasm derived from fibroblasts

Front 11

a "papillo-" or "papillary" neoplasm would mean?

Back 11

a neoplasm with the (gross or microscopic) appearance of warty projections

Front 12

what would you expect to see in a "cysto-" or "cystic" neoplasm?

Back 12

a neoplasm with the (gross or microscopic) pattern of cystic spaces

Front 13

oat cell neoplasms are now termed?

Back 13

small cell neoplasms

Front 14

a benign neoplasm that contained mature cells indigenous to that site would be called?

Back 14

hamartoma

Front 15

a benign mass of histologically normal tissue found in an abnormal location would be called?

Back 15

choristoma

Front 16

1. adenocarcinoma
2. liposarcoma
3. squamous cell carcinoma

Back 16

1. malignant neoplasm of a gland producing tissue
2. malignant neoplasm arising from adipose tissue
3. malignant neoplasm arising from squamous cells

Front 17

1. melanoma
2. lymphoma
3. astrocytoma

Back 17

1. MALIGNANT neoplasm arising from melanocytes (exception to rules)
2. MALIGNANT neoplasm arising from lymphocytes (exception to rules)
3. MALIGNANT neoplasm arising from astrocytes of the brain (another exception)

Front 18

what is anaplasia

Back 18

a neoplasm with no differentiating features (can't determine cells of origin)

Most often associated with a malignancy

Front 19

which type of tumor is more biologically active: a well differentiated one or an anaplastic one?

Back 19

a well differentiated one

Front 20

1. which type of neoplasm is slow growing?
2. which type of neoplasm is known for rapid and erratic growth?

Back 20

1. benign
2. malignant

Front 21

1. what is grading
2. what is staging

Back 21

1. measure of histological differentiation
2. measure of clinical extent and progression

Front 22

how many "grades" for neoplasms are there?
what are they?

Back 22

four grades
grade I - well differentiated
grade II - moderately differentiated
grade III - poorly differentiated
grade IV - anaplastic

Front 23

how could tumor markers be useful?

Back 23

1. diagnosis (cell of origin)
2. treatment (certain receptors or genetic alterations)
3. early detection in serum
(monitor therapy response or recurrence)

Front 24

what does TNM in TNM staging mean?

Back 24

T - tumor (how big, how far spread)
N - nodes (spread?, distant?)
M - metastatic (where, how many)

Front 25

what are four effects the tumor can have on the host?

Back 25

1. local effects (compression, infarction, ulceration, hemorrhage)
2. hormonal/paraneoplastic effects
3. cachexia/metabolic effects
4. systemic effects

Front 26

what are para-neoplastic effects?

Back 26

secretion of hormone-like substances from the tumor

Front 27

what are the three cancers that most commonly cause para - neoplastic syndromes.

Back 27

Bronchiogenic carcinoma
Renal cell carcinoma
pancreatic carcinoma

Front 28

why do most cancer patients have hypercalcemia?

Back 28

metastatic lesions in the bone

Front 29

what para-neoplastic factors would be released in carcinoid syndrome? (3)

Back 29

seratonin
bradykinin
prostaglandin

Front 30

what would cause polycythemia?

Back 30

increased erythropoietin (or erythropoietin like substance)

Front 31

which hematologic change is commonly seen with chemotherapy?

Back 31

pancytopenia

Front 32

What is Trousseau's sign?

Back 32

A DVT is the presenting symptom in a number of cancers (mainly pancreatic cancer)

Front 33

what is Acanthosis nigrans?

Back 33

hyperpigmentation
hyperkeratosis
* half of patients that develop this have underlying cancer*

Front 34

which 2 inflammatory cells are involved with the inflammatory response to a tumor?

Back 34

T-cells
macrophages
mostly a cell mediated mechanism

Front 35

recently; which cancer has increased?
which 2 cancers have decreased?

Back 35

increased - lung
decreased - stomach, cervical

Front 36

what are some factors that cause variation in cancers?

Back 36

age
sex
race
geography
environmental

Front 37

currently, what are the 5 most common cancers in men?

Back 37

prostate
lung
colon
bladder
melanoma

Front 38

currently, what are the 5 most common cancers in women?

Back 38

breast
lung
colon
uterus
ovary

Front 39

what is an index cancer?

Back 39

cancer that occurs with the same frequency in all ethnic, racial and geopgraphic populations.
(prototype = Wilm's tumor)

Front 40

genetic damage lies at the heart of carcinogenesis. what are the two categories of ways this damage can occur?

Back 40

1. inherited in the germ line
2. aquired later in life by somatic cell mutation

Front 41

what do we mean when we say tumors are monoclonal?

Back 41

tumor came from a clonal expansion of ONE progenitor cell that had aquired a mutation (and sustained the genetic damage)

Front 42

if tumors are monoclonal - why do we see that tumors are heterogenous?

Back 42

all cells came from the same progenetor cell
-however-
they aquired additional individual mutations during the growth of the tumor making them heterogenous

Front 43

there are two classes of regulatory genes that are the primary targets of genetic damage leading to oncogenesis. what are they?

Back 43

1. oncogenes (growth promoting)
2. tumor suppressor genes (growth inhibiting)

Front 44

describe the genetics of growth promoting oncogenes

Back 44

growth promoting oncogenes are known as "dominant oncogenes"
* mutant alleles considered dominant*

Front 45

describe the genetics of tumor suppressor genes

Back 45

tumor suppressor genes are sometimes referred to as "repressive oncogenes"
* both allelles must be mutatant for transmission of effect*

Front 46

what can maybe account for the fact that a tumor progresses over time?

Back 46

mutations accumulate (cell becomes more anaplastic and heterogenous)

Front 47

where in the gene would the transcription and other factors bind to control the level of gene expression?

Back 47

regulatory region (non-coding region)

Front 48

what are some possible ways to alter gene expression?

Back 48

1. Change transcription factor levels
2. Mutate regulatory region that controls interaction with transcription factors or RNA polymerase
3. Translocation ("borrowed", new more powerful promoter)
4. mutation within coding area of the gene

Front 49

how does contact inhibition differ between normal and malignant cells

Back 49

normal - still have, grow as a single layer of cells
malignant - lost it, grow as a multilayer of cells

Front 50

would immortal cells in culture show normal or malignant characteristics?

Back 50

can show both (or either)

Front 51

oncogenes are derived from ?

Back 51

proto-oncogenes

*proto-oncogenes (normal) mutate into oncogenes*

Front 52

how were oncogenes first discovered?

Back 52

"hitchhiking" on retroviruses

(a result of recombination with the human genome)

Front 53

are human neoplasms normally caused by retroviruses?

Back 53

NO
(the retroviruses just assisted us in discovering the causative oncogenes)

Front 54

oncogenes cause alterations in what controls of cell growth and division? (4)

Back 54

1. growth factors
2. growth factor receptors
3. signal transduction (2nd messenger system)
4. transcription factors

Front 55

what is an autocrine loop?

Back 55

cell stimulates its own growth

-growth factor is normally overproduced
- excess growth factor binds to the same cells growth factor receptors resulting in further stimulation of growth factor production

Front 56

can increased growth factor alone cause neoplasia?

Back 56

NO

- increases risk of spontaneous or induced mutations
- favors progression

Front 57

what happens when there is a mutation in the growth factor receptor?

Back 57

persistent tyrosine kinase activity occurs (even when there is no growth receptor bound)

- result is continuous signal for cell division -

Front 58

what are the two most common types of mutations in the tyrosine kinase receptor that lead to neoplasia?

Back 58

1. point mutations
2. truncation

Front 59

besides mutation of the growth factor receptor, what is a common mechanism of growth receptor alteration resulting in neoplasia?

Back 59

overexpression of normal growth factor receptors

Front 60

what is the connection between expression of growth factor receptors and prognosis?

Back 60

the more the growth factor receptors are overexpressed -the worse the prognosis

Front 61

several oncoproteins mimic the function of the normal signal transducing proteins. which class of proteins is the "most important" in regards to oncogenesis?

Back 61

GTP-binding proteins
(Ras is one of them)

Front 62

describe the MOA of the unmutated Ras

Back 62

* cycles back and forth between active and inactive forms
* Inactive – bound to GDP
* Active – exchanges GDP for GTP
(ras is only activated for a short period: an intrinsic GTPase constantly returns ras to its inactive state)
* GAPs (GTPase activating proteins). “brakes” that prevent uncontrolled ras activity, they catalyze the inactivation of ras

Front 63

describe what happens when ras becomes an oncogene

Back 63

the mutated ras protein binds to GAP, but for some reason their intrinsic GTPases are not enhanced

* ras is trapped in the active state: results in unregulated signal transduction

Front 64

mutations affecting genes that encode nuclear regulatory proteins are associated with malignancy. what is the most common transcription factor that is mutated?

Back 64

myc gene is the most commonly involved in human tumors
(others include jun, fos)

Front 65

describe the MOA of the unmutated myc

Back 65

* c-myc moves to nucleus and forms a heterodimer with max
* c-myc/max heterodimer binds to DNA sequences in growth-related genes and activates transcription
* myc is tightly regulated and only expressed during parts of cell cycle

Front 66

what are the two major mechanisms that mediate conversion of a pro-oncogene into an oncogene?

Back 66

1. Change in Structure (ie. point mutation)
2. Change in Regulation (ie. translocation, gene aplification)

Front 67

1. describe a point mutation.
2. what is the best studied example?

Back 67

1. one base change in DNA sequence alters entire protein
2. Ras (ACTIVATION BY POINT MUTATION)

Front 68

describe a chromosomal translocation

Back 68

gene moves to a different chromosome (results in different regulation)

Front 69

2 types of chromosomal translocations that result in oncoprotein formation?

Back 69

1. translocation with overexpression (Burkitt's lymphoma)
2. translocation with genetic damage to gene (results in a newly formed gene)

Front 70

what is the result of amplification of gene expression?

Back 70

overexpression of protein products
(often an amplification of a transcription factor)

Front 71

retinoblastoma is caused by a mutation in what type of gene?

Back 71

caused by a mutation in the tumor suppressor gene

Front 72

inheritance pattern of Retinoblastoma?

Back 72

autosomal dominant
however; both normal alleles of Rb must be mutated for the development of retinoblastoma

Front 73

describe the two-hit hypothesis

Back 73

two mutations are required to cause cancer
- either one inherited and one somatic
-or-
- two somatic aquired mutations

Front 74

What is loss of heterozygosity?

Back 74

conversion of a genetic locus to homozygous: many tumors are associated with homozygosity

Front 75

give an example of two genes that, when they undergo loss of heterozygosity, mediate many human cancers?

Back 75

p53, Rb

Front 76

describe the regulation domains of the Rb gene

Back 76

regulation of cell growth

protein products are involved in
- cell cycle control
- regulation of apoptosis

Front 77

describe the mutation that occurs in the Rb gene

Back 77

MUTATION RESULTS IN LOSS OF GROWTH INHIBITION

loss of heterozygosity causes a defect in Rb protein function

Front 78

describe the MOA of the Rb gene

Back 78

active state - underphosphorylated form
inactive state - hyperphosphorylated form

* Rb is normally active: it stops cells from entering the S phase of the cell cycle. (does this by sequestering transcription factors)

* when cells are stimulated to divide the Rb protein is inactivated and the cell divides (transcription factors are no longer sequestered)
* Rb is activated again by dephosphorylation

Front 79

where do mutations of the Rb gene normally occur

Back 79

mutations involve the transcription binding domain of the Rb gene (transcription factors themselves can't be regulated)

Front 80

describe the concept of genetic instability and tumor growth

Back 80

constant, random mutations of cells that are already cancerous promotes malignancy

Front 81

most tumor supressor genes encode products that have what function?

Back 81

nuclear transcription factors
(Rb)

Front 82

is p53 a major player in the regulation of cell growth?

Back 82

NO
if the cell is unmutated, p53 is not present

Front 83

if both alleles of p53 are mutated what is the result?

Back 83

formation of mutations without a proofreading/repair function

* allows mutations to accumulate

* allows genetic instability to be fixed in the abnormal population

Front 84

why is p53 elevated when it is mutated in cells?

Back 84

mutation keeps p53 from degrading properly.
(tells us there is a mutation)

Front 85

what would happen if you had a p53 mutation in a cell that doesn't grow

Back 85

nothing
cell must be growing for mutation to have an effect

Front 86

it is not rapid growth that defines cancer, instead it is?

Back 86

progression of malignant cells that are
* genetically unstable
* do not undergo apoptosis

Front 87

what is the MOA of almost all chemotherapeutic agents?

Back 87

induction of apoptosis

(chemo resistance is usually because the cell will not undergo apoptosis)

Front 88

what is multistep carcinogenesis?

Back 88

cancer is not a result of one mutation in one gene.

*There must a mutation of several oncogenes and at least 2 tumor supressor genes*

Front 89

what is the growth fraction?

Back 89

the proportion of cells within a tumor that are in a proliferative pool

Front 90

describe the size of the proliferative pool as tumor size progresses

Back 90

early - most cells are within proliferative pool

late - most cells are not in proliferatiave pool

Front 91

how does the growth fraction help us clinically?

Back 91

a tumor with a larger growth fraction responds better to chemotherapy

(vs. lower growth fraction cancers - breast, colon - refractory to chemo)

Front 92

what do tumors do to obtain a blood supply

Back 92

they release ANGIOGENESIS FACTORS - factors that stimulate host blood vessel growth

Front 93

what else secretes angiogenic factors?

Back 93

inflammatory cells secrete them because they sense a necrotic area

Front 94

what are the three distinct steps in tumor invasion and metastasis?

Back 94

1. Invasion of the ECM
2. Vascular dissemination
3. Tumor cell growth in new location

Front 95

how exactly do tumor cells degrade the ECM?

Back 95

they secrete proteases (or induce host cell to secrete proteases)
* serine proteases
* cysteine proteases
* metalloproteases

Front 96

describe penetration of the basement membrane

Back 96

1. Loss of Cell Attachment
2. must attach to matrix
3. must degrade ECM
4. locomotion (migration through BM)

Front 97

what do tumor cells do when they are in circulation?

Back 97

they like to clump together

Front 98

can all tumor cells metastasize?

Back 98

NO
only a small percentage of cells can metastasize

Front 99

prostate cancer prefers to metastasize to?

Back 99

bone

Front 100

breast cancer prefers to metastasize to?

Back 100

bone

Front 101

ovarian cancer prefers to metastasize to?

Back 101

brain

Front 102

what are the two stages of chemical carcinogenesis?

Back 102

1. initiation
2. promotion
*neither are sufficient for tumor formation when they are alone*

Front 103

does initiation cause temporary or permanent damage?

Back 103

permanent

Front 104

in relation to chemical carcinogenesis:
what is the difference between a direct acting compound and an indirect acting compound?

Back 104

direct - requires no chemical transformation for carcinogenicity
indirect - require metabolic conversion

Front 105

in regards to chemical carcinogenesis:
what effect do promoters have on the 2nd messenger pathway?

Back 105

they speed the pathway up

*speeds up cell division*

Front 106

what effect do electrophiles have on DNA?

Back 106

electrophiles damage DNA

(they are attracted to DNA and proteins)

Front 107

what are two examples of radiation carcinogens?

Back 107

1. UV rays
2. Ionizing radation (X-rays, gamma rays)

Front 108

three wavelength ranges of UV rays?

Back 108

UVA
UVB
UVC - most carcinogenic: ozone layer keeps it out

Front 109

what is the only human retrovirus that is implicated in human cancer?

Back 109

HTLV-1
(Human T-cell Leukemia Virus type I -> luekemia/lymphoma)

Front 110

1. HTVL-1 binds to?
2. is transmitted by?

Back 110

1. CD4+ T cells
2. body fluids (semen/blood/breast milk)

Front 111

what are the three DNA viruses that show a strong correlation with human cancer?

Back 111

1. HPV
2. EBV
3. HepB

Front 112

what is an episome?

Back 112

a piece of DNA that is not integrated into the DNA.

Front 113

which DNA virus "lives" in an episome?

Back 113

EBV

(also, certain forms of HPV)

Front 114

EBV is associated with what type of cancer?

Back 114

Burkitt's lymphoma

(prone to develop in Africa: reason for this unknown)

Front 115

HBV is associated with what type of cancer?

Back 115

hepatocellular carcinomas

Front 116

what is the theory behind hepatocellular carcinoma caused by HBV?

Back 116

HBV damages hepatocytes
Liver regenerates
regeneration keeps going resulting in a tumor

Front 117

HPV is associated with what type of CA?

Back 117

Cervical cancer
(HPV DNA seen in 90-100% of cases)

Front 118

there are subtypes of HPV. which two are:
1. linked to warts?
2. indicated to cancer?

Back 118

1. HPV 6 and 11
2. HPV 16 and 18 (20% chance of developing CA)

Front 119

Describe the HPV lifecycle

Back 119

1. HPV infection requires a mucosal epithelial cell that is still able to proliferate
2. virus lies dormant in epithelial cells as they migrate and mature
3. close to the surface - virus replicates and infects cells

Front 120

what cells does HPV target?

Back 120

HPV targets the cells in the basal layer of the cervical epithelium

Front 121

HPV produces E6 - what does this protein do?

Back 121

E6 inactivates p53

Front 122

HPV produces E7 - what does this protein do?

Back 122

E7 inactivates Rb protein (sits in active site)

*results in uncontrolled cell division

Front 123

What about E2?

Back 123

CONTROLS expression of E5, 6, 7

(high risk HPV has a nonfunctional E2 = loss of control of expression)

Front 124

How is the HPV genome related to low and high risk of infection?

Back 124

low risk: HPV DNA is an episome, does not integrate into host cell
high risk: HPV DNA is integrated into the host chromosome (the integration cleaves E2 gene)

Front 125

what happens when the E2 gene is damaged?

Back 125

E6 and 7 are able to be active: they shut down p53 and Rb

Front 126

besides HPV, what are two other co-factors in generation of Cervical Tumors?

Back 126

smoking
immunosuppression

Front 127

anatomically, where does the HPV infect cervical cells?

Back 127

in the transition zone