Robbins Neoplasia pg. 1-45 Flashcards
1
Q
T or F: Cancer cells are subject to Darwinian selection.
A
T
2
Q
What does the phrase “all tumor cells are clonal” mean?
A
they arise from 1 cell
3
Q
What are the 8 hallmarks of cancer?
A
- autonomous growth (don’t rely on outside growth signals)
- unregulated growth (do not respond to inhib signals)
- evade death (do not undergo apoptosis) in in conditions normal cells would
- limitless replication
- angiogenesis
- invade tissues and spread to other tissues
- reprogram metabolic pathways
- evade immune system
4
Q
What is the (simplest) distinction between a malignant and a benign tumor?
A
benign: remain localized and can be removed surgically
Malignant: the lesion can invade and destroy adjacent structures and spread to distant site to cause death
5
Q
What to malignant and benign tumors have in common? (think structure/organization)
A
same 2 basic components: parenchyma and stroma
6
Q
What are the transformed cells in a turmor called?
A
parenchyma
7
Q
What is the stroma? (in a tumor)
A
supporting, non-neoplastic cells in a tumor
8
Q
What type cells can make up the stroma?
A
connective tissue, blood vessels, inflammatory cells (host derived ones)
9
Q
What does the suffix “-oma” mean?
A
usually indicates a benign tumor
10
Q
What are papillomas?
A
benign epithelial neoplasms
11
Q
What shape does a papilloma take?
A
finger-like fronds (macro and microscopic)
12
Q
What is a polyp?
A
benign mass that projects from a mucosal surface (macrscopic)
13
Q
WHat is a benign hollow cystic mass that usually arises in the ovary?
A
cystadenomas
14
Q
What is an adenoma?
A
benign epithelial tumor producing a gland pattern (diff pattern than papillomas)
15
Q
What are malignant neoplasms that arise in solid mesenchymal tissues?
A
sarcoma
16
Q
What are malignant neoplasms that arise from mesenchymal blood cells called?
A
leukemias and lymphomas
17
Q
What are carcinomas?
A
malignant tumors of epithelial cells
18
Q
What are carcinomas that grow in a glandular pattern?
A
adenocarcinomas
19
Q
What are malignant squamous cell tumors called?
A
squamous cell carcinomas
20
Q
What is divergent differentiation?
A
All tumors have a monoclonal origin but at some point during a tumors development it can switch types to create a mixed tumor
Ex: mixed tumor of salivary gland can have epithelial components dispersed in a fibromyxoid stroma with islands of cartilage or bone
21
Q
What is another name for a mixed tumor?
A
pleomorphic adenoma
22
Q
What type of malignant tumor contains recognizable mature or immature cells/tissues of more than one germ layer?
A
Teratoma
23
Q
From what do teratomas originate from?
A
totipotential germ cells such as those present in the ovary and testies (often from more than one germ layer) * they are malignant
**Since they are totipotent in origin, the tumors often have many diff cell types in them (bone, nerve, muscle, fat, etc)
24
Q
What malignancies end in “-oma”
A
lymphoma, melanoma, mesothelioma, and seminoma (testicular epithelium)
25
What is a mass of disorganized tissue indigenous to particular site?
Hamartoma (i.e. a nodule in the lung containing cartilage, bronchi, and blood vessels)
26
What is a congenital anomaly consisting of a heterotopic rest of cells? (i.e. organized pancreatic tissue found in the submucosa of the stomach)
Choristoma
27
What are the 4 fundamental features by which benign and malignant tumors can be distinguished?
1. differentiation and anaplasia
2. rate of growth
3. local invasion
4. metastasis
28
In what part of the tumor is differentiation and anaplasia seen?
parenchymal cells
29
The differentiation of tumor cells refers to ...
the extent to which tumor cells resemble their normal cell counterparts.
30
Describe the difference in differentiation between benign and malignant parenchymal cells?
benign cells are well differentiated and closely resemble their normal counterparts
Malignant cells have a wide range of differentiation--looking similarly and vastly different from their normal counterparts
31
What does it mean for a neoplasm to be anaplastic?
it is composed of undifferentiated cells
32
If cells are anaplasic, are they more likely to be malignant or benign?
malignant
33
Describe the microscopic appearance of anaplastic cells.
- vary in size and shape (pleomorphic)
- extremely hyperchromatic (dark staining)
- larger nuclei (almost equal amt of nucleus to cytoplasm)
- giant cells
- variable shaped and sized nuclei
- numerous mitoses (and can br atypical)
34
In a neoplasm, what are giant cells?
big cells that can contain an enormous nucleus or several nuclei
35
T or F: The more rapidly growing and more anaplastic a tumor, the less likely it is to have specialized functional activity.
true
36
What is the loss in the uniformity of individual cells and their architectural orientation?
dysplasia
37
In what type of cells does dysplasia principally occur?
epithelial cells
38
T or F: Dysplasia is a type of neoplastic proliferation
F not neoplastic (can develop into neoplasia)
39
What is a dysplastic change involving the entire thickness of the epithelium?
carcinoma in situ
40
What is a pre-invasive stage of cancer?
carcinoma in situ
41
T or F: Mild to moderate dysplasia that does not involve the entire thickness of the epithelium can regress completely.
True: IF the inciting cause is REMOVED
42
In general, _____ tumors grow slowly and ____ tumors grow much faster.
benign; cancer
43
In general, do poorly or well differentiated malignant tumors grow faster?
poorly differentiated
44
A benign neoplasm does not have the capacity to ...
infiltrate, invade, or metastasize to distant sites
45
encapsulated neoplasms are ______
benign
46
T or F: all benign neoplasms are encapsulated
F: they are not all encapsulated
47
Cancers grow by progressive ...
infiltration, invasion, and penetration of the surrounding tissues
48
Next to metastases, _____ is the most relable feature that distinguishes malignant tumors from benign tumors.
local invasiveness
49
In general, what characteristics increase the likelihood of metastatic spread?
more anaplastic and larger neoplasms
50
What are the 3 pathways that malignant tumors spread?
1. seeding within body cavities
2. lymphatic spread
3. hematogenous spread
51
Carcinomas typically spread via _____
lymphatic spread
52
Sarcomas typically spread via _____
hematogenous spread
53
What is a "skip metastases"?
cancer is not found in lymph nodes near the primary site... it spreads and seeds in lymph nodes far away from
54
What is a sentinel lymph node?
first regional lymph node that receives lymph from a primary tumor
55
Enlarged lymph nodes near the primary neoplasm does not always indicate metastatic spread. Why?
necrotic products of the neoplasm and tumor Ags often evoke immunologic responses
56
Are arteries or veins penetrated by tumors more readily?
veins
57
What organs are most frequently involved in secondary sites of hematogenous dissemination? Why?
liver and lungs
bc all portal veins drain to the liver and all caval veins drain to the lungs
58
Most cancer deaths occur between ages ...
55 and 75
59
Autosomal dominant cancer syndromes typically involve the inheritance of ...
a single mutant gene that greatly inc the risk of developing a tumor (i.e. inheritance of a germ line mutation of a cancer suppressor gene)
60
Autosomal recessive cancer syndrome are characterized by ...
chromosomal or DNA instability (usually defect in DNA repair)
61
What are the features of familial cancers?
- early ago of onset
- tumors in 2 or more close relatives
- multiple or bilateral tumors
62
What are pre-neoplastic lesions?
aquired condition that inc the likelihood of malignancy but does not always (or usually) progress to cancer. Their removal or reversal may prevent the development of cancer.
***HOW is this different than dysplasia... Is it different??
63
Autosomal dominant or recessive mode of inheritance for development of cancer?
defects in DNA repair
recessive
64
Autosomal dominant or recessive mode of inheritance for development of cancer?
mut tumor suppressor gene
dominant
65
T or F: lethal genetic damage lies at the heart of carcinogenesis
F: non-lethal
66
What are the principle targets for genetic damage leading to cancer?
1. growth-promoting proto-oncogenes
2. growth inhibiting tumor suppressor genes
3. genes that regulate apoptosis
4. DNA repair genes
67
What are oncogenes and what are proto-oncogenes?
proto-oncogenes are normal cellular genes that are mutated to become oncogenes (oncogenes induce a transformation of phenotype)
68
What do most oncogenes encode?
Tx factors, growth regulating proteins, proteins involved in cell survival, proteins involved in cell-cell or cell-ECM interactions
69
T or F: usually only 1 allele of a tumor suppressor gene needs to be damaged for transformation to occur.,
F: both alleles
70
What is haploinsufficiency?
When 1 mutated allele can cause a disease phenotype
71
What are the 2 groups of tumor suppressor genes?
guardians and governors
72
What is the difference between governor and guardian tumor suppressor genes?
governor genes encode a factor that inhibits growth while guardian genes sense genomic damage and cause proliferation to stop
73
What is the consequence of a mutation in a governor tumor suppressor gene?
cells transform into tumors bc they never receive a signal to stop growing
74
What is the consequence of a mutation in a guardian tumor suppressor gene?
mutations will accumulate and can eventually lead to the development of cancer (p53)
*recessive mode of inheritance (generally)
75
What is the difference between a mutation in an oncogenes and a mutation in a tumor suppressor gene?
only 1 allele needs to be mutated in an oncogene to lead to the development of cancer while 2 mutated alleles of tumor suppressor genes are generally needed to lead to cancer
*note, some tumor supressor genes act like oncogenes in that they only need 1 mut allele to cause cancer
76
What are the common types of non-random structural abnormalities in tumor cells?
1. balanced translocation
2. deletions
3. duplications (gene amplification) `
77
How do balanced translocations lead to development of neoplasms ?
over expression of pro-oncogenes by removing them from their normal promoter to one that causes them to be under the control of a highly active promoter --> over expression
78
What are 2 neoplasms that develop from balanced translocations?
Burkitt lymphoma and follicular B cell lymphoma
79
What is the molecular basis of Burkitt lymphoma?
translocation between chrom 8 and 14 which leads to over expression of MYC gene on chrom 8 bc it is placed under the same control as Ig heavy chain regulatory elements on chrom 14
80
What is the molecular basis of follicular B cell lymphoma?
reciprocal translocation between chrom 14 and 18 which leads to over expresson on BCL2 (anti-apoptotic gene) when it is moved to chrom 14 and placed under the same reg control of Ig heavy chains
81
How can a deletion lead to the development of a neoplasm?
can delete a tumor supressor gene (needs both copies KO so the other allele would have a pt mutation)
82
How does gene amplification lead to the development of neoplasms?
causes over expression of proto-oncogenes
83
T or F: Aneuploids in an established cause of carcinogenesis
F: it is an established consequence of it
84
How does aneuploidy arise in cancer cells?
errors in mitotic checkpoint which leads to mis-segregation of chromosomes
85
What role do miRNAs have in neoplastic transformation? (think oncogenes and tumor supressor genes)
if miRNA levels for an oncogene decrease, it will cause an over expression of the oncoprotein -->
If the miRNAs for a tummor suppressor gene are over expressed it causes a dec in tumor suppressor protein -->
inc proliferation
reduced apoptosis
inc invasiveness
angiogenesis
86
What are reversible, heritable changes in gene expressin that occur without mutation?
epigenetic changes
87
Describe the epigenetic modifications present in cancer cells.
global DNA hypomethylation and selective promoter hypermethylation of tumor suppressor gene or DNA repair gene promoters
88
What is carcinogenesis?
a multistep process resulting from the accumulation of multiple genetic alterations that collectively give rise to a transformed phenotype
89
What is tumor progression?
over time, tumors become more aggressive and acquire greater malignant potential
90
T or F: tumor progression is correlated to an inc in tumor size
False: not correlated to size
91
T or F: Because malignant tumors are monoclonal in origin, the constituent cells are homogenous.
F: they are extremely heterogeneous --> darwinian selection
92
What type of cells are selected for during tumor progression?
- more adapt at evading immune system
- more aggressive cells
- less responsive to therapy over time
93
All normal cells require ____ to undergo proliferation.
stimulation by growth factors (via paracrine signaling)
94
How do tumor cells acquire growth self sufficiency?
1. they synthesize the same growth factor to which they are responsive = POSITIVE feedback loop
* *normal cells are not able to do this, they lack the receptor that recognizes the GF they make
2. they mutate the recpetor so that there are continuous mitogenic signaling to cells (even in the absence of GF)
3. they over express the receptor so that they are hyper-responsive to the GF and will proliferate at GF concentrations that normally do not trigger proliferation
4. Mutate RAS or ABL
5. Mut nuclear Tx Factors (MYC)
6. mut that activate cyclins or inactivate CDK inhibitors
* basically anything that drives cell cycle to become dysregulated by via mutations or amplification
95
What is the most commonly mutated proto-oncogene in human tumors?
RAS (mutation interferes with hydrolysis of bound GTP so that RAS will always be active and thus always signaling for the cell cycle to continue
96
What is the normla function of RAS protein?
switches between a GDP (inactive) and GTP (active) bound states. When active, its activates expression of MYC protein* --> cell cycle progression
*via P13 kinase/AKT pathway or RAF/ERK/MAP pathway
97
What is the role of ABL in carcinogenesis?
ABL gene translocates to form a BCR-ABL hybrid. This mutates the Tyr Kinase to make it constitutively active --> this activates everything downstream of RAS --> MYC constitutively expressed --> cell cycle progresses continuously
98
What is the consequence of constiuitively active MYC?
inc expression of CDK and decreases expression of CDK inhibitors --> cell cycle ON
99
At what point in the cell cycle do cells become committed to DNA replication? What protein is primarily responsible for controlling this step?
G1-S transition via cyclins
100
What check point monitors the integrity of DNA before replication?
G1-S checkpoint
101
What check point monitors DNA aftetr replication to determine whether it can safely enter into mitosis?
G2-M checkpoint
102
All cancer cells seem to have genetic lesions that disable the _____ checkpoint.
G1-S so that the cells continuously enter S phase
103
How many mutations are needed to cause retinoblastoma?
Both RB genes
| Pts with retinoblastoma are usually born heterozygous and then loose their normal copy
104
T or F: A cell that is heterozygous at the RB locus is neoplastic
F: not neoplastic
105
Describe the role of active and inactive RB in the cell cycle:
Inactive: it is in a hyperphosphorylated state; it cannot find to E2F --> E2F can turn on Tx of S phase genes --> cell cycle proceeds to S phase
Active RB: in a hypophosphoylated state in which it can bind E2F --> Tx OFF --> cell cycle does NOT go into S phase
106
Describe how RB becomes activated and inactivated.
Growth factors (EGF, PDGF) activate cyclin D/Cdk4, 6 and cyclin E/Cdk2 to phosphorylate RB --> RB inactive --> cell cycle goes into S phase
Growth inhibitors (TGF-B, p53) inactivate cyclin D/Cdk4, 6 and cyclin E/Cdk2 --> RB active --> cell cycle does NOT go into S phase
107
RB exerts ________ effects by controlling the G1-S phase transition of the cell cycle.
anti-proliferative
*when RB is active it turns off cell cycle by inhibiting E2F
108
What happens to the cell cycle if there is non-functional RB?
E2F would not be controlled --> cell cycle always proceeding to S phase
109
What os the normal role of p53?
senses DNA damage -> upregs Cdk inhibitors to stop cell cycle at G1 and allow repair of damage
If DNA damage is too great to repair, p53 triggers senescence or apoptosis (via BAX or PUMA gene induction)
110
What is Li-Fraumeni syndrome?
persons have 1 mutated copy of p53 gene, therefore, they are predisposed to developing malignant tumors
111
What activates p53 expression? (3)
1. anoxia (= NO oxygen)
2. inappropriate oncogene signaling (MYC or RAS)
3. DNA damage
112
Describe the normal TGF-Beta signaling pathway.
TGF-B binds to receptors and inhibits proliferation by...
- activating Cdk inhibitors
- inhibiting expression of MYC and cyclins
113
In 100% of _____ cancers and 83% of ____ cancers, at least one component of the TGF-beta pathway is mutated.
pancreatic and colon
114
What is WNT and what is its normal function in cell cycle?
a soluble pro-proliferative factor
MOA: prevents degradation of Beta-catenin by APC so Beta-catenin can go into the nucleus to work with TCF and turn on proliferative genes
115
APC gene exerts _____ actions by regulating destruction of Beta-catenin.
anti-proliferative
116
Would a mutated APC gene or protein so that it could not interact with Beta-catenin be pro- or anti-proliferative
pro-proliferative bc B-catenin would not be destroyed/it could go into the nucleus to turn on pro-proliferative genes
117
What is the mutation in adenomatous polyposis syndrome?
germ line mut in APC gene
118
In 100% of _____ cancers and 83% of ____ cancers, at least one component of the TGF-beta pathway is mutated.
pancreatic and colon
119
What is WNT and what is its normal function in cell cycle?
a soluble pro-proliferative factor
MOA: prevents degradation of Beta-catenin by APC so Beta-catenin can go into the nucleus to work with TCF and turn on proliferative genes
120
APC gene exerts _____ actions by regulating destruction of Beta-catenin.
anti-proliferative
121
Would a mutated APC gene or protein so that it could not interact with Beta-catenin be pro- or anti-proliferative
pro-proliferative bc B-catenin would not be destroyed/it could go into the nucleus to turn on pro-proliferative genes
122
What is the mutation in adenomatous polyposis syndrome?
germ line mut in APC gene
