Chapter 6: Neoplasia Flashcards
All of these questions are based on the blue ‘summary’ boxes in the book
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Benign and malignant tumors can be distinguished from one another based on….
the degree of differentiation, rate of growth, local invasiveness, and distant spread.
Fill in: Benign tumors resemble the tissue of origin and are poorly/well differentiated; malignant tumors are poorly/well or differentiated
well and poorly respectively
What does anaplastic mean?
These are malignant tumors that are completely undifferentiated
Do benign tumors grow slower or faster than malignant?
Slower
True/false: Benign tumors are poorly circumscribed and invade the surrounding normal tissues.
False, this explains malignant tumors. Benign tumors are well circumscribed and have a capsule.
Fill in: … remain localized to the site of origin, whereas … are locally invasive and metastasize to distant sites.
Benign tumors, malignant tumors respectively
The incidence of cancer varies… with what?
age, geographic factors and genetic background
How can geographic factors be explained?
It results mostly from different environmental exposures.
True/false: cancer only occurs in older adults
False, though it is more common
What are some environmental factors that implicated in carcinogenesis?
These include infectious agents, smoking, alcohol, diet, obesity, reproductive history, and exposure to carcinogens.
Cancer risk rises in certain tissues in the setting of increased cellular proliferation caused by …
chronic inflammation or hormonal stimulation
Epithelial cell linings may develop morphologic changes that signify an increased risk for developing cancer; such lesions are referred to as …
precursor lesions.
True/false: The risk for developing cancer is modified by interactions between environmental exposures and genetic variants.
True
Mutations in cancer cells fall into two major classes. Which two?
driver (pathogenic) mutations and passenger (neutral) mutations.
Can driver mutations become passenger mutations?
Yes, passenger mutations may become driver mutations if selective pressure on the tumor changes, for example, in the setting of treatment with an effective therapeutic drug.
Tumor cells may acquire driver mutations through several means. What are some examples of those?
Point mutations and nonrandom chromosomal abnormalities that contribute to malignancy; these include gene rearrangements, deletions, and amplifications.
What is the most common gene rearrangement?
Translocations
How can a gene rearrangement contribute to carcinogenesis?
by overexpression of oncogenes or generation of novel fusion proteins with altered signaling capacity.
How do deletions impact carcinogenesis?
By affecting tumor suppressor genes
How do gene amplifications impact carcinogenesis?
By the increasing expression of oncogenes
Overexpression of miRNAs can contribute to carcinogenesis. How?
By reducing the expression of tumor suppressors
Deletion or loss of expression of miRNAs can also contribute to carciongenesis. How?
By overexpression of proto-oncogenes
Tumor suppressor genes and DNA repair genes also may be silenced by epigenetic changes, which involve reversible, heritable changes in gene expression that occur not by mutation but by …
methylation of the promoter.
What are proto-oncogenes?
normal cellular genes whose products promote cell proliferation
What are oncogenes?
mutant or overexpressed versions of proto-oncogenes that function autonomously without a requirement for normal growth-promoting signals
Oncoproteints promote uncontrolled cell proliferation by several mechanisms. Name some of them
(get familiar with this list, but they’ll be discussed in further detail later!)
• Stimulus-independent expression of growth factor and its
receptor, setting up an autocrine loop of cell proliferation
(e.g., PDGF–PDGF receptor in brain tumors)
• Mutations in genes encoding growth factor receptors or
tyrosine kinases leading to constitutive signaling
• Amplification of EGF receptor family genes such as HER2 in
breast cancer
• Fusion of portions of the ABL tyrosine kinase gene and the
BCR protein gene, creating a BCR-ABL fusion gene encoding
a constitutively active tyrosine kinase, in certain leukemias
• Mutations in genes encoding signaling molecules
• RAS commonly is mutated in human cancers and normally
flips between resting GDP-bound state and active GTP- bound state; mutations block hydrolysis of GTP to GDP, leading to unchecked signaling
• Overproduction or unregulated activity of transcription factors
• Translocation of MYC in some lymphomas leads to overexpression and unregulated expression of its target genes controlling cell cycling and survival
• Mutations that activate cyclin genes or inactivate negative regulators of cyclins and cyclin-dependent kinases
What do complexes of cyclins with CDKs do?
They drive the cell cycle by phosphorylating various substrates and normally are controlled by CDK inhibitors
What happens when there are mutations in the genes encoding cyclins, CDKs, and CDK inhibitors
Uncontrolled cell cycle progression (found in melanomas and brain, lung and pancreatic cancers)
What is Rb also called?
The governor of the cell
What is P53 also called?
The guardian of the genome
Is Rb a tumor suppressor, or a tumor oncogene?
Suppressor
What does suppressor mean?
That both copies of Rb need to be dysfunctional for a tumor development to occur
Do both copies of Rb need to be dysfunctional for tumor development?
Yes, but the exception is familial retinoblastoma, where one is already defect
RB exerts anti-proliferative effects by controlling the G1-to-S transition of the cell cycle. What does it do in it’s active and inactive form?
In its active form, RB is hypophosphorylated and binds to E2F transcription factors. This interaction prevents transcription of genes like cyclin E that are needed for DNA replication, and so the cells are arrested in G1.
What does growth factor signaling lead to?
Cyclin D expression, activation of cyclin D-CDK4/6 complexes, inactivation of RB by phosphorylation, and thus release of E2F
True/false: Almost all cancers have a disabled G1 checkpoint due to mutation of either RB or genes that affect RB function, such as cyclin D, CDK4, and CDKIs.
True
How do viruses contemplate to cancer?
Many oncogenic DNA viruses, like HPV, encode proteins (e.g., E7) that bind RB and render it nonfunctional.
What is the gene of p53?
TP53
What does TP53 do?
TP53 encodes p53, the central monitor of stress in the cell, which can be activated by anoxia, inappropriate oncogene signaling, or DNA damage. Activated p53 controls the expression and activity of genes involved in cell cycle arrest, DNA repair, cellular senescence, and apoptosis.
What happens (with regard to p53) when DNA is damages (in a normal cell)
DNA damage leads to activation of p53 by phosphorylation. Activated p53 drives transcription of CDKN1A (p21), which prevents RB phosphorylation, thereby causing a G1-S block in the cell cycle. This pause allows the cells to repair DNA damage.
When happens when DNA damage cannot be repaired?
p53 induces cellular senescence or apoptosis.
How many % of the human tumors demonstrate biallelic mutations in TP53 (both need to be mutated)? What is an exception to this rule?
70%. Patients with the rare Li-Fraumeni syndrome inherit one defective copy of TP53 in the germ line, such that only one additional mutation is required to lose normal p53 function. Li-Fraumeni syndrome patients are prone to develop a wide variety of tumors.
Can p53 be incapacitated by viruses?
As with RB, p53 can be incapacitated when bound by proteins encoded by oncogenic DNA viruses such as HPV.
What does TGF-β do?
TGF-β inhibits proliferation of many cell types by activation of growth-inhibiting genes such as CDKIs and suppression of growth-promoting genes such as MYC and those encoding cyclins.
What parts of TGF-β function are compromised/ mutated in tumors?
TGF-β function is compromised in many tumors by mutations in its receptors (colon, stomach, endometrium) or by mutational inactivation of SMAD genes that transduce TGF-β signaling (pancreas).
What does E-cadherin do?
It maintains contact inhibition (that is lost in malignant cells)
What does the APC gene do? What happens when it doesn’t work?
The APC gene exerts anti-proliferative actions by regulating the destruction of the cytoplasmic protein β-catenin. With a loss of APC, β-catenin is not destroyed, and it translocates to the nucleus, where it acts as a growth-promoting transcription factor.
