Neoplasia (Molecular Basis) Flashcards
What are the three stages of direct invasion by neoplastic cells?
- Detachment from surrounding cells; 2. Degradation of basement membranes; 3. Adhesion to extracellular matrix then degradation of it, followed by acquisition of motility factors and migration
Define the term “tumor progression.”
The process by which cells that have undergone neoplastic transformation acquire more and more characteristics that are deleterious to the host
Approximately how many different genes (of the tens of thousands of genes that comprise the mammalian genome) can, when mutated, lead to development of neoplasia?
Only a few hundred
In which two stages of the cell cycle do cells increase their mass in preparation for division?
G1 and G2 (G for growth)
Explain briefly the mechanism for development of tumor heterogeneity.
Tumor growth starts with a single cell that has undergone neoplastic transformation, and the incipient tumor develops by clonal expansion of this one cell. Initially, all cells in the mass are identical but, due to the lack of regulation of chromosomal integrity, the tumor cells acquire genetic changes that give rise to tumor heterogeneity.
Name two cell cycle checkpoints.
G1-S and G2-M
In a developing neoplasm, new subclones arise from descendants of the original transformed cell. What general characteristics are selected for in these subclones?
Subclones are more adept at evading host defenses and are likely to be more aggressive
List three of the general classes of proto-oncogene products.
- Growth factors
- Growth factor receptors
- Intracellular signal transducers
- Nuclear regulatory proteins
- Cell cycle regulators
Where in the cell cycle do the tumor suppressor genes p53 and RB cause cell-cycle arrest in response to DNA damage?
At the G1-S checkpoint
What is the term for a normal gene (i.e., a sequence of DNA) that regulates the growth and differentiation of a cell?
A proto-oncogene
Explain the “soil and seed” hypothesis of metastasis.
This theory states that interactions between the cancer cell (the “seed”) and the host target organ (the “soil”) determine where metastatic tumors arise. The “soil” can potentially have more favorable or less favorable conditions for metastasis. Since extravasation requires adhesion to endothelial cells, tumor cell attachment may be directed to specific sites by receptor and ligand interactions.
What happens at the two cell cycle checkpoints G1-S and G2-M, and why?
The cell cycle arrests while DNA is checked for fidelity. If DNA damage or infidelity is detected the cell can attempt to repair it or direct itself to undergo apoptosis. This prevents mutations becoming embedded within the genome, which could potentially lead to neoplasia.
The immune system provides antitumor mechanisms. Name two cell types responsible for the more specific of these mechanisms (i.e., those requiring antigen-specific priming by dendritic cells).
- T lymphocytes (cell mediated immunity)
- B lymphocytes (humoral immunity)
Tumor suppressor genes (TSGs) encode proteins that have two major functions. What are these two functions?
- Arrest cell cycling to allow a cell “breathing time” to detect and repair DNA damage; 2. Direct a cell to undergo apoptosis if DNA damage is irreparable
The immune system provides antitumor mechanisms. Name two cell types responsible for the less specific of these mechanisms (i.e., those not requiring antigen-specific priming by dendritic cells).
- Natural killer cells
- Macrophages
All cells in a developing neoplasm are, early on, identical clones. True or false?
True. Tumor growth starts with a single cell that has undergone neoplastic transformation, and the incipient tumor develops by clonal expansion of this one cell.
What is the term for the process by which cells that have undergone neoplastic transformation acquire more and more characteristics that are deleterious to the host?
Tumor progression
Expression of proto-oncogenes causes cancer. True or false?
False. Proto-oncogenes are normal genes that regulate the growth and differentiation of cells. Their expression is normal and necessary, but is very tightly regulated. When proto-oncogenes are mutated, and their expression becomes dysregulated (uncontrolled), proto-oncogenes are termed ONCOGENES.
All cells in a developing neoplasm are initially identical. However, due to the lack of regulation of chromosomal integrity, the tumor cells acquire genetic changes that lead to development of different populations of subclones. What is the term for this?
Tumor heterogeneity (tumor progression is OK too)
By the time most tumors become clinically evident, they have probably been developing in the host for many years. True or false?
True. The smallest clinically detectable mass is about 1cm in diameter and contains about one billion cells. To form a tumor that size, a single transformed cell must undergo about 30 rounds of cell division. Thus, by the time most tumors become clinically evident, they have probably been developing in the host for many years.
What is the term for a cell that has gained the ability to replicate more than a certain, predetermined number of times?
Immortalized
With progressive growth, a tumor mass becomes enriched for subclone variants with certain “skills,” all of which are bad news for the host. Name 5 “skills” that can be selected for in neoplastic cells.
- Metastatic ability; 2. Invasive ability; 3. Requirement for fewer growth factors; 4. Failure to express antigens (thus evading the immune system); 5. Resistance to chemotherapy; 6. Resistance to radiation therapy; 7. Ability to survive with little oxygen; 8. Ability to resist cold or heat; 9 … etc.
What is the term for the development of new blood vessels, such as that induced by developing neoplasms?
Angiogenesis
How tightly regulated is the expression of the various proto-oncogenes?
Very tightly regulated. [Dysregulation of proto-oncogenes can lead to inappropriate expression of their product, which may lead to neoplasia.]
Explain why cells with defects in proofreading genes are at higher risk for development of neoplasia.
These cells have impaired production of the proteins that check copied DNA for fidelity. Errors in DNA replication (e.g., mismatched bases) are not detected and so accumulate In the genome at an increased rate. If these errors are within critical genes such as proto-oncogenes or tumor suppressor genes the cell may be predisposed to development of neoplasia.
What is the definition of the term proto-oncogene?
A normal gene (i.e., a sequence of DNA) that regulates the growth and differentiation of a cell
Explain why, once tumors reach clinically detectable size (about 1 cm in diameter), their growth may appear to accelerate and become very rapid.
It has taken approximately 30 rounds to cell division to go from a single transformed cell to a 1 cm diameter (= approximately 1 g) mass. It only takes 10 further rounds of cell division, however, to convert a 1 g mass to a 1 kg mass. Therefore, growth seems more rapid.
In which stage of the cell cycle does a cell duplicate its chromosomes?
S (S for synthesis)
A 1 cm diameter neoplasm is composed of approximately one billion cells. Approximately how many cells are shed each day into circulation by this tumor?
One million
Explain how immortalized cells are at higher risk for development of neoplasia.
Immortalized cells have gained the ability to replicate more than a certain, predetermined number of times. This permits cells to cycle indefinitely, which provides more chances for mutations to occur, to accumulate and to become fixed in the genome of these abnormally old cells.
What two broad characteristics typify the genetic mutations that lead to neoplasia?
- The mutation is not lethal to the cell; 2. The mutation affects a particular, critical subset of genes involved in cell cycle regulation, apoptosis, tumor suppression etc. (only a few hundred of the tens of thousands of genes that comprise the mammalian genome)
In which stage of the cell cycle does a cell undergo mitosis?
M (M for mitosis)
What are tumor suppressor genes and what is their function?
Tumor suppressor genes (TSGs) are genes whose products play a critical role in the control of normal cell growth. Their products serve as the “brakes” to cell replication. When tumor suppressor genes are inactivated, cells lose regulatory control of cell proliferation, which predisposes them to neoplasia.
What is the approximate maximum diameter a neoplasm can reach before development of new blood vessels is required?
About 1-2 mm
What class of gene encodes proteins that (a) arrest cell cycling to allow a cell “breathing time” to detect and repair DNA damage and (b) direct a cell to undergo apoptosis if DNA damage is irreparable?
Tumor suppressor genes
Define, and explain the difference between proto-oncogenes and oncogenes.
Proto-oncogenes are normal genes that regulate the growth and differentiation of cells. Their expression is normal and necessary, but is very tightly regulated. When proto-oncogenes are mutated, and their expression becomes dysregulated (uncontrolled), proto-oncogenes are termed ONCOGENES. Dysregulated expression of oncogenes (i.e., underexpression, overexpression or production of a mutated protein) may lead to uncontrolled cell cycling (i.e., neoplasia).
The critical subset of genes that, when mutated, can lead to development of neoplasia can be divided into four classes. What are they?
- Proto-oncogenes; 2. Tumor suppressor genes; 3. “Immortality genes”; 4. Proof-reading genes
Name three ways in which tumor cells may evade the immune system.
- Antigen masking/loss (failure to produce tumor antigen means cells are “invisible”)
- Altered MHC expression (mutations in MHC genes or genes needed for antigen processing)
- Immunosuppression (production of immunosuppressive proteins)
What are tumor suppressor genes and what can happen when they are mutated or inactivated?
Tumor suppressor genes (TSGs) are genes whose products play a critical role in the control of normal cell growth. Their products serve as the “brakes” to cell replication. When tumor suppressor genes are mutated or inactivated, cells lose regulatory control of cell proliferation, which predisposes them to neoplasia.
The smallest clinically detectable mass is about 1cm in diameter. Approximately how many rounds of cell division have the cells in this mass undergone to produce a tumor of this size?
About 30
The RB (retinoblastoma) gene belongs to which class of gene? (a) “Immortality” genes; (b) Proof-reading genes; (c) Proto-oncogenes; (d) Tumor suppressor genes.
(d) Tumor suppressor genes
Conversion of oncogenes to proto-oncogenes can lead to development of neoplasia. True or false?
False. It’s the other way around: conversion of proto-oncogenes to oncogenes can lead to development of neoplasia.
With respect to a developing neoplasm, what is the meaning of the term latent period?
The time period in which a neoplasm is developing but before it becomes clinically detectable
The p53 gene belongs to which class of gene? (a) “Immortality” genes; (b) Proof-reading genes; (c) Proto-oncogenes; (d) Tumor suppressor genes.
(d) Tumor suppressor genes
A 1 cm diameter neoplasm is composed of approximately one billion cells and sheds approximately one million cells into circulation each day. Why then is metastasis a relatively infrequent event?
The vast majority of these circulating cells do not metastasize because they do not have the capability to traverse all steps of the metastatic cascade.
Why is angiogenesis important for developing neoplasms?
Continued growth of solid tumors absolutely depends on an adequate blood supply to provide oxygen and nutrients to tumor cells. Without the development of new blood vessels, a process termed angiogenesis, tumors are limited to a maximum diameter of 1 to 2mm.
What is the term for introduction of irreversible genetic change into a cell by the action of a mutagenic initiating agent?
Transformation
The smallest clinically detectable mass is about 1cm in diameter. Approximately how many cells are contained within this mass?
One billion (10 to the 9th)
What is the term for the time period in which a neoplasm is developing but before it becomes clinically detectable?
Latent period
Growth factor receptors are a product of which class of gene? (a) “Immortality” genes; (b) Proof-reading genes; (c) Proto-oncogenes; (d) Tumor suppressor genes.
(c) Proto-oncogenes
List, in order, all steps of the metastatic cascade.
- Tumor proliferation (via initiation, promotion, and progression)
- Primary tumor angiogenesis
- Detachment
- Invasion of local tissues
- Intravasation
- Circulation, arrest, and interaction with local tissues
- Attachment
- Extravasation
- Invasion of local tissues
- Secondary tumor angiogenesis.
- Cycle repeats again (“metastases of a metastasis”)
Transformed cells initially appear morphologically normal and may remain quiescent for many years. True or false?
TRUE
Name two tumor suppressor genes.
p53; RB
How does the vascular entrapment theory of metastasis explain the fact that the lungs and liver are the most frequent sites of metastasis?
This theory states that the vast majority of tumor cells are arrested in the first capillary bed they encounter. In the systemic circulation (i.e., returning to heart via vena cava) this is the lung. In the gastrointestinal circulation (i.e., returning to liver via hepatic portal vein) this is the liver.
In which stage of the cell cycle is a cell quiescent?
G0 (that’s a zero, not an o)
Both alleles (copies) of a tumor suppressor gene must be present or normal to maintain control of cell proliferation. True or false?
False. A single intact copy of a tumor suppressor gene is sufficient to maintain control of cell proliferation. When both alleles are lost or damaged, however, the affected cell has a high risk of neoplastic transformation.
All normal cells have the capacity for immortality. True or false?
False. Very few cell types in the body have the ability to replicate more than a certain, predetermined number of times. Cells that gain the ability to keep replicating after this point have become “immortalized”, which can predispose them to development of neoplasia.
Intracellular signal transducers are a product of which class of gene? (a) “Immortality” genes; (b) Proof-reading genes; (c) Proto-oncogenes; (d) Tumor suppressor genes.
(c) Proto-oncogenes
Immortalization of cells is a necessary step in prevention of neoplasia. True or false?
False. Very few cell types in the body have the ability to replicate more than a certain, predetermined number of times. Cells that gain the ability to keep replicating after this point have become “immortalized”, which can predispose them to development of neoplasia.
Imagine a quiescent cell about to enter the cell cycle. Put the following stages of the cell cycle into their correct order: G0, G1, G2, M and S.
G0 -> G1 -> S -> G2 -> M
Roughly how many different proto-oncogenes are known? (a) 10; (b) 100; (c) 1,000; (d) 10,000.
(b) 100
How are normal blood vessels different from those induced by a developing neoplasm through angiogenesis?
Compared with normal vessels, tumor vessels are tortuous and irregularly shaped. In contrast to the stable vessel network of normal tissue, the networks formed by tumor vessels are unstable and leaky. In the tumor, vessels are disorganized and specific vessel types cannot be identified.
Growth factors are a product of which class of gene? (a) “Immortality” genes; (b) Proof-reading genes; (c) Proto-oncogenes; (d) Tumor suppressor genes.
(c) Proto-oncogenes
