Path Book: Chapter 5 Neoplasia pg. 178-190 Flashcards
Carcinogenesis is a multistep process resulting from the accumulation of multiple genetic alterations that collectively give rise to the transformed phenotype.
Many cancers arise from non-neoplastic precursor lesions, which molecular analyses have shown already possess some of the mutations needed to establish a full-blown cancer. Presumably these mutations provide the cells of the precursor lesion with a selective advantage. Once initiated, cancers continue to undergo darwinian selection.
What are some phenotypic manifestations of malignant neoplasms?
excessive growth, local invasiveness, and the ability to form distant metastases.
What is tumor progression?
Over a period of time, many tumors become more aggressive and acquire greater malignant potential.
T or F. Increasing malignancy often is acquired in an incremental fashion.
T. At the molecular level, tumor progression and associated heterogeneity are most likely to result from multiple mutations that accumulate independently in different cells, generating subclones with different characteristics such as ability to invade, rate of growth, metastatic ability, etc
Some of the mutations may be lethal; others may spur cell growth by affecting proto-oncogenes or cancer suppressor genes.
Thus even though most malignant tumors are monoclonal in origin, by the time they become clinically evident their con- stituent cells may be extremely heterogeneous.
Thus even though most malignant tumors are monoclonal in origin, by the time they become clinically evident their con- stituent cells may be extremely heterogeneous.
During progression, how are tumor cells subjected to immune and nominate section pressures?
For example, cells that are highly antigenic are destroyed by host defenses, whereas those with reduced growth factor requirements are positively selected.
A growing tumor, therefore, tends to be enriched for subclones that “beat the odds” and are adept at survival, growth, invasion, and metastasis.
What is a major significance of the selective pressure of tumors?
The recurrent tumor is almost always resistant to the drug regimen if it is given again.
What are some of the hallmarks of cancer cell growth/behavior?
• Self-sufficiency in growth signals • Insensitivity to growth inhibitory signals • Evasion of cell death • Limitless replicative potential • Development of sustained angiogenesis • Ability to invade and metastasize
Also, reprogramming of energy metabolism and evasion of the immune system
How does normal cell growth/proliferation occur?
- The binding of a growth factor to its specific receptor on the cell membrane
- Transient and limited activation of the growth factor receptor, which in turn activates several signal- transducing proteins on the inner leaflet of the plasma membrane
- Transmission of the transduced signal across the cytosol to the nucleus by second messengers or a cascade of signal transduction molecules
- Induction and activation of nuclear regulatory factors that initiate and regulate DNA transcription
- Entry and progression of the cell into the cell cycle, resulting ultimately in cell division
All cells need growth factors to grow. Are most growth factors autocrine, paracrine, or endocrine?
paracrine- most cells that make growth factors don’t express their receptor. This prevents positive feedback loops in the cell
How do cancer cells evade the growth factor requirement?
- Many acquire the ability to synthesize the same growth factors to which they are responsive. Similar autocrine loops are fairly common in many types of cancer.
- Cancer cells acquire growth self-sufficiency is by interaction with stroma. In some cases, tumor cells send signals to activate normal cells in the supporting stroma, which in turn produce growth factors that promote tumor growth.
How can mutated growth receptors stimulate cancer formation?
Mutant receptor proteins deliver continuous mitogenic signals to cells, even in the absence of the growth factor in the environment.
However, mutated receptors are not very common causes of cancer formation
Growth receptors still play a significant role in cancer formation even though mutation is not common. How?
More common than mutations is overexpression of growth factor receptors, which can render cancer cells hyperresponsive to levels of the growth factor that would not normally trigger proliferation.
What the result of a mutated HER2/NEU receptor? Treatment? Prognosis?
The gene encoding a related receptor, HER2/NEU (ERBB2), is amplified in 25% to 30% of breast cancers and adenocarcinomas of the lung, ovary, and salivary glands.
These tumors are exquisitely sensitive to the mitogenic effects of small amounts of growth factors, and a high level of HER2/NEU protein in breast cancer cells is a harbinger of poor prognosis.
Treatment of breast cancer with anti- HER2/NEU antibody is an elegant example of “bench to bedside” medicine.
What are RAS and ABL?
A relatively common mechanism by which cancer cells acquire growth autonomy is mutations in genes that encode various components of the signaling pathways down- stream of growth factor receptors.
These signaling proteins couple growth factor receptors to their nuclear targets. They receive signals from activated growth factor receptors and transmit them to the nucleus, either through second messengers or through a cascade of phosphorylation and activation of signal transduction molecules.
RAS is the most commonly mutated proto- oncogene in human tumors.
RAS is the most commonly mutated proto- oncogene in human tumors.
Indeed, approximately 30% of all human tumors contain mutated versions of the RAS gene, and the frequency is even higher in some specific cancers (e.g., colon and pancreatic adenocarcinomas).
What is RAS specifically?
a G-receptor coupled protein that is inactivated when bound to GDP and active when bound to GTP
How are GRCPs like RAS inactivated?
Activated state is short-lived because the intrinsic GTPase activity of RAS hydrolyzes GTP to GDP, releasing a phosphate group and returning the protein to its quiescent GDP-bound state.
In its mutated (aka cancer causing) state, RAS can no longer be inactivated due to point mutations
What is BRAF? What kind of cancer is its mutated form present in?
a GRCP that lies in the RAS/RAF/ERK/MAP kinase pathway, is mutated in more than 60% of melanomas.
What is ABL?
a non–receptor-associated tyrosine kinase that functions as a signal transduction molecule.
Mutation is common with cancer formation
How is ABL mutated in chronic myelogenous leukemia and certain acute leukemias?
A part of the ABL gene is translocated from its normal abode on chromosome 9 to chromosome 22, where it fuses with part of the breakpoint cluster region (BCR) gene.
The BCR-ABL hybrid protein maintains the tyrosine kinase domain; the BCR domain self- associates, a property that unleashes a constitutive tyrosine kinase activity. Of interest, there is cross-talk between BCR-ABL and RAS pathways, since BCR-ABL protein activates all of the signals that are downstream of RAS.
How would/could you treat chronic myelogenous leukemia?
BCR-ABL kinase inhibitors
What is Gleevec?
imatinib mesylate (Gleevec) is a BCR-ABL kinase inhibitor used in cancer therapy
What is oncogene addiction?
case in which a tumor is profoundly dependent on a single signaling molecule (such as BCR-ABL). Common in leukemia
remember: BCR-ABL fusion gene formation is an early, perhaps initiating, event that drives leukemo- genesis.
T or F. The ultimate consequence of signaling through mutated oncoproteins such as RAS or ABL is inappropriate and continuous stimulation of nuclear tran- scription factors that drive the expression of growth- promoting genes.
T. Thus, in addition to growth factor pathway mutations, growth autonomy may thus be a consequence of mutations affecting genes that regulate transcription of DNA
What are some important transcription factors/genes/proteins that play a role in cancer formation when mutated?
A host of oncoproteins, including products of the MYC, MYB, JUN, FOS, and REL oncogenes, function as transcription factors that regulate the expression of growth-promoting genes, such as cyclins.
Of these, the MYC gene is involved most commonly in human tumors (the MYC gene makes MYC protein).
What does the MYC protein do?
The MYC protein can either activate or repress the transcription of other genes.
MYC also is a key regulator of intermediate metabolism, upregulating genes that promote aerobic glycolysis (Warburg effect) and the increased utilization of glutamine, two metabolic changes that are hallmarks of cancer cells.
Which growth-factor promoting genes does/can MYC activate?
Cyclin- dependent kinases (CDKs).
In contrast, they repress transcription of CDK inhibitors (CDKIs)
Thus, dysregulation of MYC promotes tumorigenesis by increasing expression of genes that promote progression through the cell cycle and repressing genes that slow or prevent progression through the cell cycle.
How is MYC affected in Burkitt lymphoma?
Dysregulation of the MYC gene resulting from a t(8;14) translocation occurs in Burkitt lymphoma, a B cell tumor.
The replication of cells is stimulated by growth factors or by signaling from ECM components through integrins.
The replication of cells is stimulated by growth factors or by signaling from ECM components through integrins.
What are the main checkpoints of the cell cycle?
The cell cycle has multiple checkpoints, particularly during emergence from G0 into G1 and the transition from G1 to S phase.
The orderly progression of cells through the various phases of the cell cycle is orchestrated by ______.
CDKs, which are activated by binding to the cyclin
The CDK–cyclin complexes phosphorylate crucial target proteins that drive the cell through the cell cycle.
What happens to cyclin levels when they accomplish their task?
cyclin levels decline rapidly.
What happens if cell surveillance mechanisms such as CDKIs sense that DNA is too damaged to complete a cell cycle?
If DNA damage is too severe to be repaired, the cells are eliminated by apoptosis, or enter a nonreplicative state called senescence, primarily through p53-dependent mechanisms.
Mutations in genes regulating these checkpoints allow cells with damaged DNA to divide, producing daughter cells carrying mutations.
Which CDK-cyclin complexes regulate entry into the S phase from G1? How?
cyclin D–CDK4, cyclin D–CDK6, and cyclin E–CDK2 regulate the G1-to-S transition by phosphorylating the Rb protein (pRb).
Which CDK-cyclin complexes are active in S phase?
Cyclin A–CDK2 and cyclin A–CDK1 are active in the S phase.
Which CDK-cyclin complex is essential for the G2-to-M transition?
Cyclin B–CDK1
What do INK4 CDKIs do? Members?
The so-called INK4 inhibitors, composed of p15, p16, p18, and p19, act on cyclin D–CDK4 and cyclin D–CDK6.
The other family of three inhibitors, p21, p27, and p57, can inhibit all CDKs.
All cancers appear to have genetic lesions that disable the G1-S checkpoint, causing cells to continually reenter the S phase. For unclear reasons, particular lesions vary widely in frequency across tumor types.
All cancers appear to have genetic lesions that disable the G1-S checkpoint, causing cells to continually reenter the S phase. For unclear reasons, particular lesions vary widely in frequency across tumor types.
Mutation of which CDK is most common in neoplastic transformation?
CDK4. Mutations affecting cyclins B and E and other CDKs also occur, but they are much less frequent than those affecting cyclin CDK4.
