Molecular Neoplasia 2 Flashcards
Describe what is meant by “carinogenesis is a multistep process.”
carcinogenesis begins and proceeds by accumulation of multiple DNA mutations, the order and timing of which are important
all tumors show activation of multiple oncogenes and loss of usually 2 or more tumor suppressor genes
- List the 7 general molecular features of cancer.
self-sufficiency in growth signals insensitivity to anti growth signals evasion from apoptosis limitless replicative potential sustained angiogensis tissue invasion and/or metastasis genetic/genomic instability
- Contrast pro to-oncogenes, cellular oncogenes and viral oncogenes.
proto-ocogenes are normal cellular genes required for normal growth and differentiation
cellular oncogenes are proto-oncogenes leading to increased function
viral oncogenes are found in retroviruses and are genes that can lead to tumors/cellular transformation
- What are the 5 functional classes of oncogenes?
growth factors growth factor receptors signal traducing proteins transcription factors cell cycle protein
What is the roll of growth factors in carcinogenesis?
increased production/activity of GF leads to increased cellular proliferation
although it is not sufficient for transformation, platelet derived growth factor is a potent mitogen often associated with tumor development
What is the roll of growth factor receptor in carcinogenesis?
increased density or activation leads to increased cellular proliferation
excessive activity may also occur if receptor associated molecules, like tyrosine kinase, are active constitutively, without ligand binding)
EGF receptor family receptors are often implicated (breast, ovary and lung cancer)
What is the roll of signal transducing proteins in carcinogenesis?
mutation can result in excessive signaling to induce transcription, ie. RAS family has a GTP binding protein that can be mutated, leading to constitutive activation of the pathway for transcription (occurs in 10-20% tumors of lung, colon and pancreas)
What is the roll of nuclear transcription proteins in carcinogenesis?
these regulate the transcription from specific genes, ie. MYC transcription protein causes transcription of genes involved in cellular cycle regulation, if over expressed can lead to Burkitt lymphoma, neuroblastoma (pro to-oncogene expressed in almost all cells)
What is the roll of cell cycle proteins in carcinogenesis?
dysregulation of cell cycle can be implicated in neplasia, specifically proteins like cyclins and cyclin-dependent kinases that regulate cell cycle check points
- List and briefly explain the 4 mechanisms of oncogene activation.
mutational activation: change in structure of gene and/or gene product
chromosomal activation: creation of a new fusion gene product
transcriptional activation: change in gene expression levels
epigenetic changes: reversible, heritable changes in gene transcription without DNA mutation (methylation, histone modification etc.)
- Contrast point mutation, gene rearrangement and chromosomal translocation.
> point mutation, single nucleotide altered (ie. RAS mutation)
chromosomal translocation leads to a portion of one chromosome becoming attached to another chromosome (over expression due to promoter translocation or new fusion product with altered function) (Philidelphia chromosome)
transcriptional activation resulting from translocation or gene amplification (ie. N-MYC in neuroblastoma is bobbled by minute chromosomes)
- How do alterations in epigenetic and microRNAs participate in the development of neoplasm?
- DNA methylation reversibly represses transcription
- histone modification alters the “packing” of DNA around histones (which modulates DNA able to be actively transcribed
- MiRNAs are small, noncoding RNAs which can induce mRNA destruction and increase cell proliferation if target is a tumor suppressor protein, miRNAs that interact with pro to-oncogenes can also be reduced
- What are the characteristics that define tumor suppressor genes? What are the roles of RB, p53 and APC in tumor suppression?
normal function is to down-regulated cell growth
mutation result in loss of function
APC- inhibits cell signaling
RB- regulates cell cycle (leads to retinoblastomas or osteosarcomas)
p53-ubiquitous cell cycle regulator and initiates apoptosis
RB and p53 are important in regulating
Why is p53 considered the “gatekeeper”
is a nuclear factor that prevents propagation of genetically damaged cells, can induce cell cycle arrest for DNA repair or apoptosis
associated with Li-Faurmeni Syndrome and p53 mutations can help to predict response to therapy (mutation means less likely to respond to treatment)
- How can altered apoptosis lead to cancer development? How are bax, bcl-2 mitochondria, cytochrome c involved in regulating apoptosis?
programmed cell death is important for eliminating cells from the organisms, preventing apoptosis can result in retention of genetically damaged (extrinsic and intrinsic pathways)
intrinsic pathway way for apoptosis is regulated by the balance of bcl-2 proteins which compete to keep Bak and Bax from dimerizing and forming a pore in the outer mitochondrial membrane (releasing cytochome c leading to caspase cascade)
In the Bcl-2 system, which are anti-apoptotic proteins and which are pro-apoptotic?
anti: Bcl2, Bcl-XL, MCL-1
pro: Bad, Bim, Noxa, Puma
note follicular lymphoma is cased by amplification of Bcl-2 causing excessive cell proliferation
- What is cellular senescence v. cellular immortalization and what is the role of telomerase in this process?
senescence describes the quality that cells can only replicate a limited number of times because telomeres shorten with replication; telomerase activity (enzymes that adds hexanuleotide repeats) can lead to immortalization by extending telomeres
without telomeres, fusion of chromosomes occurs, making metaphase separation difficult and leading fragmentation in strange places
- What is the importance of angiogenesis in cancer development and list three categories of molecules that play a role in angiogenesis.
angiogenesis is important for supporting the metabolic needs of tumors, categories of molecules that are involved include soluble factors and receptors (VEGF, FGF), cell adhesion molecules
(can also down regulate angiogenesis inhibitors (angiostatin, endostatin)
- What general categories of molecules are involved in invasion and metastasis and why is important?
invasion and metastasis include cell adhesion molecules (cadherins, integrins) and extracellular proteases, which is important because to spread a cancer cell must break intercellular bonds and marginate through the basal membrane to other tissues
- What is the difference in geneomic and genetic instability?
genetic instability refers to multiple mutation, esp. those who participate in DNA repair
genome instability refers to the bizarre kayrotypes associated with extra chromosomes or fragments
- What is the Warburg effect?
in the vast majority of malignant neoplasms, there is shift in glucose metabolism away from myochondria to the glycolytic pathway (helpful in PET scans where radioactive glucose is selectively taken up by neoplastic cells
How is stem cell theory different than clonal expansion theory for the genesis of cancer?
in clonal theory there is a linear of clonal cells that mutate in a fashion that favors those with greatest proliferative function
in stem cell theory there is a small pool of very tumorgenic cells that mutate in many ways as they differentiation which leads to a heterogenous cellular population
