T8 Flashcards
Differ between malignant and benign tumours.
Malignant tumours spread (metastasize) into the territory of other cells whilst benign tumours are contained within territory of source tissue.
What two heritable properties define cancers?
- Reproduction in defiance of normal cell growth/reproduction
- Colonization/invasion of territories normally reserved for other cells
What are the two general categories of cancers and what two cancer types don’t fit in either category?
Carcinomas arise from epithelial tissue, sarcomas from muscle/connetive tissue. Cancers of hemopoietic cells, in addition to cancers of nervous system.
Is a cancer necessarily a result of change in DNA sequence?
No, an epigenetic change may change gene expression leading to neoplasia. These include affecting heteromerization and gene silencing through methylation of cysteine.
What defines progression of cancer from on aberrant cell to a tumour?
Gradual development of degree of mutation, so that the parent cell may have had a few mutations whilst advanced daughter cells have aquired further mutations, changing the nature of the growth.
How can a cancer be likened to a species evolving?
Both follow the same rules for a successful proliferation:
- mutation rate
- number of reproducing individuals
- rate of reproduction
- selective advantage
What does genetic instability infer on cancerous cells?
That the DNA maintenance genes may be mutated in a way that increases incidence of further mutation in the cancer cell genome. This may or may not increase the malignancy of the cancer, depending on how much the DNA changes (approaches the optimum level of mutation/aquired properties).
Name two normally occurring cellular functions that if disturbed (up/down-regulated) can lead to neoplasia.
Cell division and apoptosis
How can cells with inactivated DNA-damage response mechanisms develop into cancers when the completion of their cell cycles sigbificantly slow down?
Accumulation over time of mutated cells eventually form a high-number basis, the division of which can be detected. This explains in part why cancers develop over many years before being detected.
How are replicative cell senescence mechanisms modulated in cancer cells?
Checkpoint mechanism, for example mediated by p53, is disabled through mutation of p53-gene so that replication continues despite de-capping of telomeres. Another modulation is the maintenance of telomerase activity, even when the activity would normally have been discontinued.
How is the cancer cell population maintained and enlarged?
Through divison of cancer stem cells into cancer strm cells or transit amplifying cells. These progress through mutations and epigenetic changes into malignant cancer stem cells.
Outline the steps leading to metastasis formation.
- Cancers cells manage to escape into the blood through the ‘leaky’ blood vessles supplying the tumour, or a lymph vessle.
- Cancer cells adhere to endothelium, penetrating it and forming a micrometastasis.
- Parenchym is infiltrated and a full metastasis, cancer colony, is formed.
How does tumour angiogenesis lead to evolving of aggressive cancers?
The vessles formed are leaky and partyl malformed, leading to areas of hypoxia in the tumour. This makes for selection of cells that better withstand these hardh conditions. Metastasizing of these cells is more effective as they survive better in harsh conditions.
What is HIF-1α and what is its role in tumours?
Hypoxia inducible factor-1α, mediates tumour angiogenesis in hypoxic conditions.
What is the role of thre stroma for the tumour?
Throug extracellular signaling the stroma and tumour work together. The stroma induces tumour growth and the tumour excretes protein signal and proteases to modify the ECM.
List 9 properties that contribute to cancerous growth.
- Self-sufficiency, no need fot survival sigbals
- Insesitive to anti-proliferation signals
- Less prone to apoptosis
- Defective intracellular control mechanisms that respond to stress or DNA damage
- Induction of help from normal stromal cells
- Induction of angiogenesis
- Metastasization
- Genetic instability
- Recruit ways of stabilizing telomeres
Are all carcinogens chemicals?
No. Ex. radiation is classified as carcinogenic.
Name a commo, rapid, test for mutagens.
The Ames test.
How come most carcinogenic chemicals are relatively inert as such?
They are converted enzymatically, ex. by liver cytochrome P-450, into more potent forms that induce mutation.
What combinations of tumour initiator and promotor exposure can lead to cancer?
- One initiator and immediate rapid succession of multiple promoters
- One initiator and delayed rapid succession of multiple promoters
- Multiple, far spaced, initiator exposures
What are common tumour promoters?
Phorbol esters such as TPA (tetradecanoylphorbol acetate which activate PKC and phosphatidylinositol signaling pathway.
What is the first sign of initiator + promoter exposure in skin cancer?
Formation of a papilloma.
Are infections, for example by viruses, directly responsible for cancers?
Usually no. They mostly promote cancer formation. Ex. HIV virus weakens the immune response, making it easy for herpes virus HHV-8 to infect and directly cause Kaposi’s sarcoma. Hepatitis B and C cause inflammation in the liver, increasing the chance of cancer formation. Also parasite may promote cancer formation.
What is a suggested most potent carcinogen?
Aflatoxin B1
Define cancer-critical genes.
Genes who alteration of which frequently leads to cancer.
What classes can cancer-critical genes be divided into?
- Proto-oncogenes (overexpressed mutant form called oncogenes)
- Tumour supressor genes(loss-of-function genes)
- DNA maintenance genes (mutation results in genomic instability)
How do proto-oncogenes and tumour supressing genes differ in their activation into carcinogenic form?
Proto-oncogene mutation usually results in a dominant oncogene, whilst the mutation of a tumour supressor gene is usually recessive and need to by homozygous for it to take effect.
Why is Ras an oncogene in many cancer cells?
The mutation of Ras makes it unable to hydrolize GTP to GDP causing chronic activation and subsequent cancer.
What’s so special about Rb gene and protein in oncology?
The Rb gene is commonly missing not only in retinobladtoma but aldo in many other forms of cancers. It is a tumour supressing gene.
Whilst a tumour supressing genes function may fail through loss of heterozygosity, are DNA sequence alterations the only possible way for tumour supressing gene alteration to occur?
No. Epigenetic changes may pack the gene into heterochromstin or silence it through cytosine methylation.
In what three ways may overexpression of a gene occur?
- Point mutation or deletion leads to a hyperactive protein or protein overproduction
- Gene amplification (multiple gene copies) caused by error in DNA replication
- Chromosomal rearrangement leading to overproduction or production of hyperactive protein
How is EGF and Myc related to tumour formation?
Deletion of part of the extracellular domain of the EGF receptor leads to ligand-independent activation. Myc overexpression leads to cellular proliferation past normal boundries.
Outlone the Rb mediated control of cell proliferation.
Rb inhibits E2F and is itself inhibited by cyclin D-Cdk4 complex which is inhibited by p16
What part of the PI3/Akt pathway is usually affected when a cell exhibits the Warburg effect?
Then PTEN phosphatase which regulates Akt.
The mutation of what apoptosis-controlling gene allows cancer cells to survive?
Bcl2
What affects p53 and what are the consequences of it.
Hyperproliferayive signals (overexpressed Myc), DNA damage, telomere shortening and hypoxia. Effects are cell cycle arrest, senescence and apoptosis.
Give an example of how replication of damaged DNA increases the risk of tumour formstion.
Chromosome breakage so that a telomere is lost makes for sister chromatid end-to-end joining after replication. ‘Separation’ of the sistet chromatids leads to formation of one chromosome with two copies of specific genes.
What is the mechanism of papillomavirus tumour formation?
The two oncogenes E6 and E7 bind key tumour supressor proteins Rb and p53.
What are the key difficult points in metastasis formation?
Entry into blood or lymph and survival of tumour cells in colonized tissue. Traveling and exiting of tumour cell from a blood vessle is easy.
What is a possible marker for a good metastasizing ability of a tumour?
The Rho-family GTPase RhoC. It helps mediate actin-based cell motility.
What is a key feature of the EMT (epithelial-to-mesenchymal transition)?
A change in the E-cadherin gene which nornally serves to keep cells bonded together through adherens junctions.
Name an affected oncogene found in up to 40% of coloractal cancer cells.
K-Ras.
How does loss of heterozygosity of Apc trigger tumour formation and what type of cancer may this mechanism often be found?
Apc is an inhibitory protein for the Wnt-signaling pathway. Apc binds nirnally to β-catenin, inhibiting it from entering thr nucleus. When β-catenin is free to enter the nucleus in a stem cell the stem cell population expands uncontrollably leading to tumour formation. Loss of Apc activity also leads to increased frequency of mitotic spindle defects. The mechanism is usual in FAP (familial adenomatous polyposis coli).
What is another possible way for cancer, ex. colon cancer, to arise apart from defective signaling pathways?
Malfunction of the DNA mismatch repair system.
Outline a theoretical histological progression of colorectal cancer with relevant biomolecular signal defects.
- Normal epithelium progresses through loss of Apc to hyperplastic epithelium
- Development into early adenoma
- Early adrnoma turns into intermediate adenoma through activation of K-Ras
- Development into late adenoma adter loss of Smad4 and other tumour supressors
- Loss of p53 causes carcinom
- Other unknown alterations lead to invasion and metastasis
What common activation patterns may be expected for wrparate tumours?
The sltered signal pathways and the order in which they are altered serm to correlate.
How is PARP inhibition an effective treatment of cancer?
It inhibits a pathway for DNA strand breakage repair. Whilst normal cells have many paths for breakage repair many cancers, like those that have inactivated Brca1 and Brca2 genes that function in DNA recombinant events, only have one accessible pathway (PARP mediated). When it is blocked the tumour cell dies.
What role does Mdr1 play in tumour drug resistance?
Mdr1 codes for a plasma-membrane-bound transport ATPase that excretes lipophilic substances, such as drugs, from the cell.
What is the phenomenon of oncogene addiction?
A tumour with oncogene addiction is highly dependent on one overproduced or hyperactive protein. Blocking the production of thsi protein combats the cancer.
Give an example of a small molecule that can inhibit specific oncogenic proteins.
Gleevec fits into the ATP binding groove of the Brb-Abl-fusion protein, inhibiting it from activating signal protein for cell proliferation/survival.
How does inhibition of the VGEF-receptor (vascular endothelial growth factor) combat cancer?
The inhibition of the effects of VEGF makes for poor angiogenesis in the tumour and thus lessened blood supply.
Why is multi-drug therapy a more efficient way of treating cancer, compared to successive drugs?
It disallows drug resistance and following selection to occur in the cancer cells.
