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Losses of cellular regulation that cause cancer are most often due to _____ ______ accompanied by what 3 things.
Losses of cellular regulation that cause cancer are most often due to genetic damage accompanied by tumor-promoting chemicals, hormones and/or viruses.
- Proto-oncogenes normally promote regulated growth; mutated to oncogenes = excessive growth promotion
Tumor-suppressors and functions
Tumor-suppressors normally restrain growth; mutations that inactive them = inappropriate cell division
Genes that inhibit cell division. These are the "car brakes".
Mutations in caretaker genes
Mutations in caretaker genes, that normally protect genomic integrity can cause uncontrolled cell division = cancer
Malignant tumor classes:
Cancer cells exhibit an unusual...
The cancer-forming process, oncogenesis or tumorigenesis is the result of
In absence of blood supply, a tumor can growth to
Cell division on the outside of the tumor mass is balanced by death of cells in the center that lack
- Some tumors secrete hormones that stimulate new blood vessel formation and invasion into the tumor
- The creating of blood vessels. Cancer cells often transmit signals to grow vessels. This provides oxygen and other nutrients to sustain the cancer mass.
- Tumors secrete basic fibroblast growth factor (bFGF), transforming growth factor ␣ (TGF␣), and vascular endothelial cell growth factor (VEGF), all of which are angiogenic.
- Hypoxia induces these genes in the center of rapidly growing tumors
Hypoxia induces these genes by activating a transcription factor called
- HIF-1 not only induces the release of angiogenic hormones from tumors, it also changes the metabolic profile of tumors, allowing them to grow in relatively less oxygen.
- For example, HIF-1 increases expression of glycolytic enzymes.
Cancers usually originate in what type of cells and why?
- Cancers usually originate in proliferating cells.
- This is because mutations that lead to cancer must be passed onto progeny cells
Genetic alterations in cancerous stem cells can make them _______, so they could attain ________ _______
Genetic alterations in cancerous stem cells can make them niche-independent, so they could attain autonomous self-renewal
Mutations may give progenitor cells the stem-cell property of ______. This loss of ______ could lead to tumor formation.
Mutations may give progenitor cells the stem-cell property of self-renewal. This loss of growth control could lead to tumor formation.
Normal ras participates in many ________ signaling processes, and is a _______. It is activated when ____ is bound; it is a _____ and cleaves _____ to form _____, which inactivates ras.
Normal ras participates in many growth-oriented signaling Processes, and is a GTP-binding protein. It is activated when GTP is bound; it is a GTPase and cleaves GTP to form GDP, which inactivates ras.
RasD has a mutation where the _____ at position 12 is replaced with a _____; this form of ras hydrolyzes ___ very slowly to ____, so it remains active too long. The result is that rasD is autonomously (or constitutively) active, which “contributes” to oncogenic transformation.
RasD has a mutation where the glycine at position 12 is replaced with a valine; this form of ras hydrolyzes GTP very slowly to GDP, so it remains active too long. The result is that rasD is autonomously (or constitutively) active, which “contributes” to oncogenic transformation.
- As it turns out, mouse 3T3 cells have a loss-of-function mutation in the tumor suppressor gene that encodes p53. So, the combination of the gain-of-function mutation in rasD with the loss-of-function mutation in p53 is what allows for the oncogenic transformation.
- Normal cells transfected with rasD cannot transform into tumor cells
Multi-hit Model of Cancer Induction
Multiple mutations are required for tumor induction in transgenic mice
Mice with a mutant rasV12, which is one version of rasD, or the c-myc proto-oncogene overexpressed exhibit a lower rate of tumor formation than mice overexpressing both rasV12 and c-myc
- a mutation in one cell might give it a slight growth advantage, so this cell would give rise to a bunch of cells called a “clone”
- If one progeny cell then undergoes another mutation that would allow progeny to grow relatively less controlled,
it would form a benign tumor.
- But, a third mutation in a cell in this tumor would allow it to outgrow others and to overcome constraints by the tumor microenvironment, and its progeny, all of which would have all 3 mutations, would become metastatic.
- Virtually all human tumors have inactivating mutations in checkpoint genes
- Most cancers have inactivating mutations in one or more proteins that restrict progression through G1
List 4 mechanisms can produce oncogenes from corresponding proto-oncogenes, gain-of-function mutations...
1- Point mutations
2- Chromosomal translocation (type 1)
3- Chromosomal translocation (type 2)
4- Amplification of DNA segment encoding oncogene so too many copies are made
Point mutations are
Chromosomal translocation (Type 1)
- gene fusion encoding new hybrid oncogenic protein
- that fuses two genes together to produce a hybrid gene encoding a chimeric protein whose activity, unlike that of the parent proteins, often is constitutive, always active
Chromosomal translocation (Type 2)
Oncogenesis via either of first two mechanisms encodes an ______ that differs from the _______
Oncogenesis via either of first two mechanisms encodes an oncoprotein that differs from the normal protein.
Oncogenesis via the second two mechanisms generate oncoproteins that are identical to original, but …
- Oncogenesis via the second two mechanisms generate oncoproteins that are identical to original, but produced at higher than normal levels or in cells that normally don’t produce them
- Normally, checkpoints would inhibit oncogenic growth via second two mechanisms, implying coincident defects in caretaker genes
Cancer Causing Viruses Contain _______, or Actvate Cellular ________
Cancer Causing Viruses Contain Oncogenes, or Actvate Cellular Proto-oncogenes
Rous sarcoma virus (RSV)
The RSV genome contains
- Normal cells also shown to have a gene closely related to v-src, called c-src, and it does not transform
- However, v-src acts in a dominant manner over endogenous c-src = transformation in days
RSV is a transducing retrovirus, meaning...
A Few DNA Viruses are Oncogenic, how do they work?
Loss-of-Function Mutations in Tumor Suppressor Genes are Oncogenic. What are the 5 broad classes of proteins encoded by tumor-suppresor genes?
1- Intracellular proteins that inhibit progression through specific part of cell cycle (e.g. Rb for G1)
2- Receptors or signal transducers for secreted hormones that norally inhibit cell proliferation (e.g. TGF␣)
3- Checkpoint control proteins that arrest cell cycle if DNA is damaged (e.g. p53)
4- Proteins that promote apoptosis
5- Enzymes that participate in DNA repair
Tumor-supressor mutations that are recessive are due to
Proto-oncogenes become oncogenes because
1) of a genetic mutation or
2) a chromosomal translocation resulting in gene fusion.
- In either case, the protein is altered and the mutation is usually dominant. Alternatively, a chromosomal translocation or gene amplification can result in abnormally high expression of the normal protein.
Tumor suppressor genes, typically recesssive, are usually:
1)Negative regulators of the cell cycle (Rb, p16).
2)Receptors or signal transducers that inhibit proliferation (TGFβ).
3)Checkpoint mutations controlling cell cycle and apoptosis (p53).
4)Proteins involved in DNA repair (mismatch repair, nucleotide excision repair, repair of double-strand breaks – XP, FA, BRCA – Table 25-2.) Also known as caretaker genes, which encode proteins that reverse or prevent DNA damage
Rb is what kind of protein and is a key regulator of ______, and how?
Mutations in Rb that inactivate it can cause…
- Mutations in Rb that inactivate it can cause cancers, first found in hereditary retinoblastoma
- Interestingly, it has been found that Rb is inactivated in almost all cancer cells, either by mutations in the Rb alleles, or by mutations that cause an abnormal regulation of Rb phosphorylation
Loss of Heterozygosity (LOH)
- How does it result in cancer?
- Normally, heterozygous for a tumor-suppressor mutation will not result in cancer.- However, if you begin as heterozygous, then lose or Inactivate the normal allele, you become homozygous for the mutation, resulting in cancer
List two ways to lose heterozygosity (LOH) of tumor-supressor genes
1. via mis-segregation, (3:1 segregation) a.k.a., non-disjunction, during mitosis, due to failure of the spindle assembly checkpoint.
2.via mitotic recombination. Mitotic recomination between a chromosome with a wild-type and a mutant allele, followed by chromosome segregation, can produce a cell that contains two copies of the mutant allele.
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