Lecture 29: Cancer 2 Flashcards
What type of proteins are usually encoded by tumor suppressor genes?
Proteins that inhibit cell proliferation
What are the 2 major categories of proteins that tumor suppressor genes encode?
Proteins that normally restrict cell growth and proliferation
Proteins that maintain integrity of the genome
What are examples of proteins that normally restrict cell growth and proliferation?
Rb, CKI, proteins that promote apoptosis (caspases)
What are examples of proteins that maintain the integrity of the genome?
ATM, ATR (checkpoint control - detect DNA damage), DNA repair enzymes or pathways
What type of gene is Rb?
A tumor suppressor - it prevents over-proliferation of cells and inhibits cell division
What are the 2 forms of retinoblastoma?
Hereditary
Sporadic
Are the majority of Retinoblastoma cases hereditary or sporadic?
Sporadic = 60%
What is the difference between hereditary and sporadic retinoblastoma?
Hereditary = familial, BOTH eyes are affected
Sporadic = NO family history, single tumor in one eye
Which type of retinoblastoma is associated with a loss of heterozygosity?
Hereditary
What leads to the loss of heterozygosity?
Person initially starts one Rb deletion in every cell (inherited), then somatic event occurs and eliminates the one good copy –> tumor forms
In the sporadic form of Rb, you start off with all normal cells - no mutations of Rb. What hypothesis describes the development of Retinoblastoma in this case?
Two-hit hypothesis - first Rb gene obtains mutation, then another mutation must occur to develop Retinoblastoma
What binds to the promoters of G1/S cyclin and S cyclin genes to drive the cell cycle and what is the effect of the Rb protein on this interaction?
E2F - this is inhibited by interaction with the Rb protein, so Rb inhibits cell division
When Rb is mutated, cell division proceeds uncontrolled –> cancer
True or false: The Rb pathway includes tumor suppressor genes only, not oncogenes
False – the Rb pathway can include both tumor suppressor genes and oncogenes
What is the action of an active CKI (p16)?
Inhibits Cdk, so Cdk-cyclin complex will not phosphorylate Rb
Rb then binds E2F and blocks it, inhibiting cell proliferation
What is the action of Cdk-cyclin in the absence of a CKI?
Cdk will remain permanently active, Cdk-cyclin complex can now phosphorylate Rb
Rb will be inactive and E2F will drive S-Cdk activation by making more cyclins
What type of gene are Cdks or cyclins considered when they are overproduced, why?
Oncogenes - bc overproduction can overcome the amount of CKIs and lead to uncontrolled growth –> cancer
What type of genes are CKI and Rb considered, why?
Tumor suppressor genes, because if these are lost, there is no control of Cdk-cycling or suppression of entry into the cell cycle –> cancer
What tumor suppressor gene is considered the guardian of the genomic galaxy because it is mutated in the majority of cancers
p53
What are the 4 processes that p53 is primarily involved in?
- Cell cycle arrest
- DNA repair
- Apoptosis
- Block of angiogenesis
If you lose p53, what functions are you losing?
- Loss of checkpoint control in cell cycle
- Loss of cell cycle arrest d/t DNA damage
- Loss of DNA repair
- Loss of apoptosis d/t DNA damage
What are the 2 functions of p53 as a gene regulatory protein?
Stimulates transcription of gene encoding CKI called p21
Activates expression of pro-apoptotic proteins BH123 and BH-3
What 2 conditions are caused by papilloma viruses?
Warts and cervical cancer
How does viral DNA exist in human cells after infection with the virus?
Extrachromosomal material - like a plasmid
What occurs if viral DNA integrates into host DNA in terms of tumor development?
Viral DNA will interfere with control of cell division in basal cells –> malignant tumor development
True or false - papilloma viruses lead to malignant tumor development after infection of host cell prior to integration into host genome
False - prior to integration into host genome, HPV causes benign warts. If accidental integration of viral DNA occurs, unregulated production of viral proteins drives cell proliferation leading to a malignant tumor
What are the 2 viral proteins of papilloma virus?
E6 and E7
The viral proteins of papilloma virus E6 and E7 bind to which 2 tumor suppressor genes? What does this cause?
Rb and p53
Uncontrolled cell proliferation
In a tumor cell resulting from HPV, viral protein _____ binds to Rb so _____ can cause overexpression of G1/S-Cdk and S-Cdk and cells grow and divide
Viral protein ____ binds to p53 and inactivates it so ______ is not produced –> Cdk’s can act uncontrollably
E7; E2F
E6; CKI
A ______________ is a normal gene, usually involved in regulation of cell proliferation that can be converted into a cancer-causing oncogene by a mutation
Proto-oncogene
Transgenic (Tg) mice are a tool for studying oncogenes. What is the difference in the results in:
Myc Tg mice
Ras Tg mice
Myc Tg x Ras Tg mice
Myc Tg mice - cell proliferation occurs but most cells to not give rise to cancer
Ras Tg mice - more severe - tumors occur earlier
Myc Tg x Ras Tg - Develops tumors earlier and faster
Is Bcl-2 an oncogene or tumor suppressor gene?
Oncogene
How does Bcl2 function as an oncogene?
A Bcl2 mutation stops apoptosis
For most cancers, the first step of metastasis is local invasion - is this an easy or difficult step?
Difficult! Only a few cancer cells will pass this barrier
The initial entry into blood or lymphatic vessels is facilitated by ___________ of new blood or lymphatic vessels. Is this an easy or difficult step?
Easy - most cancer cells have acquired this ability before becoming invasive through mutations in genes that control apoptosis
Many cancer cells survive in circulation and exit at remote sites to colonize new tissues - is this an easy or difficult step?
Difficult - some cells die after entering foreign tissues, others fail to proliferate. Only a few metastasis-competent cells continue to proliferate in foreign tissue and form tumors
Colorectal cancer is one of the most preventable cancers. Where does it arise?
In the epithelial lining of the large intestine (highly organized, renewed by stem cells every week)
There are 600,000 deaths annually from colon cancer, what percentage of total cancer deaths are due to colorectal cancer?
10%
Colonoscopies are important for early detection of colorectal cancer - they detect small, protruding tumors called polyps, which are considered ___________
Adenomas
What happens when a colorectal polyp (adenoma) is left alone
A malignant tumor develops
40% of colorectal cancers have point mutations in ______
60% have an inactivating mutation of _______
An important loss is a ______ mutation
K-Ras
p53
APC
Familial adenomatous polyposis coli is characterized by hundreds of polyps - of which at least one will certainly become malignant. What will ultimately cause this malignancy?
Inactivation of tumor suppressor gene APC - leading to loss of heterozygosity so NO APC is transcribed
[because in familial cases they already only have one functioning copy of APC]
T/F: most colorectal cancers are hereditary
False, more than 80% show inactivation of both copies of APC acquired throughout lifetime
What is Hereditary non-polyposis colorectal cancer (HPNCC)?
In most cases of colon cancer, there is high degree of genetic instability (multiple copies of chromosomes); with HPNCC, there is a normal number, or near-normal number of chromosomes
What is the purpose of chemotherapy and how does this lead to the common side effects of hair loss, nausea, anemia & immune dysfunction?
Chemotherapy stops cell division, and this includes hair follicle cells, stomach-lining cells, and blood-producing cells
The Philadelphia Chromosome has a reciprocal translocation between chromosomes 9 and 22, which is responsible for chronic myelogenous leukemia. What does this translocation do to bring about CML?
There is a break point in two genes - Bcr (22) and Abl (9), these come together and fuse
When the N-terminus of Bcr joins Abl, it makes it hyperactive as a tyrosine kinase leading to a high degree of cell proliferation
CML involves a Bcr-Abl protein, what is the treatment for CML?
Gleevec - inhibits tyrosine kinase activity by taking the place of ATP on Bcr-Abl so the substrate does not change, and causes disappearance of Philadelphia chromosome in 80% of patients
What is the reason for combination therapy to treat cancer?
Treating patients with drugs simultaneously is an advantage for cancer therapy because it can kill different types of cells that might have the ability to survive one treatment alone
Cancers can be very heterogenous - meaning that they are different in everyone. What is the future of cancer treatment?
Custom-driven treatments selected to target specific disregulated cancer-critical proteins
Personalized-medicine!!!
What is the basis of Anti-angiogenesis therapy?
Prevents new blood vessel formation by tumors. In mice, repeated treatments with this therapy resulted in the tumor growing back 6 times, but on the 7th time there was no tumor growth. However this does not translate to human use - only works in some
