Four Letter Words and Cancer PART 2 Flashcards
What is the first step in cancer metastasis?
Loosening of tumor cells. E-cadherin fails due to mutation, B-catenin activation, or by SNAIL and TWIST.
What is the second step in cancer metastasis?
Local degradation of the basement membrane and interstitial connective tissue.
Proteases and MMPs (matrix metalloproteases) are either secreted by tumor cells or stromal cells.
They remodel the basement membrane and interstitium.
What’s the third step in cancer metastasis?
Changing the attachment of tumor cells to ECM proteins.
Cleavage of the basement membrane, Type IV collagen, and laminin by MMPs generate novel binding sites for tumor surface proteins.
What is the 4th and final step in cancer metastasis?
Migration through the basement membrane, now that tumor cells have established contact.
The tumors generate Autocrine Mobility Factors that influence their movement.
OR - stromal cells secrete mobility cytokines like HGF/SCF (hepatocyte growth factor/scatter factor)
Most tumor cells migrate through the vasculature in what form?
Single cells.
What determines WHERE a cancer will metastasize if single cells are already in the vasculature?
- Most cancers metastasize in the first capillary bed they encounter.
- Some have adhesion molecules for a specific organ.
- Some follow chemokines to find their target organ.
How do you know where breast cancer cells in the vasculature will metastasize next?
Breast cancer cells express high levels of chemokine receptors CXCR4 and CCR7. Organs that these cells are attracted to express the ligands for those receptors, so breast cancer naturally follows the chemokines these organs produce.
The switch of tumor cells to aerobic glycolysis is called……
the Warburg Effect.
Tumors that adopt this energy utilization mechanism are the FASTEST GROWING
The survival of a tumor in a secondary site is dependent on what?
The receptive stromal cells in that area.
What proteins are responsible for EMT (Epithelial to Mesenchymal) transition?
SNAIL and TWIST - down regulate E-cadherin and promote metastasis.
Why is the Warburg effect so efficient for rapidly reproducing cells?
Glucose is the main source for carbons that are used for lipid synthesis.
(Need it for membrane of new cells)
We can use the glucose in tumors to scan for them. What is this scanning technique called?
PET scan - inject a radiographic, nonmetabolizable form of glucose and see where it goes.
Most tumors are PET scan +
Positron Emission Tomography
What are the 3 types of DNA repair?
- Mismatch repair
- Nucleotide Excision Repair
- Recombination Repair
HNPCC (Hereditary Non-Polypisis Colon Carcinoma Syndrome) is caused by a defect in what type of DNA repair?
Defect in DNA MISMATCH REPAIR
WHat is a micro satellite and what does it have to do with colon cancer?
Microsatellites are tandem repeats of 1-6 nts found throughout the genome.
Microsatellite instability is found in 15% of sporadic colon cancers
Patients with Xeroderma Pigmentosum have defects in what?
Nucleotide excision repair.
Upon exposure to UV light, thiamin dimers occur, and there is no repair.
What protein detects DNA damage from ionizing radiation and activates p53?
ATM -ataxia tenagiectasia mutated
What type of DNA repair is lost in breast cancers with BRCA1/BRCA2 mutations?
Homologous recombination repair by the protein products of BRCA1/2 genes.
THese genes encode DNA repair proteins.
Without them, cells develop chromosomal breaks and develop sever aneuploidy.
If a patient has mutation in BRCA1 but not BRCA2, can they develop cancer?
No. Much like Tumor Suppressor Genes, BRCA genes must have 2 hits.
Mutations in BOTH genes is necessary for cancer.
WHy?: you can still repair gene breaks from homologous recombination with one protein. The absence of both is what sucks.
Do sporadic breast cancers have BRCA mutations?
NO! These are inherited.
Defects in RAG and AID enzymes result in what types of cancer?
Why?
Lymphoid neoplasms
Makes sense because RAG and AID (cytidine deaminase) are necessary for lymphocyte development.
THEY INTRODUCE GENOMIC INSTABILITY
How does chronic inflammation induce tumor cell formation?
Constantly proliferating cell populations are at high risk for developing/accumulating mutations.
In chronic inflammation, there is COMPENSATORY proliferation to repair the tissue damage, as well as producing inflammatory cytokines, ROS, etc… that can cause DNA damage.
What microbe causes constant liver cell proliferation during chronic infection?
HEP B and C
What microbe causes a lot of gastric cancer?
H. Pylori
Tumors accumulate sequential mutations that vary by the type of cancer. What is the sequence of mutations that lead to colon cancer?
APC –> RAS –> p53 –> CANCER
pg 199 in book: Figure 5-30
What is the most potent indirect-acting carcinogen?
What is an indirect-acting carcinogen anyway?
Indirect-acting carcinogens are chemicals that require metabolic conversion into ULTIMATE CARCINOGENS.
Ex: POLYCYCLIC HYDROCARBONS in cigarette smoke.
What are the principle active products in polycyclic hydrocarbons?
Epoxides that form covalent adducts with DNA, RNA, and proteins in the cell.
What type of carcinogen is an alkylating agent? Aren’t they supposed to treat cancer, not cause it?
Alkylating agents (like cyclophosphamide) are DIRECT-ACTING carcinogens.
They cure one type of cancer, only to make a person susceptible to another, usually LYMPHOMA.
After exposure to the radioactive aftermath of the atomic bomb, residents of Nagasaki and Hiroshima got what type of cancer?
Myelogenous Leukemia
What is the main type of DNA damage caused by radiation?
Double strand breaks.
____________ tumors are associated with total sun exposure, but ______________ (cancer type) are associated with intermittent sun exposure.
Non-melanoma cancers (Like Squamous Cell Carcinomas) = accumulation of total sun exposure = risk
Melanoma = intermittent sun exposure.
What oncogene is responsible for the Warburg Effect?
MYC - TF causes up regulation of genes that promotes aerobic glycolysis.
What fraction of cancers can be contributed to viral infection?
1/5 (20%)
Viruses are the leading cause of what two types of cancer?
Liver (HEP B/C) and Genital (HPV)
What 2 viruses cause mutations in membrane-associated proteins?
KSHV (Herpes) - constitutively active GPCR
EBV - constitutively active Latency Membrane
Protein -1 (LMP-1)
BOTH are herpesvirus subtypes.
EBV infection causes what cancer? Why?
Burkitt’s Lymphoma - It upregulates CMYC expression in B-cells.
EBV causing Burkitt’s lymphoma has nothing to do with LMP-1.
KHSV infection leads to what cancer?
Kaposi Sarcoma - a lymphatic epithelial cancer
What’s the story of how to remember EBV’s viral mechanism?
EBV attacks and infects B cells via CD21 receptor. Causes LMP-1 (transmembrane signaling protein) to oligomerize in absence of ligand, leading to constitutive synthesis of BCL2, an apoptosis preventer.
EBV uses p21. Have to be 21 to get into a BARR.
Met a girl at the bar, slept with her, and she missed her LMP - last menstrual period.
Other mechanism: Upregulation of CMYC in Burkitt’s Lymphoma.
What is the cancer-causing mechanism of HPV?
HPV is a circular genome that may or may not integrate. (but integration is seen in metastatic tumors).
It codes viral proteins E7 and E6 which bind to Rb and p53, respectively.
CELL CYCLE DISRUPTOR. –> leads to uncontrolled proliferation.
Which oncogenic virus utilizes its core protein as its carcinogenic effector?
Hep C (HCV)
Why is it weird that EBV causes epithelial cancers as well as B cell cancers?
Because epithelial cells don’t express CD21, but EBV gets in there anyway.
HEP C and B are the main causes of what cancer?
Hepatocellular cancer
The HBx protein is associated with which virus? HBV or HCV?
HBV
Strains of H. pylori associated with gastric adenocarcinoma encode a pathogenicity island containing what gene?
CagA - H. Pylori secretes it and it mimics GF stimulation.
What is a tumor-specific antigen?
An antigen that is only expressed on the surface of tumor cells and no other cells.
What is a tumor-associated antigen?
Antigens present on both normal and tumor cells, but may be over expressed or abnormally expressed on tumor cells.
What cell type is the main immune responder to tumor cells?
CTLs
Tumor cells display weird antigens on MHC-1s and activate CTLs.
Unique, mutated peptides of what 4 oncogenes/TSGs are generally displayed on MHC-1s?
B-catenin, RAS, p53, and CDK4
What protein is mutated/overproduced in Melanoma? (also produced by normal, healthy melanocytes)
Tyrosinase
What gene that is usually only in the testis is expressed on 37% of MELANOMAS?
MAGE (Melanoma Associated Gene)
Others are RAGE, GAGE, and BAGE
The expression of these genes outside the testis indicates cancer. Altered methylation patterns. CTLs can attack cells that present these proteins because the immune system has no tolerance to them. (testes are immunoprivileged)
If a tumor down regulates MHC-1 expression in attempt to avoid the immune system, what cell can still attack it? What is the necessary receptor?
NK cells can detect cells with no MHC-1 expression.
NKG2D –> NK cells Got 2 Die
Many tumors can secrete ________ in an effort to evade the immune system.
TGF-B –> upregulates Tregs and prevents clonal expansion
What can tumor cells express that ends up killing a CTL that tries to kill the tumor?
FasL - binds to Fas on CTL and kills it.
What is another word for cachexin?
TNF
