Molecular Basis of Cancer Flashcards
Define cancer in terms of cell division/cell growth/cell loss
Genetic diseases in which abnormal cells divide without control
- Cell growth rate exceeds cell loss rate
What is clonal expansion?
A single mutated cell gives rise to a subpopulation of genetically identical (mutated) cells which can then also mutate and replicate, and so on
Define tumor. What are the four classes of tumors and what cell types does each arise/originate from?
Tumor:
- Carcinomas: arise from epithelial cells (lung, prostate, breast, skin, colon)
- Sarcomas: arise from cells of supporting tissues (blood vessels, adipose, muscle, bone)
- Lymphomas: arise from cells of immune system (mass of WBCs)
- Leukemias: arise from cells of blood-forming tissue (lymphatic system, bone marrow)
What are the three stages of tumor development? Describe each step
- Initiation: mutation in a single cell that gives it the potential for abnormal growth (altered genetically)
- Promotion: that single mutated cell is stimulated by external factors and replicates; cell cycle checkpoints off
- Progression: cell has enough mutations that it can grow without any stimulation (doesn’t depend on growth factors)
What are the four major causes of cancer?
- Chemical and environmental factors
- Viruses
- Genetic factors
- Obesity
What are two examples of chemical and environmental factors that cause cancer? Which one more commonly causes cancer, and what is the most common cancer type associated with the other?
- Chemical carcinogens (80% of cancers caused by carcinogens)
- Radiation sources (commonly associated with skin cancer)
How do carcinogens cause cancer? Provide five examples
Carcinogens cause cancer by damaging DNA structure
- Free radicals from normal metabolism
- Tobacco
- Alcohol
- Arsenic
- Asbestos
How does radiation cause cancer? Provide three examples
Radiation sources can damage/destroy DNA structure, as well
- UV light
- X-rays
- Gamma-rays
What are tumor initiators? What are tumor promoters? Provide (at least) four examples of each
Tumor initiators: directly cause DNA damage
- Examples: tobacco, herbicides, pesticides, radiation, UV light
Tumor promoters: do not directly cause DNA damage but do increase proliferation of damaged DNA
- Examples: chronic inflammation, infection, hormones, alcohol, tobacco, drugs
What are the two types of genetic material in viruses? Provide an example of each and the type of cancer it causes
DNA virus
- Example: Human papillomavirus (HPV) causes cervical cancer
RNA virus
- Example: Hepatitis C virus causes liver cancer via cirrhosis
What are the two proteins involved with HPV and cancer development? Describe the function of each (i.e. what it binds to) and what this results in
E6 protein binds to p53 and destroys it
- No p21 protein production so cyclin-CDK complexes never inhibited and cell cycle always on
- Inhibition of apoptosis (no cell death)
E7 protein binds to Rb protein
- Disrupts its ability to bind to E2F to halt cells at the R checkpoint so E2F is free to stimulate transcription of S phase genes and there is constant cell division
What is the vaccine associated with HPV and how does it work to protect against cancer if exposed?
Gardasil vaccine contains coat proteins of two HPV strains that cause 75% of cervical cancers
- If exposed, these proteins would stimulate an immune response to defend the body against the proteins
What are the three genetic factors that can cause cancer?
- Oncogenes
- Inactivated tumor suppressor genes
- Inherited mutations/alleles (predisposition to cancer)
What are the three modes of mutations that can occur in oncogenes? Provide one example of each
- Point mutations: Ras gene
- Gene amplification: MYC gene
- Gene rearrangement: MYC protein (Burkitt’s Lymphoma), CML gene (Philadelphia Chromosome)
Where are the two locations on the Ras gene where a mutation can occur, and what does each lead to?
- Mutation at coding region: causes hyperactive protein
- Mutation at promoter region: causes over expression of gene
If there is a point mutation in the Ras gene, what downstream affect does this have on the cell cycle?
Point mutation of Gly to Val causes Ras gene to always be on
- MAP Kinase cascade always on
- MYC gene always on
- CyclinD production always on
What is the normal function of the MYC gene? How is this altered with gene amplification?
Normally, the MYC gene is a transcription factor that binds to DNA to stimulate gene transcription
- If mutated via gene amplification, the actual MYC gene function is normal but there is too much of it, leading to excess MYC mRNA transcripts
What is the process by which translocation occurs in the MYC protein (Burkitt’s Lymphoma)? What does this result in?
Reciprocal translocation between chromosomes 8 and 14 resulting in IgH gene and MYC gene on the same chromosome (14)
- Leads to overproduction of MYC protein
What is the process by which translocation occurs in the CML protein (Philadelphia Chromosome)? What does this result in?
Reciprocal translocation between chromosomes 9 and 22
- Creates a new fusion oncogene called BCR-ABL that then produces the BCR-ABL fusion protein (tyrosine kinase is always active and does not depend on growth factor)
What are the four normal functions of tumor suppressor genes (TSGs)?
TSGs code for proteins that regulate the cell cycle/cell division by…
- Preventing the cell from dividing when it’s not supposed to
- Slowing or halting the cell cycle upon DNA damage
- Repairing damaged DNA
- Inducing apoptosis
If TSGs are mutated, what does this result in? What are two examples of tumor suppressor genes?
TSGs are inactivated and lose their function
- Results in uncontrolled cell growth
Examples: TP53 and Rb
What is the normal function of the TP53 gene? Explain the mechanism behind a mutation in the TP53 gene
Normally, TP53 is the gene that encodes the p53 protein (detects DNA damage, becomes phosphorylated and acts as transcription factor to activate p21 expression AND triggers apoptosis)
- With mutation of TP53, p53 is inactivated so there is no DNA repair, apoptosis or cell cycle arrest
What is the normal function of the Rb gene? Explain the mechanism behind a mutation in the Rb gene
Normally, Rb protein is bound to E2F which does not allow for the production of S phase genes; it can be phosphorylated to release from E2F and allow for S phase gene transcription
- With mutation of Rb, Rb cannot bind to E2F so E2F can perform constant transcription of S phase genes and DNA synthesis is constantly on
Regarding oncogenes and TSGs, which is a gain-of-function mutation and which is a loss-of-function mutation? How many copies of a mutated gene are necessary to promote cancer?
- Oncogenes: gain-of-function mutation (only requires 1 mutated gene to promote cancer)
- TSGs: loss-of-function mutation (requires 2 mutated genes to promote cancer)
What is Loss of Heterozygosity?
In hereditary cancer syndromes, individuals that are heterozygous start life with a germline mutation in one of their alleles but it is balanced by a normal counterpart allele
- Loss of Heterozygosity: loss of the normal counterpart (becomes homozygous for mutated genotype)
What is Knudsen’s Hypothesis?
Knudsen’s Hypothesis: most genes require 2 mutations to cause a phenotypic change
What are five examples of cancers cause by autosomal dominant patterns?
- Retinoblastoma
- Li-Fraumeni Syndrome
- Neurofibromatosis Type 1 (NF1)
- Hereditary Non-Polyposis Colon Cancer (HNPCC)
- Familial breast cancer
What is the mutation in retinoblastoma, and what are the two types of Retinoblastoma? Describe each type
Retinoblastoma is a mutation in the Rb protein
- Sporadic: occurs in children with NO family history of retinoblastoma
- Hereditary: occurs in children with positive family history for retinoblastoma
What is the mutation in Li-Fraumeni Syndrome? How does this present in families, and is it more common or rare?
Li-Fraumeni Syndrome is a mutation in the TP53 gene
- VERY rare
- Occurs in families and with each generation, the affected age is younger
What is the mutation in Neurofibromatosis Type 1? How does this gene function normally and what occurs with the mutation of this gene?
Neurofibromatosis Type 1 is a mutation of both copies of the NF1 gene
- Normally, NF1 gene encodes the protein neurofibromin which serves as a GTPase Activating Protein (GAP) and facilitates deactivation of Ras gene
- With mutation, Ras gene is always on so it stimulates cell division
What are the three symptoms associated with Neurofibromatosis Type 1?
- Skin hyperpigmentation
- Neurofibromas
- Lisch nodules
What is the mutation in Hereditary Non-Polyposis Colon Cancer (HNPCC)? How does this gene function normally and what occurs with the mutation of this gene?
Hereditary Non-Polyposis Colon Cancer (HNPCC) is a mutation in the MSH2 and MLH1 genes
- Normally, MSH2 and MLH1 genes work together to detect errors in DNA and remove the affected section so it can be corrected
- With mutation, MSH2 and MLH1 cannot correct DNA replication mistakes
What is the mutation in Familial Breast Cancer? How does this gene function normally and what occurs with the mutation of this gene?
Familial Breast Cancer is a mutation in the BRCA1 and BRCA2 genes
- Normally, BRCA1 and BRCA2 produce proteins involved in DNA repair
- With mutation, BRCA1 and BRCA2 cannot assist with DNA repair
Besides breast cancer, what other cancer is commonly associated with mutations in the BRCA1 and BRCA2 genes?
Ovarian cancer
What is one example of cancer cause by autosomal recessive patterns?
Xeroderma Pigmentosum (XP)
What is the mutation in Xeroderma Pigmentosum? How does this gene function normally and what occurs with the mutation of this gene?
Xeroderma Pigmentosum (XP) is a mutation in the genes involved in repairing DNA that is damaged by UV radiation
- Normally, pyrimidine dimers in DNA that are formed upon sunlight exposure are repaired before they can cause problems
- With mutation, DNA damage is not repaired correctly and as more abnormalities form in the DNA, cells malfunction and eventually become cancerous and die
What is the correlation between obesity and cancer risk? What type of receptors are often found in increased levels with cancer?
Strong correlation between obesity and cancer risk (obese = higher risk for CA)
- Insulin receptors are often in abundance
What are the six properties of cancer cells?
- Self-sufficiency in growth signals
- Limitless replicative potential and loss of contact inhibition
- Genetic instability
- Tissue invasion and metastasis
- Sustained angiogenesis
- Evading apoptosis
With self-sufficiency in growth signals, what happens normally and what happens in cancer cells?
Normally, cells depend on growth factors in order to grow
- With cancer, cells are able to grow in the absence of growth factors and they can produce their own growth factors (neighboring cells respond and also proliferate)
With limitless replicative potential, what happens normally and what happens in cancer cells?
Normally, each cell exhibits a limited capacity for cell division
- With cancer, cells continue to divide indefinitely (“immortal”)
With loss of contact inhibition, what happens normally and what happens in cancer cells?
Normally, cells exhibit growth inhibition with surrounding cells in the petri dish
- With cancer, cells will continue to grow and pile on top of each other (layer)
With genetic instability, what happens normally and what happens in cancer cells?
Normally, cell cycle checkpoints are enabled and if there is an abnormal chromosome content in a cell, apoptosis is activated (normal differentiation)
- With cancer, cell cycle checkpoints are disabled, and cells are unable to repair DNA damage or abnormal chromosome counts so abnormal cells are produced/differentiated
What is tissue invasion?
Tissue invasion: direct extension and infiltration of cancer cells into the surrounding tissue
What is metastasis?
Metastasis: ability of cancer cells to journey through circulation to invade the basement layer and extracellular matrix of normal tissues elsewhere in the body
Describe the process of metastasis in eight steps
Mutation occurs → growth factor supports expansion of mutated cells → intravasation → migration → adhesion to endothelium → extravasation (out of blood vessel) → induction of angiogenesis (formation of new blood vessels) → growth in metastatic location
Provide two examples of common metastases pathways
- Primary GI or colon cancer commonly metastasizes to liver
- Primary breast or prostate cancer commonly metastasizes to bone
What is angiogenesis? What happens normally? What is happening with sustained angiogenesis and cancer cells?
Angiogenesis: new blood vessel formation
- Normally, it occurs due to hypoxia → hypoxia causes elevated levels of HIF-1 which in turn increases levels of VEGF
- With cancer, tumor cells grow and eventually become hypoxic, inducing angiogenesis, which provides O2 and nutrients to the tumor cells (induction of angiogenesis is NOT normal) → disorganized and leaky blood vessels are produced, resulting in even more hypoxia
What are four inducers of angiogenesis?
- VEGF (vascular endothelial growth factor)
- ANG (angiopoietin)
- FGF (fibroblast growth factor)
- TGF-beta (transforming growth factor-beta)
What is the apoptosis cascade? What protein is involved, and what is this protein called in its inactive precursor form? How is this inactive form activated?
Apoptotic cascade: when necessary, cells activate a signal cascade via caspases (proteins)
- Caspases cut off contact with surrounding cells, shut down cellular metabolism and trigger signals for phagocytosis
- Inactive precursor caspases are called procaspases, which are activated by proteolytic cleavage
What are the two apoptosis pathways?
- Intrinsic apoptotic pathway
- Extrinsic apoptotic pathway
What happens normally in the intrinsic apoptotic pathway? What happens when cancer is present?
Normally, p53 inhibits anti-apoptotic factors (like BCL-2) and increases production of pro-apoptotic factors (like BAX), which promote apoptosis of damaged cells
- With cancer, p53 is inactivated so pro-apoptotic factors are not produced and anti-apoptotic factors are found in increased levels, suppressing cells death and allowing mutated cells to divide
What are four groups of chemotherapy drugs, and at which phase in the cell cycle is each designed to treat?
- Antimetabolites: S phase
- Mitotic inhibitors: mitosis
- Anti-tumor antibiotics: interphase
- Alkylating agents: interphase
What is the function of antimetabolites? Provide a medication example and its mode of action
Antimetabolites: disrupt DNA production → prevent cell division and tumor growth
- Methotrexate: blocks regeneration of THF, thus inhibiting dTMP and purine synthesis (lacking nucleotides = compromises DNA synthesis)
What is the function of mitotic inhibitors? Provide a medication example and its mode of action
Mitotic inhibitors: mitosis arrested → prevent cell division and leads to cell death
- Taxol (Paclitaxel): binds to microtubules and stabilizes the structure to inhibit the reorganization of microtubule network
What is the function of anti-tumor antibiotics? Provide a medication example
Anti-tumor antibiotics: inserts itself into DNA → DNA cannot synthesize normally, blocking cell growth
- Doxorubicin
What is the function of alkylating agents? Provide a medication example and its two modes of action
Alkylating agents: attach alkyl groups to outside of DNA bases, damaging the DNA by forming cross-bridges → DNA cannot synthesize normally because it is linked and not separated
- Cisplatin: creates covalent interstrand and intrastrand crosslinks between purine bases within the DNA, AND forms adducts with proteins
What are the three types of targeted therapy?
- Immunotherapy
- Inhibition of cancer-promoting genes
- Inhibition of angiogenesis
What is the method of immunotherapy? Provide a medication example and its mode of action
Immunotherapy: using antibodies against tumor cells
- Herceptin: treats the overexpressed HER2 genes in breast cancer by binding to the extracellular domain of HER2 gene, which in turn inhibits its intrinsic tyrosine kinase activity and blocks downstream signaling pathways
What is the method of inhibition of cancer-promoting genes? Provide a medication example and its mode of action
Inhibition of cancer-promoting genes: activity of proteins are selectively blocked so that population of malignant cells is destroyed
- Gleevec (Imatinib): binds to the BCR-ABL fusion protein in CML where ATP would normally bind, so the substrate cannot be phosphorylated and its tyrosine kinase activity is inhibited
What is the method of inhibition of angiogenesis? Provide a medication example and its mode of action
Inhibition of angiogenesis: prevents the growth of blood vessels that nourish and oxygenate the tumor
- Avastin (Bevacizumab): inhibitor of VEGF receptor – binds to VEGF extracellularly to prevent interaction with VEGF receptors, thereby inhibiting its activities and further proliferation
What is multi-drug treatment of cancer?
Treatment with multiple drugs simultaneously can ensure that no cells are resistant to the drugs and the cancer is “under control”
