Neoplasia Part 2 Flashcards
Describe monoclonal nature of cancer.
A tumor is formed by the clonal expansion of a single precursor cell
What is non lethal genetic damage?
Cell is still around with damage, continues to proliferate, picks up new mutations
What are the four classes of normal regulatory genes for cancer?
Proto-oncogenes-normal cellular genes whose products
promote cell proliferation (normal cell growth)
Growth-inhibiting tumor suppressor genes: stops cell proliferation
DNA repair genes
Apoptosis genes
What are oncogenes? What process are they involved in? Can a single oncogene cause cancer?
Mutated or over expressed versions of proto-oncogenes causing uncontrolled growth
Carcinogenesis
No (several oncogenes AND several tumor suppressor genes must be involved)
Is the progression of a tumor due to one single factor? Describe the steps of tumor progression.
No it has heterogeneity from a original single cell
environment factors, genetics etc contribute to etiology
Transformation (normal cell to tumor cell), progression, proliferation of genetically unstable cells, tumor cell variants: heterogeneity
What are 3 carcinogenic (cancer-causing) agents?
Chemicals
Radiant Energy
Microbial agents
Describe the carcinogenic chemicals: Nitrosamines, Asbestos, Arsenic, Alkylating agents, Vinyl chloride, Napthlyamine.
Nitrosamines: gastric adenocarcinoma
Asbestos: mesotheliomas, renal cell carcinoma, lung carcinoma
Arsenic: squamous cell carcinoma of skin and
lung, angiosarcoma of the liver
Alkylating agents: leukemia, lymphoma
Vinyl chloride: angiosarcoma of the liver
Napthlyamine: bladder cancer (cigarettes)
What carcinogenic chemical is associated with chemotherapy, explaining how people receiving chemo can develop other cancers?
Alkylating agents
Describe the initiation/promotion concept of carcinogenesis. What order do they act in?
Both initiators AND Promoters are needed
Neither can cause cancer by themselves
Promoters must take effect after initiation, not before
Describe initiators in carcinogenesis.
Carcinogens
Inflict Non-lethal damage to DNA that cannot be repaired
Describe promoters in carcinogenesis.
Promoters enhance the proliferation of initiated cells (damaged)
Promoters can induce tumors to arise from initiated cells
Promoters are nontumorigenic by themselves (can’t form tumors alone)
Act after initiators
What are 4 examples of promoters that can act on initiators (carcinogen)?
Hormones (ex: estrogen)
Phorbol esters
Phenols (ex: alcohols, juice)
Drugs
What are 2 direct-acting compounds?
Alkylating and acylating agents
Describe indirect acting compounds.
Require metabolic conversion in vivo to produce carcinogens to transform cells
Leads to mutation in cells by affecting the functions of oncogenes, tumor suppressor genes and apoptotic
Doesn’t bind to DNA
Hat kind of ultraviolet light is considered a radiation carcinogen?
UVB
How does UVB affect the cells?
Produces pyrimidine (T and C) dimers in DNA leading to
transcriptional errors and mutations of oncogenes and tumor suppressor genes
What disorder can be caused by UVB carcinogen?
Xeroderma pigmentosum (genetic disorder):
Mutations in DNA repair genes
Can have ocular surface defects as cells can’t repair
What are some examples of ionizing radiation as radiation carcinogens?
X-rays, Ɣ-rays, α particles, β particles, protons, neutrons
How does ionizing radiation lead to cancer? What types of cancer can it cause?
Causes chromosomal breakage, translocations,
and, less frequently, point mutations
Thyroid cancer, lung cancer, leukemia
What 5 types of viruses can lead to cancer? (Viral caginogens)
Human papillovirus (HPV)→ Cervical carcinoma
Epstein-Barr virus (EBV)→ Burkitt Lymphoma
Hepatitis B & C (HBV & HCV)→ Liver cancer
Human T-Cell leukemia virus type 1 (HTLV1→T-Cell leukemia/lymphoma
Kaposi’s sarcoma-associated herpesvirus (KSHV)→ Kaposi Sarcoma
What is an example of bacterial carcinogen?
H. Pylori- linked to gastric carcinomas and gastric lymphomas (people with frequent ulcers are at risk)
What are 5 types of gene mutations?
Point
Translocation
Deletions
Amplifications
Overexpression
How can miRNA involvement lead to development of cancer?
miRNA-negative regulators of genes: suppress genes involved in cancer development, overexpression lead to uncontrolled cell growth
Overexpression of miRNAs→ reduced tumor suppressor
proteins→ increased risk of cancer
Deletion or loss of expression of miRNAs→ overexpression of oncogenes→ increased risk of cancer
How can epigenetics changes lead to increased risk of cancer?
Hypermethylation of promoter sequences for tumor suppressing genes and DNA repair genes→inhibit transcription→increased risk of cancer
Describe how chromosomal translocation can lead to increased risk of myelogenous leukemia?
In myelogenous leukemia a BCR-ABL hybrid gene (philedelphia chromosome) is produced with makes tyrosine kinase
Tyrosine kinase is an enzyme that promotes cell proliferation (unregulated cell growth)
What could be used as treatment for chronic myelogenous leukemia?
Tyrosine kinase inhibitor
what affects do inherited mutations have on DNA damaged cells?
Affect DNA repair
Cell growth or apoptosis
What factors, proteins and receptors can oncogenes affect?
Growth factors
Growth factor receptors
Signal transduction proteins
Nuclear regulatory factors
Cell cycle regulators
Describe the process of the normal cell cycle. Which step are at ricks for tampering by cancer cells?
Binding of growth factor to receptor
Transient, limited activation of receptor, initiating signal transduction on plasma membrane
Transmission of signal through second messengers to nucleus
Entry and progression into cell cycle with induction and activation of nuclear regulatory factors that initiate DNA
transcription
Mitoses and cell division
All steps
Describe the differences in actions of growth factors on normal cells and cancer cells. What is one example?
Normal cells→→paracrine action (cell next to it)
Cancer cells→→autocrine action (self cell proliferation)
Ex: many glioblastomas secrete platelet-derived growth factor (PDGF) and express the PDGF receptor, and many sarcomas make both transforming growth factor-α (TGF-α) and its receptor.
How do growth factors lead to the development of a tumor?
GFs bind to proto-oncogenes and trigger overexpression, amplification or genetic mutation to create tumor
What would happen is there was a mutation in GAP?
GTP could not be hydrolyzed to GDP, RAS could not be inactivated
There would be uncontrolled cell growth
Describe RAS. How can mutations lead to issues?
Binds GTP and GDP
Mutation block hydrolysis of GTP to GDP leading to unchecked signaling
MOST COMMON abnormality of dominant oncogenes in human tumors
In about 1/3 of all human cancers
Describe MYC. What is one example?
Regulator gene that codes for a transcription factors
The protein encoded by this gene plays a role in cell
cycle progression and apoptosis
Can either activate or repress the transcription of other
genes
Activate: cyclin-dependent kinases (CDKs)→promote cell
proliferation
Repress: CDK inhibitors (CDKIs)→promote cell proliferation
Dysregulation of the MYC gene resulting from a t(8;14) translocation occurs in Burkitt lymphoma
Describe the function of cycling and cyclin-dependent kinases. Where do the checkpoint occur?
Regulate progression through the cell cycle, particularly at the G1-S transition
CDK-cyclin complexes phosphorylate target proteins that drive the cell through the cell cycle
CDK inhibitors (CDKIs) regulate the CDK-cyclin complexes The G1 -S checkpoint monitors the integrity of DNA before DNA replication, G2-M checkpoint checks DNA after replication
Mutations in genes regulating these checkpoints allow cells with damaged DNA to divide, producing daughter cells carrying mutations.
Describe tumor suppressor genes. How can mutation occur?
Encode proteins that inhibit cellular proliferation by regulating the cell cycle.
Unlike oncogenes, both copies of the gene must be dysfunctional for tumor development to occur.
Describe the RB (retinoblastoma) gene.
Homozygous loss of this gene causes retinoblastoma as well as breast cancer, small cell cancer of the lung, and bladder cancer.
Rb exerts antiproliferative effects by controlling the G1-to-S transition of the cell cycle. In its active form, Rb is hypophosphorylated and binds to E2F transcription factor. This interaction prevents transcription of genes like cyclin E that are needed for DNA replication, and so the cells are arrested in G1
How are RB mutations commonly acquired?
First is inherited, second is spontaneous
In RB when do we have unregulated cell growth?
Hyperpolarization
Describe the tumor suppressor gene TP53 gene.
Encodes p53
Senses internal stress
- Activate temporary cell cycle arrest (quiescence),
- Induce permanent cell cycle arrest (senescence)
- Trigger programmed cell death (apoptosis)
How prevalent is TP53? How can p53 be effected?
Mutated in more than 70% of all human cancer
p53 can be incapacitated by binding to proteins encoded by oncogenic DNA viruses such as HPV (virus causing cancer).
What are some apoptotic genes? What can mutations in these genes lead to? What apoptotic gene is involved in B cell lymphomas?
Mutations in the genes that regulate apoptosis (BAX,
BAK, BCL2, BCL-XL,,p53, MYC etc) can lead to evasion of cell death
In 85% of follicular B cell lymphomas, the anti-apoptotic gene BCL2 is activated by the t(14;18) translocation
Describe limitless replicative potential. What is the function of telomeres?
Telomeres determine the limited number of duplications a cell will have
Telomerase (produced by cancer cells), present in >90% of human cancers, changes telomeres so they will have UNLIMITED replicative potential
Describe the development of sustained angiogenesis. What are some inhibitors or triggers?
Vascualrization of tumors is essential for growth, and controlled by angiogenic and anti-angiogenic factors produced by tumor and stromal cells
Hypoxia triggers angiogenesis though HIF-a on the transcription of pro-angiogenic factor VEGF
VHL gene is a tumor suppressor as it can degrade HIF-a
P53 induced synthesis of angiogenesis inhibitor TSP
Inheritance of VHL mutations causes VHL syndrome (develops tumors)
Describe Von Hippel- Lindau disease.
Hemangioblastoma
Enlarged/abnormal retinal arteries and veins in posterior pole
Benign
What components of the immune system can react to tumor cells?
Cytotoxic T lymphocytes
NK cells
Macrophages
How do tumor cells escape immune surveillance?
Selective outgrowth of antigen-negative variants (tumor cell will affect APC so that T cells cannot recognize and fight against them)
Loss or down regulation of MHC molecules
Activation of immunoregulatory pathways
Secretion of immunosuppressive factors by cancer cell
Intro of regulatory T cells (Tregs)
What are the invasion factors of tumor cells?
Detachment (loosening of cell-cell contacts)
Attachment to ECM components
Degredation of ECM
Migration of tumor cells
Describe the steps by which transformed cells enter blood vessels and become metastatic tumors.
Transformation
Growth
BM invasion
Angiogenesis
Intravasation
Embolization
Adhesion
Extravasation
Metastatic growth
What determines the ability for a transformed cell to invade and metastasize the BM and interstitial matrix?
BM and interstitial matrix is degraded by proteolytic enzymes secreted by tumor cells and stromal cells (MMPs and cathepsins)
What determines the location where many tumors metastasize?
Predicted by location of the primary tumor
Many tumors arrest in the first capillary bed they encounter (lung and liver common)
What are the hallmarks of cancer?
Evading apoptosis
Self-sufficiency in growth signals
Insensitivity to anti-growth signals
Sustained angiogenesis
Limitless replicative potential
Tissue invasion and metastasis
What are the effects of a tumor on the host?
Location: Anatomic encroachment (impair tissue or organ function as they grow for benign or affect function for metastatic)
Hormone production
Infection
Bleeding
Acute symptoms (rupture,infarction)
Metastases
What are the clinical aspect of tumors?
Cachexia
Grading of tumors
Staging
What is cachexia?
Loss of fat and lean muscle (equal)
Weakness, anorexia, anemia
Systemic inflammation
Release of TNFa can contribute
Proteolytic inducing factor (PIF): released from tumor cells, loss of muscle mass
Describe the grading and staging of tumors? Which is more important?
Grading: How differentiated (close to the original) are the cells?
Staging: How much anatomic extension?
T= primary tumor size
N= regional lymph node involvement
M= metastases
Scale= 0-4
Staging is more important
What are paraneoplastic syndromes?
Symptoms in individuals with cancer that cannot be explained by tumor spread or release of hormones of tumor
Earliest manifestation of occult neoplasm
Neoplasms release hormones that mimic other syndromes
Can paraneoplastic syndromes affects the eye?
Yes
How can we sample a possible tumor in a patient?
Excision/biopsy
Fine needle aspiration (visible)
Cytologies smears (mucous)
Immunohisotchemistry
PCR
Micro-arrays (DNA)
Protein assays
