Lecture 19 and 20 Flashcards
Name three differences in the growth of normal cells and cancer cells.
Cancer cells form tumors
Anchorage independent growth
Density dependent inhibition of growth
What is anchorage dependence?
Normal cells require a matrix (cancer cells can grow in suspension)
Why do cancer cells have unusual metabolism?
They rely on oxidative phosphorylation as well as aerobic glycolysis
Why are cancer cells less likely to die?
Abnormal stress response, less prone to apoptosis, escape replicative cell senescence
What are the differences in genes involved in the cell cycle expressed by normal cells vs cancer cells?
Cancer cells increase oncogene expression and do not express tumour suppressor genes
What are the 6 most common cancers?
Breast, colon/rectum, prostate, lung, stomach, uterine/cervix
Total number of deaths from cancer in 2018?
9.6 million
What is the type of cancer that arises from epithelial cells?
Carcinoma
What % of cancers does carcinoma make up?
around 80-90%
What is the type of cancer that develops from supporting and connective tissues (such as bones, cartilages, fat and muscles)?
Sarcomas
What cancer arises from cells of lymphatic and blood origin?
Lymphomas and leukemias
What cancers arise from blasts (precursor cells) of embryonic tissue?
Blastomas
Give two examples of blastomas.
Retinoblastoma (affects the eye)
Nephroblastoma (effects the kidney)
What % of cancers does lymphomas and leukemias make up?
around 7%
Where do osteosarcoma develop and who does this effect?
Growing bones
Teenagers and young adults
Where do lymphomas develop?
Any organ lymphoid tissue is present (lymph nodes, spleen, tonsil, gus skin etc.)
What can lymphomas be further catagorised into?
B-cell
T-cell
Hodgkin lymphoma
What 4 things does the spread of cancer cells require?
- Brake off tumor
- Invade local tissue
- Penetrate endothelia
- Spread via blood or lymph
What 4 factors affect cancer spreading?
Tumor microenvironment (influences cancer development)
Angiogenesis
Invasion
Metastasis
What makes up the tumor microenvironment?
Endothelial cells, stromal fibroblasts, bone marrow derived cells, macrophages, monocytes, mesenchymal stem cells
In what way do tumors and microenvironments (stroma) interact?
They communicate two ways to influence growth (e.g. cancer cells release growth factors and signal proteins, stroma releases signal proteins that stimlate growth and division, as well as proteases)
How is angiogenesis regulated?
Angiogenesis promoters make blood vessels grow towards tumor, controlled by balance of opposing factors
Name two activators of angiogenesis.
Basic fibroblast GF
Vascular endothelial GF
What happens once cancer cells release angiogenesis activators and these bind to receptor proteins on the lining of blood vessels?
Endothelial cells are synthesised, metalloproteases are secreted
Name three angiogenesis inhibitors.
Angiostatin
Endostatin
Thrombospondin
What does invasion refer to?
Direct migration and penetration of cancer cells into neighbouring tissues
What is metastasis?
The ability of cancer cells to enter the bloodstream and travel to distant sites
What 4 factors does cell invasion depend on?
Cell adhesion changes
Increased motility
Protease production
Invasion
Give an example of the plasticity of cancer cells during the invasion-metastasis process?
Epithelial-mesenchymal plasticity
Give two examples of environmental factors (chemicals, carcinogens) of cancer.
Asbestos (lung cancer)
Benzidine (antioxidant in rubber industry)- metabolised to active from in liver and caused bladder cancer
How do environmental factors cause DNA damage?
Genertate cross links between two strands of double helix, or cause breaks in one or both DNA strands
What percentage of cancers arise by mechanisms involving viruses/bacteria/parasites?
15%
Name the bacteria involved in causing stomach cancer.
Helicobacter pylori
What virus is involved in causing cervical cancer?
Human papillomavirus
What bacteria is involved in causing cervical cancer?
Chlamydia trachmatis
What oncogenic virus is involved in causing liver cancer?
Hepatitis B
What virus is involved in causing liver cancer?
Hepatitis C
Use of tanning salons increases the chances of developing what types of cancer?
Squamous cell carcinoma
Basal cell carcinoma
Melanoma
The expression of what three genes did Bob Weinberg’s lab find resulted in tumorigenic conversion of cells?
Telomerase catalytic subunit
Simian virus 40 large T product
Oncogenic H-ras protein
What are the 5 main mehcanisms of oncogene activation?
Point mutation, gene amplification, chromosomal translocation, local DNA rearrangements, insertional mutagenesis
What is a gene amplification?
A copy number increase of a restricted reigion of a chromosome arm
What is chromosomal translocation
Rearrangement of parts between non-homologous chromosomes
What can chromosomal translocation give rise to?
Increased oncogene expression, fusion gene (chimeric/fusion protein)
Give an example of a cancer caused by chromosomal translocation.
Burkitt’s lymphoma.
What does local DNA rearrangement do?
Disrupt proto-oncogene structure by insertions, deletions, inversions
What is insertional mutagenesis?
Viral DNA is intergrated into host chromosome, stimulating expression of proto-oncogene, producing too much protein
What do most oncogenes code for?
Components of growth signaling pathways
What are the 6 catagories of oncogenes?
Growth factors Receptors Plasma membrane GTP-binding proteins Nonreceptor protein kinases Transcription factors Cell cycle or apoptosis regulators
What experiment demonstrated the suppression of malignancy by cell fusion?
somatic cell hybridization experimnents (some chromosomes are lost during subsequent cell divisions, leading to cancer cell reverting back)
Name three tumor suppressor genes.
p53, Rb, APC
What does Rb gene regulate?
G1/S progression
Who proposed retinoblastoma requires the loss of both functional Rb copies?
Alfred Knudson
Deletions of which chromosome was identified suggesting loss of Rb led to tumor development?
13q14
How was it demonstrated that Rb is a tumor supressor?
Isolated (found consistently lost/mutated in retinoblastomas)
Gene transfer experiments (introducing normal Rb into cell reverses tumorigencity)
What is the most frequently mutated gene in human cancer?
p53 (around 50%)
What does p53 do?
Respond to DNA damage by arresting cell cycle for DNA repair or triggering apoptosis
How does p53 lead to cell cycle arrest>
p21 inhibits Cdk-cyclin, cannot phosphorylate Rb protein, cell cycle arrest
How does p53 lead to apoptosis?
Puma inhibits Bcl-2. Bcl-2 cannot inhibit apoptosis
How does p53 lead to senescence?
p16^INK4a inhibits cdk-cyclin, which inhibits pRb, leading to senescnece
How is cancer diagnosed?
Biopsy (large nuclear size, pleomorphic nuclear shape, high mitotic index, disorganised tissue etc.)
What are the treatment options for cancer?
Surgery (of primary tumors)
Radio-therapy (ionizing radiations damage/destroy cancer cells)
Chemotherapy
What are the 4 major catagories of chemotherapeutic drugs?
Antimetabolites
Alkylating agents
Antibiotics
Plant derived drugs
What do antimetabolites do?
Inhibit metabolic pathways required for DNA synthesis
What do alkylating agents do?
Inhibit DNA function (X-linking double DNA helix)
What do antibiotics do?
Inhibit DNA function (block topoisomerases etc.)
What do plant derived drugs do?
Block specific phases of cell cycle progression- proliferation
What is targeted therapy?
Drugs or other substances that attack cancer cells more precisely
What is immunotherapy?
Treatment that uses your body’s own immune system to help fight cancer
What is hyperhtermia?
High temperatures to kill cancer cells
What is a stem cell transplant?
Peripheral blood, bone marrow or cord blood transplants
What is photodynamic therapy?T
Treatment using photosensitizing agents along with light to kill cancer cells
What is the first antibody approved for use in cancer patients?
Herceptin
What does herceptin do?
Binds and inactivates the human epidermal growth factor receptor-2(HER2)
How does Ipilimumab work
CTLA4 is an inhibitory receptor on the surface of T cells. When blocked, T cells are more reactive and attack tumor cells that were recognized abnormal but tolerated
What cancer is ipilmumab used to treat?
Metastatic melanoma
Give an example of a targeted therapy.
Imatinib blocks chimeric Bcr-Abl tyrosine kinase in chronic myelogenous leukeamia
How many adult human body cells undergo apoptosis a day?
50-70 billion
During development, what does apoptosis play a major role in?
Morphogenesis and tissue remodelling (elimination of organs and tissues useful only during the embryonic stage)
What pathologies has excessive apoptosis been associated with?
Neurodegenerative diseases and organ failure after infarction or toxic insult
What induces apoptosis?
DNA damage, hypoxia, oxidative stress, death receptor ligands and drug treatments
What induces necrosis?
Accidents/trauma
Infections
Physical damage
Chemical damage
What happens to the contents of cells that have died by apoptosis?
Apoptotic bodies are phagocytosed by macrophages and neighbouring cells
What are some hallmarks of apoptosis?
Cellular and nuclear shrinkage, apoptotic bodies, chromatin condensation, DNA fragmentation, mitochondrial membrane permeabilization, release of cytochrome c into cytoplasm, caspases cascade
What change occurs in the plasma membrane before apoptosis occurs>
Externalization of phosphatidylserine (phospholipid flipping)
What ion is involved in triggering and regulating apoptosis?
Calcium
How is the mitochondrial membrane potential lost?
Cytochrome c is released from the mitchondria into the cytosol
What does caspases mediate during apoptosis?
Intracellular protelytic cascade
What does active initator capase activate?
Executioner caspases
What do executioner caspases do?
Cleave cytosolic protein
Cleave nuclear lamin
What are the two pathways that activate apoptosis?
Cell-surface death receptors activate extrinsic pathway
Mitochondria activates intrinsic pathway
Briefly describe the death receptor pathway.
Fas ligand on killer lymphocyte binds to Fas death receptor. Death inducing signalling complex activates caspases.
What molecule is assembled during the intrinsic pathway that becomes caspase 9?
Apotosome
What protiens control apoptosis?
Bcl-2 family (anti and pro apoptotic)
How does Bcl2 anti-apoptotic mechanism work?
Reduces permability of mitochondria, stops release of cytochrome c
Name 2 Bcl2 pro-apoptotic protiens.
Bax and Bak, both trigger cytochrome c release
What does IAP stand for and what is it?
Inhibitor of apoptosis protein
Family of endogenous inhibitor of caspases
