Cancer and Apoptosis – Flashcards
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What type of cancer affects epithelial cells?
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Carcinomas. 90% of all cancers
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What kind of cancer affects supporting tissue?
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Sarcomas this includes bone, cartilage, fat, muscle.
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What kind of cancer affects blood cells?
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Leukaemias
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What kind of cancer has lymphatic origin?
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Lymphomas. These are tumours that grow as solid masses of tissue.
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What 2 types of tumours are there?
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1. Benign 2. Malignant
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What makes a tumour benign?
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Only growing in local area.
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What makes a tumour malignant?
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A malignant tumour can affect all tissues, bloodstream, distant parts of the body.
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What are the 2 main factors that make cancer a risk.
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Anchorage independent growth Reduced sensitivity to density.
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What are the 3 main methods of cancers spreading?
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Angiogenesis - growth of blood vessels. Invasion - penetration into neighbouring tissues. Metastasis - entering the bloodstream, distinct sites of the body.
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Angiogenesis
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Is key for cancer to grow. Contrast: On the iris, there is a rich blood supply, cancer can easily grow there. However, tumour cells suspended in the anterior chamber of the eye, where there are no blood vessels, cancer cells hardly proliferate. Cancers cells grown in an isolated thyroid gland also stop growing, due to a lack of blood supply.
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What is produced by both normal and cancer cells?
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VEGF AND FGF
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VEGF is
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Vascular endothelial growth factor.
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FGF is
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Fibroblast growth factor.
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Cancer cells release
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FGF and VEGF. These bind to receptor proteins. Also forming the lining of blood vessels.
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Name 3 Angiogenesis inhibiting molecules.
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Angiostatin Endostatin Thrombospondin
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What determines whether a tumour will grow or not?
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The balance between the concentration of activators ->FGF and VEGF, and inhibitors -> Angiostatin, Endostatin and Thrombospondin.
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Invasion means...
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direct migration of cancer cells into neighbouring tissues.
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Metastasis means...
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the ability of cancer cells to enter the bloodstream and thus other parts of the body.
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Cancer spreads by
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Invasion and Metastasis
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What is required for a tumour to grow?
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Angiogenesis
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The main causes of cancer are:
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Environmental factors: chemical, infectious agents, radiation. ->exposure to asbestos (lung) ->exposure to benzidine (bladder) Lifestyle factors smoking ->lung, mouth, throat excessive alcohol consumption -> mouth, liver. Poor diet.
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2-naphthylamine
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Causes DNA damage. Disrupts normal base pairing. Generates crosslinks between the two strands of the double helix. This causes breaks in one or both DNA strands.
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Viruses and Bacteria also cause cancer. Examples of these
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Helicobacter pylori Human papilliomavirus (HPV) Hepatitis B (HBV) Hepatitis C (HCV)
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UV radiation...
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Causes Melanoma and other forms of skin cancer.
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X rays, and related forms of radiation
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remove electron from molecule; generate reactive ions; DNA damage.
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Oncogenes
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lead to cancer
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Two examples of Oncogenes
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-> Rous sarcoma virus - src gene -> RAS -> first human oncogene.
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Tumour suppressor genes
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The loss, or inactivation of these can lead to cancer.
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Proto-oncogenes
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Normal cellular structures, that are converted into oncogenes through mutation.
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Types of mutation involved in this conversion
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Point Mutation Gene Amplification Chromosomal Translocation Local DNA rearrangements Insertional Mutagenesis
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Point mutation involves
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a single nucleotide substitution. -> this creates an oncogene coding for an abnormal protein. -> differs in a single amino acid from the normal protein produced by the proto-oncogene.
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Gene amplification involves
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Multiple gene copies. Excessive production of a NORMAL PROTEIN. Human breast and ovarian cancer have amplifide copies of ERBB2 gene.
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Chromosomal translocation involves
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Moving chromosome segments from one chromosome to another. Fuse two genes together to form an oncogene coding for an abnormal protein. OR Place a proto-oncogene next to a highly active gene.
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What cancer involves chromosome translocation?
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Burkitt's Lymphoma.
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What is Burkitt's Lymphoma associated with?
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Epstein-Barr virus
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What is produced in excess?
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Excess Myc protein is produced.
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Local DNA Rearrangements involve
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Proto-oncogene disruption Production of abnormal protein, usually hyperactive -> Insertions -> Deletions -> Inversions ALL possible.
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Insertional Mutagenesis
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Viral DNA is integrated into host chromosome. May stimulate the expression of the proto-oncogene. Thus producing TOO Much protien
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Under normal functioning
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Cell proliferation control is apparent. The loss or inactivation of tumour suppressor genes may lead to cancer.
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Out of 25,000 genes
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only a few dozen exhibit the properties of tumour suppressors.
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These suppressors...
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act as brakes on the process of cell proliferation.
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Some examples of these are...
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RB, p53, APC
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What has an oncogene that produces E7 protein
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HPV -> Human Papillomavirus
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What does E7 bind to?
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RB Without RB functioning, there is NO G1 -> S restriction point. G1 -> S can proceed.
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p53 gene
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also called TP53 in humans p53 mutations - nonhereditary cancers Ergo - > chemicals, radiation, DNA damage.
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p53 gene
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mutations -> lung cancers, skin cancer p53 protein -> responds to DNA damage.
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p21 (Cdk inhibitor)
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Inhibits Cdk-cyclin Cannot phosphorylate Rb protein Cell cycle arrest.
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p53 protein is a target for...
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certain cancer viruses
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What other oncogene does HPV produce?
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E6 protein
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What does E6 do?
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Stimulates ubiquitin attachment to p53, thereby promoting p53 destruction.
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HPV
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HPV blocks the actions of the proteins produced by both the RB and p53 tumour suppressor genes.
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What are the two categories of tumour suppressor genes
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Gatekeepers Caretakers
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Genetic instability
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arises from defects in mitosis.
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Defects in mitosis...
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results in broken chromosomes and aneuploidy -> an abnormal number of chromosomes.
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Stepwise mutation drawn out...
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1. APC mutation 2. KRAS mutation 3. SMAD4 mutation 4. p53 mutation 5. other mutations, epigenetic changes . .
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Table showing differences between Benign and malignant tumours
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. .
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The Nuclear size is ....... in a benign tumour
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Small
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The Nuclear size is ....... in a malignant tumour
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Large
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N/C ratio refers to the
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Nuclear to cytoplasmic volume ratio.
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What is the N/C ratio in a benign tumour?
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Low. Therefore it is high in a malignant tumour.
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What is the Nuclear shape of a malignant tumour?
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Pleomorphic, while in a Benign tumour it is regular.
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What is Mitotic index?
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How long mitosis lasts in the cell cycle. Similarly, we can estimate the length of M phase by multiplying the generation time by the percentage of the cells that are actually in mitosis at any given time. This percentage is called the mitotic index. The mitotic index for cultured mammalian cells is often about 3-5%, which means that M phase lasts less than an hour (usually 30-45 minutes).
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How is tissue organisation different in benign and malignant tumours?
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Normal in benign. Disorganised in malignant.
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Differentiation of the the tumour is either...
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well differentiated as in benign, or poorly differentiated as in malignant.
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The tumour boundary is ..... in benign, while in malignant it is ...... .
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Well defined Malignant.
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What is a screening technique that is frequently used in early detection?
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Pap smear.
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What is the standard treatment for cancer?
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Surgery Radiation Chemotherapy
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Surgery is used to...
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remove the primary tumour.
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Radiation therapy consists of...
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X-rays or other forms of ionising radiation.
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Chemotherapy involves...
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drugs that are designed to kill dividing cells.
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What are the 4 main categories of drugs used in cancer treatment?
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Antimetabolites -> inhibit metabolic pathways required for DNA synthesis. Alkylating agents -> inhibit DNA function, e.g. crosslinking the double helix. Antibiotics -> inhibit DNA function; e.g. inhibiting topoisomerases required for DNA replication. Plant derived drugs -> inhibit topoisomerases required for DNA replication.
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What do antimetabolites do?
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Inhibit metabolic pathways required for DNA synthesis.
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What do alkylating agents do?
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inhibit DNA function, e.g. crosslinking the double helix
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Are alkylating agents and antibiotics similar in action.
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Yes, as they both inhibit DNA function.
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Show an example of antibiotic action...
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Antibiotics often inhibit topoisomerases required for DNA replication.
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Plant derived drugs
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Do exactly the same as antibiotics. -> inhibit the topoisomerases required for DNA replication.
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Name two drugs used in Immunotherapy:
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Interpheron alpha Interleukin-2
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Name a therapeutic vaccine used in cancer treatment:
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Provenge.
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What are stem cell used for in cancer treatment?
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They are used to replace destroyed cells, e.g. in bone marrow.
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What are the two different type of stem cells?
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Embryonic and adult stem cells.
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How many different types of stem cell potency is there?
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Totipotent Pluripotent Multipotent Oligopotent Unipotent
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What does Totipotent entail?
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Embryonic and an extra embryonic. -> viable organism
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What does Pluripotent entail?
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All cells.
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What does Multipotent entail?
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closely related cells.
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What does Oligopotent entail?
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Lymphoid or myeloid stem cells.
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What does Unipotent entail?
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Their own cell type -> self-renewal.
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Apoptosis.
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...
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What kind of cascade is involed in apoptosis?
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Caspase cascade is involved in apoptosis.
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What is the precursor to an active caspase?
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an inactive procaspase.
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How many cleavage sites on an inactive procaspase?
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Two One for NH2 (prodomain) And one for COOH.
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Draw this process of procaspase activation.
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...
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What is cleaved to molecules of procaspase to activate them
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Cytosolic protein.
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Then to multiply the active caspases?
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Cleavage of Nuclear lamin is required.
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Draw out the caspade cascade
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. .
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In extracellular activation, what are procaspases activated by?
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Adaptor proteins found in the TARGET CELL
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What do adaptor proteins link?
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Fas protein, with the ligand supplied from a killer lymphocyte, which has Fas ligands on its surface. And also inactive procaspase
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What is found in the target cell?
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Adaptor protein and inactive procaspase-8.
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What occurs after the killer lymphocyte with its Fas ligand and Fas protein link with the adaptor protein and the procaspase-8 molecule?
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The procaspase-8 gets activated, turning the caspase cascade off. The caspases essentially break off from the NH2, and the adaptor proteins (which are connected to the Fas protein and ligand)
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the caspase cascade initiates.
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apoptosis, destroying the cell
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In intracellular activation...
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an injured mitochondrion (extracellular matrix burst.) starts expelling cytochrome C from its intracellular matrix.
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The Cytochrome c...
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is released, and binds to Apaf-1.
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Apaf-1 is an...
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adaptor protein
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What happens when cytochrome c, Apaf-1 starts to aggregate.
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They start to bind to inactive procaspase-9.
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The activation of procaspase-9 due to the Apaf-1 results in...
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A caspase cascade
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What are Bcl-2 family proteins?
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they are proteins which help in regulating the activation of procaspases.
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Bcl-2, Bcl-XL
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thus inhibit apoptosis.
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Other Bcl-2 proteins
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promote procaspase activation and cell death.
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IAP means
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inhibitor of apoptosis proteins.
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In how many ways to they do this?
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2.
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First way of IAP action is:
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binding to some procaspases to prevent their activation.
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Second way of IAP action is:
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binding to caspases to inhibit their activity.
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What is organ and body sized determined by?
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Cell growth, cell division, cell death, SA : V ratio.
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What stimulates division?
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Mitogens.
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What are survival factors?
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survival factors promote cell survival, by suppressing apoptosis.
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An example of a mitogen
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PDGF ->platelet derived growth factor. ->circulate in the blood, stimulate blood clotting at sites of tissue damage, thus preventing excessive bleeding. ->Thus stimulating healing.
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What is survival factor released by?
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Target cells ->After the survival factor is released from the target cells, cell death matches the number of nerve cells to number of target cells. ->ERGO, if too many nerve cells compared to target cells, nerve cells get killed off by apoptosis.
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Survival factors suppress apoptosis by
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Phosphorylating the Hid protein. The phosphorylated Hid does not inhibit IAP. IAP becomes active and blocks cell death.
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If Hid is not phosphorylated.
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It becomes active. Hid promotes cell death by inhibiting IAPs.
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What does BMP stand for
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Bone morphogenetic protein
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BMP...
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triggers apoptosis, thus removing tissue between the developing digits.
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TGF-b
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is an example of an extracellular signal protein, which inhibits cell growth.
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Myostatin is...
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a member of the TGF-b family.
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Myostatin
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inhibits the proliferation of myoblasts. Myoblasts fuse to form skeletal muscle cells.
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Summary
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• Cells are destroyed by apoptosis when they are no longer needed • Apoptosis is mediated by caspases (exist as inactive procaspases) • Procaspases activation: extracellular or intracellular activation • Survival factors play important roll in apoptosis
