Chapter 26 (24) – Cancer Cells – Flashcards

means "crab" - describes disease in which tissues grow and spread unrestrained throughout the body

90% of all cancers, arise from epithelial cells that cover external and internal body surface

Develop from supporting tissues like bone, cartilage, fat and muscle

Arise from cells of blood and lymphatic origin

Not controlled by normal cell growth regulation Cell division isn't balanced with differentiation and cell death like in normal cells

Grow in confined local areas and are rarely dangerous

Capable of invading surrounding tissues entering blood stream and spread to distant places in body

Cancer cells can grow either unattached to anythin or in semi solid environment whereas normal cells cannot

Cell division stops or slows when the monolayer stage (surface is covered by single layer of cells) - cancer cells are less responsive to this

Produce telomerase to overcome the limitation placed on normal cells by the telomere - shortening prevents excessive proliferation Telomerase in cancer cells continuously add teleromers to the DNA Don't need growth factors in order to grow / divide by altering signaling pathways to create a constant signal to divide Don't respond to trigger checkpoints to limit growth in the cell cycle like normal cells Block pathways that signal apoptosis

The combination of ability to proliferate quickly and ability to spread throughout the body

Growth of blood vessels - tumors signal their own blood vessel network growth Tumors do this by increasing production of angiogenesis activators and decreasing in production of angiogenesis inhibitors

Proteins produced by cancer cells and released into surround tissue that bind to receptors on surface of endothelial cells Causes cells to divide and secrete protein-degrading enzymes called matrix metalloproteinases (MMP's)

Secreted from endothelial cells that break down the extracellular matrix permitting the endothelial cells to migrate into surrounding tissues

Cancer molecules must overcome affects of these - that normally restrain the growth of blood vessels

Invasion - Direct migration and penetration of cancer cells into neighboring tissues Metastasis - ability of cancer cells to enter bloodstream and travel to distant sites to form metastases - tumors not connected to primary tumor

1 - Cancer cells invade surrounding tissues and penetrate through walls of lymphatic and blood vessels, gaining access to bloodstream 2 - Cancer cells are transported by circulatory system throughout body 3 - Cancer cells leave the bloodstream and enter various organs where they establish new matastatic tumors

Changes in cell surface proteins that allow it to adhere to one another - in cancer these proteins are missing or defective allowing them to separate from main tumor cells more rapidly E-cadherin - cell-cell adhesive protein whose loss underlies reduced adhesiveness of many epithelial cancers Invasive cancers have less cadherin --Increased motility of cancer cells - stimulated by signaling molecules - chemoattractants Activation of Rho family GTPases plays central role in stimulation of cell motility --Ability of cancer to produce proteases - degrade protein-containing structures that would otherwise act as barriers to cancer cell movement

Dense layer of protein-containing material that separates epithelial layers from underlying tissues Usually acts as a barrier Must be breached Cancer cells secrete proteases that degrade proteins that form backbone of the basal lamina ex; plasminogen activator - enzyme that converts the inactive precursor plasminogen into active protease plasmin

Degrades components of basal lamina to allow tumor invasion Cleaves inactive precursors of matrix into active enzymes to degrade basal lamina and extracellular matrix

Cell populations derived from a single initial cell

Cells from the metastases where injected and reinjected and able to form more metastases than the original tumor cell Happens because the cell best suited for metastasizing were selected for in evolving cells

Capillaries and capillary beds

Blood flow patterns Prostate cancers usually metastasize in bone - bone cells produce specific growth factors that stimulate proliferation of prostate cancer cells

Immune surveillance theory - immune destruction of cancer cells is a common event and cancer simply reflects the occasional failure of adequate immune response to be mounted against aberrant cells Rag2 - gene expressed only in lymphocytes - mice with no functional lymphocytes exhibit increased cancer risk Less helpful for protecting against against common types of cancer Cancer cells evade the immune response

Tumors are hetero that express antigens (substances that trigger immune response) - cells containing antigens requiring strong response are destroyed Cells that lack or have weakened immune response are selected for Cancer cells also produce molecules that inhibit functioning of T lymphocytes - may surround themselves with dense supporting tissue that shields them from immune attack Some divide too quickly to be killed

Normal cells of immune system may attack cancer cells and other cells in tumor microenvironment produce TGFB - potent inhibitor of proliferation for many cell types --Cancer cells may develop mutations that allow them to continue to grow in presence of TGFB

Cancer-causing agents Precarcinogens - chemical that is capable of causing cancer only after it has been metabolically activated cytochrome P450

Measuring a chemical's mutagenic activity Used bacteria as a test organism - histidine Possible mutagen Placed in dish with histidine If mutagenic - will trigger mutations some of which might restore ability to synthesize histidine More colonies = more mutagenic potency

bind to DNA, disrupt normal base-pairing, generate crosslinks between 2 strands of double helix, chemical links between adjacent bases

DMBA causes cancer (coal and its components) Initiation - normal cells converted to a precancerous state Promotion - stimulates altered cells to divide and form tumors, gradual process requiring prolonged or repeated exposure to promoting agent DNA mutation Tumor progression - Tumor cell properties change over time as cells acquire more aberrant traits and become more aggressive Increase growth rate, invasiveness, ability to survive in bloodstream, resistance to immune attack - cells are selected for making them spread and strengthen

X-rays and related forms of radiation emitted by radioactive elements - remove electrons from molecules Ultraviolet radiation - causes cancer by damaging DNA Triggers pyrimidine dimer formation - covalent bonds between adjacent pyrimidine bases

One of the first genes to be studied - known to be mutated in many human cancers --p53 Mutations DO NOT exhibit a distinctive UV signature

Oncogenic virus - virus that causes cancer -- sarcomas - cancer in connective tissues Burkitt lymphoma - outbreaks of lymphocytic cancers of neck and jaw Epstein-Barr virus (EBV) cells can cause lymphomas Hepatitis C, HTLV, HPV H pylori - are all viruses that can cause cancer

Oncogenes - gene whose presence can trigger development of a cancer - some introduced by cancer-causing viruses, others arise from mutations --Rous sarcoma virus - src 3T3 cells - transfection - uptake of foreign DNA into cells and incorporates it into their chromosomes RAS --> Ras first human oncogene discovered ---together w other oncogenes that target p53 pathway will cause cancer Multiple mutations are required to convert normal cell into a cancer cell

Proto-oncogenes - Mutation from normal cellular genes (proto oncogenes) - not harmful alone Mutations that cause cancer: 1 - Point mutation - single nucleotide sub 2 - Gene amplification - increases # of copies like ERBB2 gene 3 - Chromosomal translocation - portion of 1 chromosome physically removed and joined to another i.e. Burkitt lymphoma, EBV MYC is moved from 8 to 14 Philadelphia chromosome - abnl 22 --> BCR-ABL 4 - Local DNA rearrangements - base sequences altered by deletions, insertions, inversions, transpositions ex: NTRK1 and TPM3 TRK oncogene --> coiled oil 5 - Insertional mutagenesis - Retroviruses cause cancer - integrate their genes into host chromosome - insertional mutagenesis - integration of viral DNA converts host cell proto to oncogene

Categories of proteins produced by oncogenes: 1 - Growth factors - Cell possesses an oncogene that produces growth factor and stimulates its own proliferation ex: v-sis gene simian sarcoma virus form of PDGF 2 - Receptors - code for mutant versions of receptors - tyrosine kinase activity is permanently activated regardless of presence of growth factor TRK, v-erb-b, EGF, ERBB2, Jak-STAT pathway, myeloproliferative leukemia virus, v-mpl, thrombopoietin 3 - Plasma membrane GTP-binding protein - Hyperactive Ras protein that retains bound GTP instead of hydrolyzing it - permanently activated state 4 - Nonreceptor protein kinase - enzymes that catalyze intercellular phosphorylation reactions - MAP kinases, BRAF, Src, Jak, Abl protein kinases 5 - Transcription factors - Alter gene expression, produce mutant forms of transcription factors in excessive quantities - Myc --> Burkitt lymphoma, 6 - Cell cycle and apoptosis regulators - Coding for cyclins, cyclin-dependent kinases (Cdk's), CDK4, CYCD1 - CDk-cyclin, inhibit apoptosis, Bcl-2, MDM2 --> destroys p53 pathway

Tumor suppressor genes - Restrain cell proliferation - if they are damaged it can lead to cancer --As long as hybrid cells retain both sets of original chromosomes - ability to form tumors is suppressed can overcome effects of RAS oncogene

hereditary retinblastoma - first tumor suppressor gene found studying this RB gene - the missing gene leading to retinoblastoma E7 protein - suppresses Rb gene and prevents HPV

p53 gene - most frequently mutated tumor suppressor gene in humans - helps with apoptosis - when damaged cell division cannot be stopped

APC gene - associated with inherited disease familial adenomatous polyposis - develops polyps in colon Wnt pathway - role in controlling cell proliferation during embryonic development - B-catenin, axin, glycogen synthase kinase 3 (GSK3) Wnt proteins APC-axin-GSK3, TCF transcription factor,

Genetic instability - cancer cells thousands of times higher than normal --Disruptions in DNA repair, --Mismatch repair --> HNPCC Xeroderma pimentosum - defects in excision repair --Mutant in BRCA1 or BRCA2 -- defects in repairing double strand breaks Defects in mitotic spindle checkpoints - normal chromosome separation

Mad or Bub proteins - components of mitotic spindle checkpoint Gatekeepers - like RB, p53, APC - loss directly opens gates to excessive cell proliferation and tumors Caretakers - genes involved in DNA repair and chromosome sorting - maintain genetic stability but are not directly involved in controlling cell proliferation and survival

Typically involves mutations in about 50-75 different protein-coding genes Breaks must be released - tumor suppressor genes Accelerator held on - oncogenes

Oncogene accompanied by loss of function mutations in suppressors APC, SMAD4 and p53

Changes in genetic sequence that doesn't involve original gene sequence --DNA methylation - CG sites near gene promoters Extensive methlyation --> epigenetic silencing of tumor suppressor genes MicroRNA's - bind to and silence translation of thousands of individual mRNA's - bind to and silence translation of mRNA's miR-155 Can either be overproduced or underproduced Can influence histone modification reactions

Multistep series of events that convert normal cells into cancer cells Hallmarks of cancer: 1 - Self-sufficiency of growth signals 2 - Insensitivity to antigrowth signals 3 - Evasion of apoptosis 4 - Limitless replicative potential 5 - Sustained angiogenesis 6 - Tissue invasion and metastasis

Microscopic examination of tissue specimens (biopsy) Tumor grading - assignment of numbered grades to tumors based on differences in appearance Pap smear - screening and detection of cervical cancer Mammography, colonoscopy PSA test - measures how prostate-specific antigen is present in bloodstream

Radiation Chemotherapy - uses drugs that kill dividing cells: 1 - antimetabolites - inhibit metabolic pathways 2 - Alkylating agents - inhibit DNA function 3 - Antibiotics - inhibit DNA function 4 - Plant-derived drugs - disrupt microtubules of mitotic spindle Multi-drug resistance transport proteins (ABC transporters - actively pump a wide range of chemically dissimilar hydrophobic drugs out the cell Immunotherapy - Exploiting immune system to recognize cancer cells - BCG, antibodies, Provenge

Drugs designed to specifically target proteins critical to the cancer cell Herceptin - ERBB2, Erbitux, Avastin, rational drug design, small molecule inhibitors, Gleevec, BCR-ABL Anti-angiogenic therapy - angiogenesis inhibitors to reverse blood vessel formation for tumors - Avastin, VEGF

Personalized medicine - choices made based on individual characteristics of patients, Transcriptome analysis - use of DNA microarrays to determine which genes are being transcribed Oncotype DX - test to measure activity of certain genes Iressa,