Cancer

formation or production of tumors

the creation of cancer

a tumor forming process

cancer derived from epithelial cells

cancer arisen from connective tissue or muslce cells

cancer derived from hemopoietic(blood) cells

• self-sufficiency in growth signals, increase in oncogene
• insensitivity to antigrowth signals, decrease checkpoint control, decrease tumor supressor genes
• evasion of apoptosis, decrease in apoptosis, increase in cell survival
• limitless replicative potential, increase telomerase
• tissue invasion and metastasis, decrease cell adhesion
• sustained angiogenesis

• activated Ras can transform immortalized cell line but not primary cell cultures. co-transfection of Src and activated src can cause primary cells to adopt a transformed phenotype
• cells grow up on top of each other, lost contact inhibition

• Loss of APC (adenomatous polyposis coli) - tumor-suppressor gene on chromosome 5
• activation of K-ras - oncogene on chromosome 12, trigger activation of MAPK
• loss of tumor suppressor gene in DCC (deleted in colon carcinoma) - chromosome 18, promote cell grwoth
• loss of p53 - tumor suppressor gene - chromosome 17, no DNA damage checkpoint

• tumor begins as a single abnormal cell with multiple mutations/genetic changes
• growth becomes mitogen dependent
• unlimited replicative potential
• becomes invasive
• then start to metastasize to other tissues
• Lack responses to antigrowth signals/apoptotic/death signals
• also, loss of DNA repair mechanisms; cannot repair DNA damage due to DNA polymerase copy error or mutations

• Stem cell niche: microenvironment, dependence of normal stem cells on the niche limit their expansion
• Expansion of the normal stem cell niche permits the expansion of cancer stem cells that arose from normal stem cells: increase in number of niche = increase of stem cells
• Cancer stem cells that arose from normal stem cells adapt to different niche along their expansion
• Cancer stem cells that arose from normal stem cells become niche independent, and self-renewal is cell-autonomous
• cancer stem cells arising from a progenitor cell - shift in the programmed deline in replication potential

• paneth cells on the bottom secret antimicrobial proteins defense, keep everything sealed
• intestinal stem cell signaling: niche: stem cells on the bottom and mesenchymal cells
• BMP on mesonchymal cells : a member of TGFbeta family protein
• Noggin - a TGFbeta inhibitor
• Dkk inhibits Wnt, Wnt from mesonchymal cells act on stem cell for proliferation

• a tumor mass composed of cell whose growth regulation is out of control but remains clustered together and contained in a signle mass
• do not metastasize and do not invade other cells

a tumor whose cells have acquired the ability to break away (by secreting proteases or protease activiators) from the original mass and invade surrounding tissue

secondary tumor located at a site distant from the original tumor

• the process by which cells from a primary tumor break away from the original mass, enter thebloodstream, and travel to distant, secondary sites
• loss of "warp" - fibrous connective tissue capsule of benign tumor
• carcinoma cells secrete proteases and degrade basement membrane by invadopodia
• EGF secreted from macrophages and diffused from blood vessels
• Carcinoma cell migrating on EcM fiber
• Tumro take advantage of EGF (growth fator that trigger growth of fiber) and grow within th efibers
• Eventually get into blood stream and circulation in blood vessels, go to: lymphnode, liver, or bone marrow
• second tumor - 1/100,000 escape

• tormor growth requires formation of new blood vessels
• in low O2, high HIF: hipoxia inducible factor and secreted VEGF: vascular endothelial growth factor
• causes cipillary to grow out and form new capillary branch
• inhibition of angiogenesis can be a caner treatment

hypoxia-inducible factor, transcription factor that respond to change in available oxygen in the cellular environment

a chemical signal produced by cells that stimulates the growth of new blood vessels, part of the system that restores the oxygen supply to tissue when blood circulation is inadequate

• the process by which cells in culture lose their "normal" characteristics and acquire many characteristics of cancer cells
• have unlimited replication ability
• anchorage indepedent - can grow in suspension, and can growth when removed from ECM (unlike normal cells)
• do not exihibit contact inhibition, grow on top of each other
• independent of growth factors

• immortal cells have unlimited replication ability
• immortal cells from after undergoing "crisis" in which a small % of cells survive and begin proliferating again
• they are selected (acquire ability) to survive in culture
• cells escape crisis after experiencing genetic mutations
• telomerase is required for immortality

immortalized fibroblasts derived from mouse embryos that have survived crisis

• Microarray analysis can identify different expression between normal vs cancer cells
• Genes are grouped together according to some critera, possibly by their function or expression patter
• red = overexpressed
• green = underexpressed

• genes that cause cancer when activated or expressed at high levels
• gain of mutations: often dominant that cuase or increase chane of cancer

genes which when mutated become oncogenes

• genes that cause cancer when loss of function occurs (by mutation or abnormal inactviation)
• mutation usually recessive

• hyperactive protein made in normal amounts - deletion or point mutation in coding sequence
• normal protein greatly overproduced - gene amplification
• nearby regulatory DNA sequence cause normal protein to be overproduced - chromosome rearrangement
• fusion to actively transcribed gene greatly overproduces fusion protein; or fusion protein is hyperactive - chromsome rearrangement

• adenomatous polyposis coli, a major gene that is invovled in causing colorectal cancer, functions in the wnt-signaling pathway
• APC usually bins axin and occupy beta catenin (inhibited)
• mutant apc - beta catenin is released and lead to gene transcription of cmyc gene

• ras mutation found in many human cancers, MAPK is phosphorylated on both Y185 and T183
• leads to c-fos gene transcription

• can be activated by mutation
• normal cellular: Tyr527 phosphorylation at the C terminus by csk inactivates c-Src; losing phosphorylation would be constutitively active
• viral: lacks the C terminis, v-src is constitutively active

• c myc is constitutively activated by a chromosomal transloation that palce it next to the imunoglobulin heavy chain promoter, cmyc moved from chromosome 8 to 14
• myc regulates cell cycles through Rb proteins

• mutated by point mutation - Valine -> Glutamine
• Neu oncoprotein
• does not need ligand, always dimerized and always active
• antibodies against Her2 are used to treat human breast cancer - causes Her2 to get degraded

• inhibition of angiogenesis - cancer treatment
• a naturally occuring 20kDa C-terminal fragment derived from type XVIII collagen

• truncation of the EGF receptor causing constitutive dimerization
• ErbB oncoprotein - constitutively active protein-tyrosine kinase
• ligand independent

• chromosome translocation
• fusing the coil coil region of tropomyosin to the intracellular domain of the Trk receptor - found in colon carcinomas
• chimeric Trk oncoprotein is constitutively active

• Spleen focus-forming virus
• FFV induces oncogenesis by producing a ligand that dimerized Epo receptor
• gp55 - a viral protein mimics a ligand and activates receptor

• chromosomal translocation causing a fusion protein between Abl and Bcr, 9 and 22
• causes constitutive activation of the kinase, makes Bcr-Abl fusion protein
• fusion protein can bind JAK2, STAT5 - substrate activated by phosphoyrlation, overactive but nonspecific
• substrate can be inhibited with Imatinib

• 1st cancer drug targetd to signal-transduction protein unique to tumor cells
• Imatinib binds to Abl in CML active site and inhibits substrate binding

• intracellular proteins that regulate or inhibit progression through a specific stage of the cell cycle, p16 and Rb(inhibit G1 - S)
• receptors or signaling proteins that inhibit cell proliferation, TGF-beta pathway
• negative regulators of pathways that promote proliferation, APC
• checkoint control proteins that arrest the cell cycle if DNA is damaged or chromosomes are abnormal, p53
• proteins that promote apoptosis, Bax or Fas
• enzymes that participate in DNA repair, cells that lack such factors accumulate in many gene,s some of which will promote tumor formation

• the kinase that activates p53
• p-p53 no longer bindsn to Mdm2 (ub ligase), disasscoation
• lead to stable, active p-p53 and bind to regulatory region of p21
• transcription of p21 gene - tranlades into p21 Cdk inhibitor protein
• CIP - cells arrest in G1 and G2

• ATM phosphorylation of p53
• Chk2 phospphorylate p53 (chk2 also phosphorylates cdc25A, leads to proteasomal degradation (decrease of cdk2) rapid G1/S block)
• ATM phosphorylation of Mdm2, since Mdm2 is the ub ligase that induces the degradation of p53, phosphorylation leads to inactive Mdm2 and stabilized p53
• Mdm2 bidning to pArf14 -inactive, more p53 activity

• receptors/signaling proteins inhbit cell proliferaion (transcription of p15 encoding cell-cycle inhibitor, Pal-1 encodes inhibitor of protease that degrades extracellular matrix proteins)
• loss of function mutants promote cell growth
• decreased produciton of p15 increases proliferation
• decreased production of Pal-1 allows increased extracellular matrix
• degradation and metastasis

• tumor suppressor, binds and inhibits cyc3 and CDK4
• once removes, active kinse which will phosphorylate Rb
• phosphorylated Rb releases E2F - activator of transcription fo proteins needed for DNA synthesis

• Telomerase is an enzyme that adds DNA sequence repeats ("TTAGGG" in all vertebrates) to the 3' end of DNA strands in the telomere regions, which are found at the ends of eukaryotic chromosomes. The telomeres contain condensed DNA material, giving stability to the chromosomes.
• loss of telomerase limits the number of cell civision - at the tip of linear dNA molecules, usually hard to replicate, are usually tandem repeats of short sequences
• recognizes telomere DNA - telomerase extends the 3'end, elongates 5 to 3, 3 is slightly longer than 5, protected from degradation
• ecah time a cell divides it loses 50-100 nucleotides