Cancer- Tumor angiogenesis and metastasis – Flashcards
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How do tumors cause illness?
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1. occupying space in critical locations (example: brain) 2. secrete hormones or peptides that affect body function 3. invade surrounding tissues and disrupt anatomy and physiology 4. metastasize to distant sites
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What does metastasis require?
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access to blood vessels
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angiogenic switch
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a signaling molecule (secreted by tumor or inducing stromal cells) that turns on angiogenesis
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vasculogenesis
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formation of primary capillary plexus from progenitor cells occurs primarily during development
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angiogenesis
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sprouting of new vessels from existing ones occurs in development and adult occurs during female reproductive cycle, pregnancy, wound healing and tissue repair, pathological conditions (inflammation, cancer)
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VEGF-A
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initiates vasculogenesis and sprouting angiogenesis vascular permeability factor Haploinsufficiency in KO mice causes lethality binds to VEGFR1/2
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VEGFR-2
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growth and permeability
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VEGFR-1
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modulates VEGF-2
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VEGFR-3
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lymphatic vessels
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angiopoietin 1 (ang1)
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does not induce EC proliferation or vessel sprouting resistance to permeability, vascular stability supports interaction with other cells and matrix KO defective in vessel remodeling, organization and sprouting, similar to TIE2 knockout repair of damaged vessels
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Ang2
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natural antagonist of Ang1/Tie2 overexpression leads to embryonic death, similar to embryos lacking Ang1 or Tie2 destabilization signal for initiation of vascular remodeling expressed at sites of vascular remodeling induced in tumors
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Tie2
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binds Ang1-4
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Ephrins
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membrane bound proteins that help define arterial-venous identity regulate processes during development including axonal guidance, formation of tissue boundaries, cell migration, and segmentation
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Eph receptors
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largest family of receptor tyrosine kinases bidirectional signaling
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Ephrin B2/EphB4
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remodeling and maturation delineate arterial (Ephrin B2) and venous (EphB4) vessels possible role for fusion of arterial/venous vessels eph receptors and ephrins are expressed in tumor cells and tumor vasculature
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What does hypoxia upregulate?
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EphB4, ephrinB2, EphA2, ephrinA1 promotes angiogenesis and cancer cell survival
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What regulates endothelial tip cell formation?
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Notch and VEGF signaling
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How is VEGF controlled?
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by oxygen levels
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What happens to HIF when cells are in normoxic conditions?
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HIF-1alpha gets modified on 2 prolines and an asparagine by hydroxylation. This is recognized by pVHL and gets poly-ubiquitinated for degradation
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pVHL
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von Hippel-Lindau E3 ubiquitin ligase that poly ubiquitinates HIF-1alpha so HIF-1alpha can be degraded
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What happens with HIF when oxygen level is low?
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HIF-alpha and HIF-beta (ARNT) dimerizes and activates genes expression
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Characteristics of tumor vessels
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chaotic architecture and blood flow highly disorganized, tortuous and dilated leaky, high permeability uneven diameter, excessive branching lack pericytes lined by a mosaic of cancer and endothelial cells imbalance of VEGF and angiopoietins (lack Ang1 or overexpress Ang2) no functional lymphatics inside the tumor
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What facilitates metastasis?
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disorganized tumor vessels allow for the EMT cells to easily get into/out of blood stream
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Vasculogenic mimicry
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formation of microvascular channels by metastatic tumor cells
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Malignant tumors
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invade surrounding tissues, spread to distant sites of the body, thus disrupting anatomy and physiology
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carcinomas
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cancer of epithelial cells
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sarcomas
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cancer of connective tissue
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leukemias
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cancer of hematopoietic cells
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adenocarcinomas
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cancer of glandular epithelial cells
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melanomas
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cancer of pigment cells
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teratomas
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cancer of germ cells/gonadal tissue
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adenomas
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benign tumors of glandular epithelial cells, do not invade or metastasize
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Anatomical staging- TNM system
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T: tumor size/invade nearby tissue (1-4) N: lymph node involvement (0-3) M: distant metastasis (0-1)
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Steps of metastasis
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1. local invasion EMT and breach of the basement membrane barrier. Dissociation of tumor cells from the bulk tumor. Invasion of the neighboring tissue 2. Intravasation into pre-existing and newly formed blood and lymph vessels 3. Survival in circulation 4. arrest at a distant organ site 5. extravasation 6. micrometastasis formation 7. metastastic colonization
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Invasion
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cells detach from the primary tumor and invade surrounding interstitial space
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intravasation
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entering the blood stream. spread by lymphatics and bloodstream
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arrest and extravasation
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exit from the circulatory system to the surrounding tisssue
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colonization and proliferation of metastatic tumor
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difficult for the cell to do
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Epithelial to Mesenchymal Transition (EMT)
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reduced cell-cell adhesion lossof E-cadherin, claudins/occludin acquire mesenchymal morphology and migratory phenotype increase in extracellular proteolytic activity proliferate
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EMT is associated
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with the invasive edge and specific gene expression changes
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Basement membrane
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comprised of about 50 proteins major components: type IV collagen (also type XV and XVIII), laminin, heparan sulfate proteoglycans (perlecan), nidogen/entactin
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MMPs (matrix metalloproteinases) help invade
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ECM
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Matrix Metalloproteinases (MMPs)
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family of more than 20 zinc dependent endopeptidases MMP2, MMP9 can degrade type IV collagen of basement membrane can promote cancer- increase cancer cell growth, migration, invasion, metastasis, angiogenesis Membrane type (MT-MMP) group are anchored in the plasma membrane. secreted type includes collagenase, gelatinase, stromelysins
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What is MMP activity regulated by?
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specific inhibitors: tissue inhibitors of MMP (TIMPS) Binding TIMP to MMP in 1:1 stoichiometry
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MMPs are upregulated in almost every type of human cancer
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can be made by cancer cells or stromal cells mice lacking MMP2, 7, 9, 11 develop fewer tumors overexpression of MMP7 or 11 renders more tumors
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Metastatic tropism
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tumor cells retain the characteristics they had in their original location. Breast cancer cells that metastasizes to liver retain breast cancer characteristics
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sites of metastasis are non-random
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sarcomas to lung, lung cancer to brain, colorectal tumor to liver breast cancer spreads to bone, liver, brain, lungs prostate cancer metastasizes to bone
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Genetic changes mediating metastasis
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metastatic gene expression signature common to many tumors. gene expression pattern predicts the probability of metastsis tumor cells isolated from metastases are more highly mestastatic than cells from primary tumor
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breast cancer metastatic gene expression
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CXCR4, IL-11, CTGF, MMP1 enhances metastasis to bone genes that mediate breast cancer metastasis to lung are distinct from those mediating bone metastasis
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Metastatic gene signatures
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CXCR4: bone homing chemokine receptor CTGF: angiogenic factor (connective tissue growth factor) IL-11: activator of osteoclast differentiation (mediators of bone resorption in bone metastases) MMP1: matrix metalloproteinase/collagenase, promotes osteolysis by cleaving a specific peptide bond in the collagen bone matrix OPN: osteopontin (consistently overexpressed in metastatic cells)
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Metastatic cancer stem cells classes
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liquid tumors: only 1-4% of transplanted leukaemic cells could form spleen colonies solid tumors: a large number of cells are required to grow tumors in xenograft models
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Metastatic cancer stem cells
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1. potential to undergo self-renewal 2. may proliferate rarely; transit amplifying cells 3. CSCs persist in tumors as a distinct population; likely causes relapses/metastasis 4. explains why many cancers are difficult to treat
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Metastasis initiating cell (MIC) clones
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unlimited self-renewal activity and metastatic (able to disseminate, survive in the systemic circulation, seed and expand in a new microenvironment); can be organ specific
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CSC clone
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unlimited self-renewal activity, non-metastatic (due to failure to disseminate or survive in the systemic circulation or seed or expand in a new microenvironment)
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non-CSC population
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poorly tumorigenic, limited self-renewal activity and non-metastatic
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pro-angiogenic factors
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VEGFs, FGFs, angiopoietins, PDGF, TGF-beta, TNFalpha, CXC chemokines, EGF, CSfs, insulin, IGF1, HGF, integrins, MMPs, Erythropoietin, NO, VE-cadherins, PECAM1
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Anti-angiogenic factors
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soluble FLT1, Endostatin, angiostatin, canstatin, tumstatin, arresten, alphastatin, fibulin-5, 2methoxyestradiol, PEDGF, platelet factor 4, terrahydrocortisol, thrombospondin-1, TIMP-2
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Constituents of vascular basement membranes are key regulators of angiogenesis
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type IV collagen, laminin, SPARC, perlecan
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basement membrane derived endogenous inhibitors of angiogenesis
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arrestin, canstatin, tumstatin, endostatin
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naturally occurring inhibitors of angiogenesis
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inhibit endothelial cell functions and suppress tumor growth in mouse models thrombospondins, angiostatin, endostatin, arrestin, canstatin, tumstatin, anastellin
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endostatin
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fragment of type XVIII collagen inhibits angiogenesis and tumor growth circulates in serum cleaved from NC1 trimer to form ES monomers inhibits endothelial cell proliferation and migration
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drug inhibitors of tumor angiogenesis
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1. Bevacizumab 2. VEGF-trap 3. Pegaptinib 4. Sorafenib
