Cellule Staminali Del Cancro II
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Transcript of Cellule Staminali Del Cancro II
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Endothelial precursors (angioblasts) in the embryo assemble in a primitive network (vasculogenesis), that expands and remodels (angiogenesis). Smooth muscle cells cover endothelial cells during vascular myogenesis, and stabilize vessels during arteriogenesis. CL: collagen; EL: elastin; Fib: fibrillin (Fib).
Development of an endothelium-lined vasculature
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Tumor growth is angiogenesis dependent
Judah Folkman
Tumor Angiogenesis
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The angiogenic balance
This discovery led to a profound paradigm shift in cancer therapy and cancer biology. Before his 1971 hypothesis, the cancer cell per se was the only target of cancer therapies. Now it is accepted that the microvascular endothelial cell recruited by tumors is a second target.
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The classical angiogenic switch
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New blood vessel formation
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Angiogenic signaling molecules
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Blood vessel co-option precedes angiogenesis in astrocytoma progression
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Anti-angiogenic agents in clinical trials
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Two modes of resistance to antiangiogenic therapy
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Induced pro-angiogenic factor substitution re-establishes tumour neovascularization
Mode I: evasion of anti-angiogenic therapy (adaptive resistance)
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Recruitment of bone marrow-derived cells can endorse restored neovascularization
Mode I: evasion of anti-angiogenic therapy (adaptive resistance)
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Increased pericyte coverage protects tumor blood vessels
Mode I: evasion of anti-angiogenic therapy (adaptive resistance)
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Increased tumor cell invasiveness to escape oxygen and nutrient deprivation
Mode I: evasion of anti-angiogenic therapy (adaptive resistance)
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Mode II: indifference to anti-angiogenic therapy (intrinsic non-responsiveness)
Pre-existing multiplicity of redundant pro-angiogenic signals.
Pre-existing inflammatory cell-mediated vascular protection.
Characteristic hypovascularity and indifference toward angiogenesis inhibitors.
Invasive (and metastatic) co-option of normal vessels without requisite angiogenesis.
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Origin of tumor vasculature
Two main cell types:
Endothelial progenitor cells: Asahara & Isner, 1997, 1999 Lyden & Rafii, 2001 Shaked et al. 2008
Locally-derived endothelial cells: Lin et al. 2001 Coussens et al., 1999, 2000 De Palma, 2003 Purhonen, 2008
Bone marrow
The relative contribution of these different pathways is subject of intense investigation and debate
Migration of Endothelial progenitors
Migration of bone-marrow derived cells
that release proangiogenic
factors
locally-derived EC
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VASCULOGENIC MIMICRY AND TUMOUR-CELL PLASTICITY: LESSONS FROM MELANOMA
VASCULOGENIC MIMICRY is the ability of certain types of cancer cells to mimic the activities of endothelial cells and to partecipate in processes such as neovascularization and formation of a fluid-conducting, matrix-rich meshwork that seems to recapitulate the embryonic development of vasculogenic networks.
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The vasculogenic-mimicry signalling cascade
Phosphorylated (P) erythropoietin-producing hepatocellular carcinoma-A2 (EPHA2) and vascular endothelial (VE)-cadherin are co-localized at the cell membrane. Phosphorylated EPHA2 subsequently interacts with phosphorylated focal adhesion kinase (FAK). The signal transduction pathways converge to activate phosphatidylinositol 3-kinase (PI3K). Downstream, PI3K regulates the activity of membrane type-1 matrix metalloproteinase (MT1-MMP), which subsequently activates pro-MMP2 to an active MMP2 proteinase. Both MT1-MMP and MMP2 promote the cleavage of laminin 5 2-chain into promigratory2 and 2x fragments. The release of these fragments can increase the migration, invasion and, ultimately, vasculogenic mimicry of aggressive melanoma tumour cells.
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1 2 3 4 5 6 7 8 Case No.
A subset of glioblastoma CD31+/CD144+ cells display tumor-specific chromosomal alterations
Ricci-Vitiani et al. Nature 468:824, 2010
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The vasculogenic mimicry is a feature associated with a pluripotent gene expression pattern in aggressive tumour cells
Cancer stem cells and angiogenesis
Maniotis, Hendrix, Am J Pathol, 1999
Do CSCs partecipate directly to new vessel formation?
Gao , Rich Cancer Res, 2006
Glioma stem cell-like cells promote tumor angiogenesis through the production of VEGF
VEGF
Tumor origin of endothelial cells in human neuroblastoma Pezzolo, J Clin Oncol, 2007
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Neural
Multipotent
0
5
10
15
Mea
n tu
mor
dia
met
er (m
m)
0
3
6
9
Mito
tic in
dex
(%)
Multipotent glioma stem cells generate small and slowly growing tumors in a microenvironment
that favors mesenchymal differentiation
Ricci Vitiani, Pallini et al. Cell Death Diff 55:568, 2008
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Multipotent Stem Cells
Commited Neural Progenitor Differentiated
Tumor hit
Neural Stem Cells
?
Cancer stem cell plasticity
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CD
31+
(%)
Tie2
+ (%
)
0
20
40
60
80
100
U87MG BTPCs BTSCs HUVECs
0
20
40
60
80
100
U87MG BTPCs BTSCs HUVECs
Endothelial medium Standard medium
Gliomastemcellsgenerateendothelialcellsinvitro
Endothelial medium Standard medium
Glioma stem cells
HUVEC
Differentiated glioma cells
Ricci-Vitiani et al. Nature 468:824, 2010
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Multipotent Stem Cells
Neural progenitors/precursors
Aberrant neural cells
Neural stem cells
Glioblastoma stem cell plasticity
Vasculogenic progenitors/precursors
Aberrant endothelial cells
Vascular stem cells
CD31+
CD31-
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Selective targeting of GSC-derived endothelial cells impairs the growth of tumor xenograft
Ricci-Vitiani et al. Nature 468:824, 2010
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Vector
Tie2-tk
PGK-tk
TUNEL Tie2 TUNEL/Tie2
LTR LTR
EGFP PGK TIE2 TK
LTR LTR
EGFP PGK PGK TK
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NOTCH1 and VEGFR2 in the differentiation process of tumor-derived endothelial progenitors (DP cells) into endothelial cells (CD105+)
Wangetal.Nature,2010
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Acidic stress promotes tumorigenesis of glioblastoma cells
Lower survival of mice bearing glioma xenografts obtained by GBM-SCs exposed to acidic stress in comparison to those obtained by GBM-SCs cultured under typical pH. The tumor size for the former xenografts showed a trend towards being greater than the latters.
Increased neurosphere formation at pH 6.5 compared to pH 7.5.
Rich,CellDeath&Di.(2011),18:82940
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Is there a future for anti-angiogenic treatment in glioblastoma?
Hypoxia, Acidic Stress Canonical angiogenesis
CSC angiogenesis
Self-renewal, Reprogramming
Anti-angiogenic treatment