cellule staminali del cancro ii

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

Tumor growth is angiogenesis dependent

Judah Folkman

Tumor Angiogenesis

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.

The classical angiogenic switch

New blood vessel formation

Angiogenic signaling molecules

Blood vessel co-option precedes angiogenesis in astrocytoma progression

Anti-angiogenic agents in clinical trials

Two modes of resistance to antiangiogenic therapy

Induced pro-angiogenic factor substitution re-establishes tumour neovascularization

Mode I: evasion of anti-angiogenic therapy (adaptive resistance)

Recruitment of bone marrow-derived cells can endorse restored neovascularization


Increased pericyte coverage protects tumor blood vessels


Increased tumor cell invasiveness to escape oxygen and nutrient deprivation


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.

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

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.

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.

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

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

Neural

Multipotent

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5

10

15

Mea

n tu

mor

dia

met

er (m

m)

0

3

6

9

Mito

tic in

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(%)

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

Multipotent Stem Cells

Commited Neural Progenitor Differentiated

Tumor hit

Neural Stem Cells

?

Cancer stem cell plasticity

CD

31+

(%)

Tie2

+ (%

)

0

20

40

60

80

100

U87MG BTPCs BTSCs HUVECs

0

20

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U87MG BTPCs BTSCs HUVECs

Endothelial medium Standard medium

Gliomastemcellsgenerateendothelialcellsinvitro

Endothelial medium Standard medium

Glioma stem cells

HUVEC

Differentiated glioma cells


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-

Selective targeting of GSC-derived endothelial cells impairs the growth of tumor xenograft


Vector

Tie2-tk

PGK-tk

TUNEL Tie2 TUNEL/Tie2

LTR LTR

EGFP PGK TIE2 TK

LTR LTR

EGFP PGK PGK TK

NOTCH1 and VEGFR2 in the differentiation process of tumor-derived endothelial progenitors (DP cells) into endothelial cells (CD105+)

Wangetal.Nature,2010

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

Is there a future for anti-angiogenic treatment in glioblastoma?

Hypoxia, Acidic Stress Canonical angiogenesis

CSC angiogenesis

Self-renewal, Reprogramming

Anti-angiogenic treatment