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Cell-cell interactions promotes metastasis The role of metastatic microenvironment. Lubor Borsig Zürich Center for Integrative Human Physiology Cancer Network Zürich University of Zürich Bratislava, May 2008.

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Cell cell interactions promotes metastasis the role of metastatic microenvironment

Cell-cell interactions promotes metastasisThe role of metastatic microenvironment

Lubor Borsig

Zürich Center for Integrative Human Physiology

Cancer Network Zürich

University of Zürich

Bratislava, May 2008


Hematogenous metastasis

Metastatic cells interact with host leukocytes and platelets when they enter the bloodstream

Hematogenous Metastasis

Clonal Expansion

Growth

Angiogenesis

Invasion of basement membrane

Passage through Extracellullar Matrix

Intravasation

Tumor Cell emboli

Adhesion to endothelium

Invasion of basement membrane

Extravasation

Growth and Angiogenesis


Metastatic tumor cells in circulation
Metastatic tumor cells in circulation when they enter the bloodstream

Integrins

Selectins

Ig CAM


Selectins and their ligands

L when they enter the bloodstream

L

P

P

P

E

E

E-selectin

L-selectin

P-selectin

Selectins and their ligands

L-selectin

Leukocyte

P-selectin

E-selectin

Platelet

Endothelial Cell

E

  • - Sialylated fucosylated lactosamine oligosaccharides

  • sLeX based ligands (O-linked =mucins, N-linked)

  • - Glycosaminoglycans (e.g. heparin, heparan sulfate)

  • Glycolipids (e.g. Sulfatides)

L

P

SELECTIN

LIGANDS


Normal and malignant epithelium

Altered sugar chains when they enter the bloodstream

CANCER

Siaa2-3Galb1-4GlcNAcb1-

3

1

a

Fuc

Sialyl Lewisx (sLex)

Normal and malignant epithelium

NORMAL

BASEMENT

MEMBRANE

Blood vessels


Cell cell interactions promotes metastasis the role of metastatic microenvironment

Prognostic significance of Sialyl Lewis when they enter the bloodstreamx (sLex) expression in patients with colon adenocarcinoma

from Nakamori et.al, 1997

Sialyl-Lex expression is associated with poor prognosis / disease progression in Adenocarcinomas of Breast, Lung, Pancreas, Bladder, Prostate, Biliary tree and Ovary


Possible interactions between carcinomas and selectins
Possible interactions between carcinomas and selectins when they enter the bloodstream

  • P-dependent interactions promote metastasis

  • Leukocytes facilitate metastasis

  • Heparin as an inhibitor of metastasis

Borsig L, NIPS 2004


Selectin deficiencies attenuate metastasis of colon carcinoma cells in syngeneic mice
Selectin deficiencies attenuate metastasis of colon carcinoma cells in syngeneic mice

Borsig L, et al, PNAS 2002


P selectin deficiency attenuates metastasis formation

P< 0.01 carcinoma cells

P-sel +/+ P-sel -/-

Mice Psel+/+ Psel-/- Psel+/+ Psel+/+

OSGPase - - - +

P-selectin deficiency attenuates metastasis formation

• Human colon carcinoma cells intravenously injected in Rag-/- mouse background

•Mice were euthanized after 6 weeks

• PCR amplification of human specific Alu sequences, quantified by Dot-blot

Borsig L, et al. PNAS 2001


Interaction of platelets with carcinoma cells is p selectin dependent in vivo
Interaction of platelets with carcinoma cells is P-selectin dependent in vivo

Calcein labeled LS180 cells were intravenously injected

Green - tumor cells

Red - CD41 stained platelets

  • P-selectin is required for optimal interactions of tumor cells with platelets

Borsig L, et al. PNAS 2001


Interaction of carcinoma cells with platelets monocytes is affected by p selectin
Interaction of carcinoma cells with platelets & monocytes is affected by P-selectin

Green:

tumor cells

Blue:

CD41+

platelets

Red:

Mac-1+

cells

Loss of the “platelet coating” allows increased association

of Mac-1-positive monocytes/macrophage precursors with tumor cells

Borsig L, et al, PNAS 2001



Leukocytes associate with tumor cells in l selectin dependent manner

* manner

p< 0.05

Lsel+/+

Lsel -/-

Leukocytes associate with tumor cells in L-selectin dependent manner


Temporal inhibition of l selectin attenuates metastasis
Temporal inhibition of L-selectin attenuates metastasis manner

MEL-14 Fab injected at +6 h and +12 h after tumor cells

Läubli et al. Cancer Res 2006


Heparin as an inhibitor of metastasis

Early Heparin manner

Late Heparin

BEFORE TC

AFTER TC

Heparin as an inhibitor of metastasis


Cell cell interactions promotes metastasis the role of metastatic microenvironment

„Late“ Heparin treatment affects metastasis manner

Heparin IV injected at +6 h and +12 h after tumor cells

„Late“ Heparin attenuates metastasis in P-selectin independent manner

Laubli et al. Cancer Res 2006


Diverse biological effects of heparin
Diverse biological effects of heparin manner

  • Inhibition of the Clotting Cascade

  • Blockade of P- and L-selectin

  • Binding of Growth factors

  • Inhibition of Angiogenesis

  • Inhibition of Heparanases

  • Effects on Proteases and ECM components

  • Inhibition of the Clotting Cascade

  • Blockade of P- and L-selectin

  • Binding of Growth factors

  • Inhibition of Angiogenesis

  • Inhibition of Heparanases

  • Effects on Proteases and ECM components

Heparin der. with a narrow biological activity


Characterization of heparin derivatives

NA-H manner„selectin specific“ inhibitor

RO.H selectin and heparanase inhibitor

NA-RO.H heparanase specific inhibitor

58

G3496

G4146

100

G4000

Characterization of Heparin derivatives

Hostettler N, et al. FASEB J 21:3562-72, 2007


Heparin treatment attenuates metastasis

GFP-quantitation manner

Number of Foci

Heparin treatment attenuates metastasis

G3496 – „P-selectin specific“ inhibitor

Heparin derivative with NO anticoagulant activity and low heparanase inhibitory activity attenuates metastasis

Hostettler N, et al. FASEB J 21:3562-72, 2007



Metastatic microenvironment
Metastatic microenvironment manner

PMN tumor cells platelets

monocytes

endothelium

Activation of microvascular endothelial cells promotes metastasis


Cell cell interactions promotes metastasis the role of metastatic microenvironment

Co-culture system manner

HT-29 and LS-180 tumor cell lines

Microvascular endothelial cells

platelets

Monocytes

PMN


Cell cell interactions promotes metastasis the role of metastatic microenvironment

Tumor cell interactions with platelets and leukocytes activate HMVEC

LS180

HT-29

3.8

4.2

Tumor cells alone

E-selectin

62.2

27.8

+ Platelets, PMN and Monocytes

CD105


Cell cell interactions promotes metastasis the role of metastatic microenvironment

Nuclear translocation of NF- activate HMVECκB

HMVEC with PMN, monocytes and platelets

- LS180

+LS180

DAPI

p65

After 40 min of co-culture

Colocalization of DAPI and p65

CD31



Leukocyte association with tumor cells
Leukocyte association with tumor cells manner

wt mice

Lsel-/- mice

Pronounced association of neutrophils and monocytes/macrophages with metastasizing tumor cells is L-selectin dependent



Tc extravasation is mediated by monocytes
TC extravasation is mediated by Monocytes manner

Heart perfusion with Tomato lectin-TR

+ 24 h liposomes

+ 24 h clodronate


Conclusions and outlook
Conclusions and Outlook manner

Cell-cell interactions and metastasis

  • Temporal inhibition of P-and L-selectin attenuate metastasis

  • Platelet and leukocyte interactions with TC facilitate metastasis

  • Endogenous selectin ligands potentiate metastasis

  • Heparin treatment reduces metastasis primarily through selectin inhibition

  • Selectin-specific heparins are equally good inhibitors of metastasis as heparin


Conclusions
Conclusions manner

Acknowledgements

University Zürich Ronzoni Institute Milano

Heinz Läubli B. Casu

Marie-A Boucabeille A. Naggi

Nina Hostettler G. Torri

Josep Garcia

Claudia Ruedin B. Rappoport F of Medicine Eric BergerI. Vlodavsky

IMCR University of Zürich

R. Schwendener

Supported by SNSF, Swiss Cancer League Zürich