Integrins and other Adhesion receptors in Invasion and Metastasis

Introduction: migration target organ

Integrin avb3 and a6b4N-CAM, N-Cad, GF’s

CD44Selectins

Prostate carcinoma: vertebrate and long bonesBreast adenocarcinoma: lungs and liver, bone, brain, adenalsSmall cell lung carcinoma: brainSporadic metastasis in spleen, kidney, intestine, heart, muscle and skin

Paget: 1889 Lancet “seed and soil” Cancer cells grow only in their right environment

Trapping mechanism

Kinsey 1960 Cancer

i.v. lung metastatic cancer cells to metastasis to lungs and ectopically lung tissue and not in ectopically places tissues in right thigh.

Microvascular endothelial cell culture:Heterogeneity of cellsPhenotypic drift due to lack of modulatory cues (matrix, factors)

Constitutive endothelial cell adhesion molecules

Auerbach PNAS 1984 Cancer Res 1987Hepatoma: liver endotheliumGlioma: brain derived endotheliaMammary tumor cells: lyphatic endothelium

Integrin

MizejewskiRole of integrins in cancer: survey of expression patterns.Proc Soc Exp Biol Med. 1999 Nov;222(2):124-38. Review

51 in most tumors down

Hynes Cancer Res 58:848 (1998)

5 hets no LOH, no more tumors in combination with p53 deficient mice

5 -/- chimeric mice no more tumors nor different tumor spectrum

Reduced blood vessel formation and tumor growth in 5 integrin negative teratocarcinomas and embryoid bodies.Reduced growth, do atrtibute to minority of tumor vasculature ……

Siu MBC12:2699(2001)

Human microvascular endothelial cellsWM239 human melanoma transmigration

v3 enriched at heterotypic cell-cell contacts blocked by Ab and RGD

PECAM-1 different localization in HMVECsL1 on both cellsAb L1 blocks, preincubation HMVECS block it

Maness JBC 278:25024 (2003)

Close homologoe of L1 (Neurons and glia) binds 1 integrins and promotes hapotactic cell migration

RGD

FnIIIIgG

RGD

TM

v3 role in angiogenesis

Hynes

Brunhilde Felding-Habermann (Scripps)JBC 271: 5892JBC277:21930 (2002)Clin Exp Met 19:427 (2002)Clin Exp Met 20:203 (2003)PNAS98:1853()

MT-MMP activates MMP2 idem BLM h-melanoma

Activated v3 leads to tumor cell arrest under dynamic flow conditions M21 cells

Soluble Fg enhances adhesion to Fg/vWF/FNNo aggregation of tumor cells but thrombus growth as that of plateletsIdem binding to platelets

MDA-MB435 human breast cancer cells activated v3 arrest with platelets no direct binding to platelets (Fg coat)

v3 in tumor cells

Clezardin FASEB J 2002CHO cells active v3 MORE bone metastasis after tail-vein injections

Strongin JBC277 7372 (2002)JBC277:9749 (2002)

v (3) alternatively processed by MT1-MMP MCF7 breast carcinoma cells (*no MMP2 or MT1-MMP)

No effect on RGD bindingEnhanced FAK activationEnhanced migration on VN

Heino Cancer Res (2003)Anti-v endogenous expression> v depletion in metastatic melanoma

Cheresh JCB 459 (2001)

Detachment and apoptosis < > IMD=integrin mediated deathUnligated integrin-subunit recruits and activates caspase-8 >apoptosisHowever not in all cell types: Not CHO HeLa + COS, CS1, Huvec

Bendicht Pauli (Cornell)

Bovine aortic endothelial cell s(BAEC) grown on organ specific matrix (organ spec. microvasculature)Different dissimination of tumor cells to organs, correlates with adhesion to BAECs grown on organ spec. matrix

Lung metastatic melanoma cells on BAEC, Abs 6D3 , Blocks B16-G10 metastasis in vivoLu-ECAM1=mCLCA1=hCLCA2

JBC 272:27853 (1997)JBC 276:25438 (2001)JBC 277:34391 (2002)

64 - CACL

endothelia of pleural, subpleural and peribronchial venules not capillary and arterial endothelial cells

Only MDA-MB231 cells bind hCACA2, these cells express 4 integrinOverlay assay and blocking Ab’s, matrilysinTumor 64 endothelium CaCL

Idem:B16-F10 bind mCLCA1 via 4 in a Met independent wayIntravascular tumor growth, FAK phosphorylation, FRNK blocks

Comoglio Cell 107:643 (2001)

64 co-receptor > HGF dependent invasive growth

Met-R - 64 via Shc/PI3K-ras

Pauli (2):Lung perfusion formaldehyde/DTT,vesicles bound to brast and lung metastatic melanomaAb > dipeptidyl peptidase IV (DPP IV)

Binds cell surface FN not solubleCorrelates with over expressing FN

DPP IV expression:

Resiratory capilaries, endothelia renal vasa recta, splenic venules bile canaliculi brush borders kidney proximal tubular epithelium and small intestine epithelium

Gerhard Christofori (basel)EMBO J 22:2318 (2003)Nat Cell Biol 3:650 (2001)BBA 1552:39 (2001)

E-cad: epithelial structure < > N-cad migratory cells (mesenchyme) (cad-11)

N-cad, N-CAM

N-CAM in RipTag -cells pancreatic tumor

N-cad -FGFR signaling

Receptor binds FGFs and prevents ligand induced FGFR internalization> Sustained MAPK activity and MMP2

Idem VE-cad-VEGFR

Hazan Cancer cell 2: 301 (2001)

MCF7 cells N-cad-FGFR> MMP-9+invasion + migration

Doherty (London) Neuron 18:231 (1997)

N-cad, NCAM and L1 lead to phosphorylation of FGFR in neurons via PCLg

Herrlich Ponta Nat. Rev Mol Cell Biol 4:33 (2003)Jothy Clin. Exp. Met. 20:195 (2003)

CD44

“Tumor progression is characterized by a generalized dysregulation of splicing”

Platform function

Platform function Co-receptor function

Co-receptor function Cytoskeletal organizer

Griffoen (Maastricht) Cancer Res 63:2322(2003)

Tumor angiogenesis modulates leucocyte vessel wall interactions by down regulating ICAM/VCAM

Exp: Nude mice TS174T colon carcinoma, C57Bl6 B16F10 melanomaLeucocytes adhere less next to ear tumors idem large flank tumorsICAM/VCAM down

In vitro bFGF/VEGF induced ICAM/VCAM downregulation

Tumor Induced endothelial cell adhesion molecules (E-P selectins, VCAM ICAM,

cancer cell adhesion ligands Lex, Lea, VLA1, LFA1)

Inducible endothelial cell adhesion molecules

Selectins E and P on endothelial cells bind tetrasaccharides sialyl-LewisX Lex and sialyl-Lewis A Lea

on glycoproteins and glycolipids

EINDE