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Integrins and other Adhesion receptors in Invasion and Metastasis

Integrins and other Adhesion receptors in Invasion and Metastasis. Introduction: migration target organ Integrin avb3 and a6b4 N-CAM, N-Cad, GF’s CD44 Selectins. Prostate carcinoma: vertebrate and long bones Breast adenocarcinoma: lungs and liver, bone, brain, adenals

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Integrins and other Adhesion receptors in Invasion and Metastasis

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  1. Integrins and other Adhesion receptors in Invasion and Metastasis Introduction: migration target organ Integrin avb3 and a6b4 N-CAM, N-Cad, GF’s CD44 Selectins

  2. Prostate carcinoma: vertebrate and long bones Breast adenocarcinoma: lungs and liver, bone, brain, adenals Small cell lung carcinoma: brain Sporadic metastasis in spleen, kidney, intestine, heart, muscle and skin

  3. 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.

  4. Microvascular endothelial cell culture: Heterogeneity of cells Phenotypic drift due to lack of modulatory cues (matrix, factors) Constitutive endothelial cell adhesion molecules Auerbach PNAS 1984 Cancer Res 1987 Hepatoma: liver endothelium Glioma: brain derived endothelia Mammary tumor cells: lyphatic endothelium

  5. Integrin

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

  7. a5b1 in most tumors down Hynes Cancer Res 58:848 (1998) a5 hets no LOH, no more tumors in combination with p53 deficient mice a5 -/- chimeric mice no more tumors nor different tumor spectrum Reduced blood vessel formation and tumor growth in a5 integrin negative teratocarcinomas and embryoid bodies. Reduced growth, do atrtibute to minority of tumor vasculature ……

  8. Siu MBC12:2699(2001) RGD IgG FnIII TM Human microvascular endothelial cells WM239 human melanoma transmigration avb3 enriched at heterotypic cell-cell contacts blocked by Ab and RGD PECAM-1 different localization in HMVECs L1 on both cells Ab L1 blocks, preincubation HMVECS block it RGD Maness JBC 278:25024 (2003) Close homologoe of L1 (Neurons and glia) binds b1 integrins and promotes hapotactic cell migration

  9. avb3 role in angiogenesis Hynes

  10. JBC 271: 5892 JBC277:21930 (2002) Clin Exp Met 19:427 (2002) Clin Exp Met 20:203 (2003) PNAS98:1853() Brunhilde Felding-Habermann (Scripps) avb3 in tumor cells MDA-MB435 human breast cancer cells activated avb3 arrest with platelets no direct binding to platelets (Fg coat) Activated avb3 leads to tumor cell arrest under dynamic flow conditions M21 cells Soluble Fg enhances adhesion to Fg/vWF/FN No aggregation of tumor cells but thrombus growth as that of platelets Idem binding to platelets MT-MMP activates MMP2 idem BLM h-melanoma

  11. Clezardin FASEB J 2002 CHO cells active avb3 MORE bone metastasis after tail-vein injections

  12. Strongin JBC277 7372 (2002) JBC277:9749 (2002) av (b3) alternatively processed by MT1-MMP MCF7 breast carcinoma cells (*no MMP2 or MT1-MMP)

  13. No effect on RGD binding Enhanced FAK activation Enhanced migration on VN

  14. Heino Cancer Res (2003) Anti-av endogenous expression> av depletion in metastatic melanoma Cheresh JCB 459 (2001) Detachment and apoptosis < > IMD=integrin mediated death Unligated integrin b-subunit recruits and activates caspase-8 >apoptosis However not in all cell types: Not CHO HeLa + COS, CS1, Huvec

  15. JBC 272:27853 (1997) JBC 276:25438 (2001) JBC 277:34391 (2002) Bendicht Pauli (Cornell) a6b4 - CACL 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 vivo Lu-ECAM1=mCLCA1=hCLCA2 endothelia of pleural, subpleural and peribronchial venules not capillary and arterial endothelial cells

  16. Only MDA-MB231 cells bind hCACA2, these cells express b4 integrin Overlay assay and blocking Ab’s, matrilysin Tumor a6b4 endothelium CaCL Idem: B16-F10 bind mCLCA1 via b4 in a Met independent way Intravascular tumor growth, FAK phosphorylation, FRNK blocks

  17. Comoglio Cell 107:643 (2001) a6b4 co-receptor > HGF dependent invasive growth Met-R - a6b4 via Shc/PI3K-ras

  18. Pauli (2): Lung perfusion formaldehyde/DTT, vesicles bound to brast and lung metastatic melanoma Ab > dipeptidyl peptidase IV (DPP IV) Binds cell surface FN not soluble Correlates 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

  19. N-cad, N-CAM EMBO J 22:2318 (2003) Nat Cell Biol 3:650 (2001) BBA 1552:39 (2001) Gerhard Christofori (basel) E-cad: epithelial structure < > N-cad migratory cells (mesenchyme) (cad-11) N-CAM in RipTag b-cells pancreatic tumor

  20. N-cad -FGFR signaling Idem VE-cad-VEGFR Receptor binds FGFs and prevents ligand induced FGFR internalization > Sustained MAPK activity and MMP2 Hazan Cancer cell 2: 301 (2001) MCF7 cells N-cad-FGFR> MMP-9 +invasion + migration

  21. Doherty (London) Neuron 18:231 (1997) N-cad, NCAM and L1 lead to phosphorylation of FGFR in neurons via PCLg

  22. CD44 Herrlich Ponta Nat. Rev Mol Cell Biol 4:33 (2003) Jothy Clin. Exp. Met. 20:195 (2003) “Tumor progression is characterized by a generalized dysregulation of splicing”

  23. Platform function Co-receptor function Platform function Co-receptor function Cytoskeletal organizer

  24. Tumor Induced endothelial cell adhesion molecules (E-P selectins, VCAM ICAM, cancer cell adhesion ligands Lex, Lea, VLA1, LFA1) 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 melanoma Leucocytes adhere less next to ear tumors idem large flank tumors ICAM/VCAM down In vitro bFGF/VEGF induced ICAM/VCAM downregulation

  25. 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

  26. EINDE

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