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HOMING

HOMING. 8-28-08. METASTATIC COLONIZATION. Ewing vs Paget. “Seed and soil” Organ-specific metastatic colonization of favorable microenvironment. Metastatic colonization is higher in the organs first encountered by the blood flow. Trapping vs homing (controlled arrest).

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HOMING

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  1. HOMING 8-28-08

  2. METASTATIC COLONIZATION Ewing vs Paget “Seed and soil” Organ-specific metastatic colonization of favorable microenvironment Metastatic colonization is higher in the organs first encountered by the blood flow Trapping vs homing (controlled arrest) ARREST in ORGANS Mechanical trapping by capillaries Specific arrest mediated by adhesion molecules

  3. 3 types of homing mechanism • selective growth: tumor cells arrest ubiquitously but selectively grow only in the organs with appropriate growth environment • selective adhesion to endothelial cells only at the site of organ homing • selective chemotaxis of circulating tumor cells to the organ producing soluble attraction factors Selective arrest

  4. B16-F10 metastasis grow specifically in some organs Hart and Fidler. Cancer Res 40:2281-7 but do not arrest specifically

  5. Does organ or site-specific homing exist?

  6. Some tumor cells can arrest specifically HT-29LMM (colon carcinoma cell line) Liver Lung Schlueter et al. Am J Pathol 169:1064-73

  7. Cell arrest can be modulated IL-1 activates the endothelium and promotes cell arrest Scherbarth and Orr. Cancer Res 57:4105-4110

  8. Trapping vs homing (“controlled arrest”) • Most cells arrest in the first capillary bed • they encounter • Tumor cells are much bigger than • blood cells • Tumor cell arrest by size restriction • - relative sizes of the cells and the capillaries • - blood pressure in the organ • deformability of the cell • In some models, selectin blocking antibodies do not inhibit metastasis • Cell arrest into vessels of bigger diameter • Selectin and integrin blockade inhibits metastasis in several models • More metastasis than expected in some organ/less in others when considering blood flow • Arrest of melanoma into narrow vessels leads to cell deformation, rupture of tumor cell membrane and necrosis

  9. Mechanism of arrest

  10. Main players in cell arrest Miles et al. Clin Exp Metastasis 25:305-24

  11. Arrest specificity • Tumor cell specificity (“homing” metastasis signature) • Organ specificity (eg. Specific CAM, receptor-ligand pairs) • Specific involvement of the microenvironment: • Endothelial cell activation state • Immune cells and platelets • Chemokines/cytokines/ROS • ECM • Shear stress

  12. Organ specific modulation of the arrest mechanism- Site specific modulation of adhesion

  13. Metastatic tumor cells induce TNF- production by Kupffer cells Kupffer cell isolated from liver

  14. Induction of adhesion molecule expression by tumor cells Highly metastatic Poorly metastatic VCAM-1 E-selectin Activation of the endothelium at specific sites (near Kupffer cells) might contribute to arrest specificity

  15. 3 types of homing mechanism • selective growth: tumor cells arrest ubiquitously but selectively grow only in the organs with appropriate growth environment • selective adhesion to endothelial cells only at the site of organ homing • selective chemotaxis of circulating tumor cells to the organ producing soluble attraction factors Selective arrest

  16. 1) Chemokine receptor expression is induced by by hypoxia (HIF-1) and VEGF or acquired by gene mutation 2) Migration towards chemokine gradient 3)Arrest at metastatic site Production of anti-apoptotic and proliferation signals Induction of TNF- (pro-inflammatory network)

  17. Expression of chemokine receptors in cancer Breast cancer cell lines Melanoma cell lines Mueller et al. Nature 410:50-56.

  18. Chemokine receptor/ligand pairs

  19. Expression of chemokines in normal tissues Mueller et al. Nature 410:50-56.

  20. Expression of chemokine ligand correlates site of metastasis CXCR4-CXCL12 (lymph node, lung, liver bone marrow) (stromal cells)CCR7-CCL19/21 (lymph node)CCR10-CCL27 (skin) Kakinuma and Hwang. J Leukoc Biol 79:639-51

  21. Chemokine-mediated migration of MDA-MD-231 cells Mueller et al. Nature 410:50-56.

  22. MDA-MB-231 chemotaxis towards protein extracts from different organs Mueller et al. Nature 410:50-56.

  23. Effect on MDA-MB-231 lung metastasis Mueller et al. Nature 410:50-56. Tail vein injection Orthotopic injection

  24. Early treatment with CXCR4 inhibitory peptide T22 inhibits metastasis Cardones et al. Cancer Res 63:6751-7 metastasis

  25. CXCR4 expression increases B16 cell adhesion to TNF- activated endothelial cells under shear stress 1.5 dynes/cm2 Cardones et al. Cancer Res 63:6751-7

  26. Adherence of CXCR4-B16 to TNF- activated endothelial cells Cardones et al. Cancer Res 63:6751-7

  27. Inhibition of CXCL12 or 1 integrin blocks pulmonary metastasis of CXCR4-B16 Cardones et al. Cancer Res 63:6751-7

  28. Conclusions • Some tumor cells arrest mechanisms are similar to leukocyte arrest mechanisms (but some aren’t) • Different arrest mechanisms depending on metastasis model (limiting step or dependence may be different) • Strong in vivo evidence for organ specific arrest is still lacking

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