HOMING

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

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

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

Does organ or site-specific homing exist?

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

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

Trapping vs homing (“controlled arrest”) 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 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

Mechanism of arrest

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

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

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

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

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

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

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)

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

Chemokine receptor/ligand pairs

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

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: Expression of chemokine ligand correlates site of metastasis

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

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

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

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

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

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

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

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