The spleen is usually the major site of HC infiltration. The malignant cells accumulate in the red pulp, while the white pulp of the enlarged spleen is greatly reduced. Within the sinuses of the red pulp, the HCs have a propensity to replace the endothelium and to remodel the sinuses so that they enlarge, forming the vascular lakes or pseudosinuses pathognomonic of the disease.42 The mechanism of splenic homing is likely to involve HC interaction with endothelium and also, via aVp3 inte-grin, with VN present in the spleen.43 The candidate chemoattractant to the red pulp is M-CSF produced by macrophages,29 while the likely first step in vascular remodeling is HC interaction with endothelial cells via a4pi-to-VCAM binding.44 This is followed by replacement of endothelial linings by HCs in a process that may involve aVp3-mediated movement of HCs in between and underneath endothelium. The likely binding partners of aVp3 during this process could be PECAM on endothelial cells and VN on basement membranes. The tendency of HCs to remain confined to the vascular spaces of the red pulp could possibly be explained by the reduced or absent expression of the chemokine receptors CCR5 and CXCR4, and by upregulation of the metallo-proteinase inhibitors TIMP-1, TIMP-4 and RECK (Table 29.3).4 This could severely limit or abolish the ability of HCs to receive stimuli for exit from the red pulp and to employ metalloproteinases to traverse basement membranes and invade other compartments of the spleen.

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