CD44 and HCELL: preventing hematogenous metastasis at step 1

Abstract

Despite great strides in our knowledge of the genetic and epigenetic changes underlying malignancy, we have limited information on the molecular basis of metastasis. Over 90% of cancer deaths are caused by spread of tumor cells from a primary site to distant organs and tissues, highlighting the pressing need to define the molecular effectors of cancer metastasis. Mounting evidence suggests that circulating tumor cells (CTCs) home to specific tissues by hijacking the normal leukocyte trafficking mechanisms. Cancer cells characteristically express CD44, and there is increasing evidence that hematopoietic cell E-/L-selectin ligand (HCELL), a sialofucosylated glycoform of CD44, serves as the major selectin ligand on cancer cells, allowing interaction of tumor cells with endothelium, leukocytes, and platelets. Here, we review the structural biology of CD44 and of HCELL, and present current data on the function of these molecules in mediating organ-specific homing/metastasis of CTCs.

Figure 1. The multi-step paradigm of cellular trafficking

The critical first step for all vascular emigration is the deceleration of blood-borne cells on the endothelial surface, a process mediated by selectins and their ligands (step 1). The common minimal binding determinant for all three selectins is the tetrasaccharide sialyl-Lewis x (sLe^x). Rolling is necessary for the cells to ‘taste’ the local milieu, i.e., to interact with locally produced chemotactic stimuli. Successful chemokine signaling results in activation of integrins (step 2), which results in firm adhesion (step 3) and finally, transendothelial migration (step 4).

Figure 2. The molecular basis of metastatic tissue tropism(s): CD44 and HCELL

Tumor cells home to specific tissues by hijacking the normal leukocyte trafficking mechanisms by expressing selectin ligands on their cell surface. The principal selectin ligand on cancer cells, HCELL, allows CTCs to interact with E- and P-selectin on activated endothelium, L-selectin on leukocytes and P-selectin on platelets. Organs that do not constitutively express E-selectin, like the liver and the lungs, can be induced to do so by intravascular LPS (derived from the gut) and by pro-inflammatory cytokines (produced by the primary tumor or by cells from the immune system). In addition to E-selectin-mediated interactions, the CD44-HA axis is important for tumor metastasis to organs rich in HA, like the liver, lungs and bone marrow. Bone marrow-derived HSPCs, known to express both HCELL and L-selectin, home to pre-metastatic sites before the arrival of tumor cells and thus may play an important role in the establishment of the pre-metastatic niche.