While numerous pieces of "in vitro" and clinical evidence continue to support this hypothesis of E-selectin-mediated cancer metastasis, "in vivo" studies of cancer metastasis have shown that E-selectin knockout only minimally affects leukemic cell adhesion to bone immediately following injection. while experimental lung metastasis is not affected by the genetic deletion of E-selectin. Furthermore, studies have also shown that primary tumor growth is increased in E-selectin knockout mice This paradox was more recently solved by a trio of studies showing that E-selectin is only constitutively expressed in the bone marrow endothelium where it is thought to perform functions vital to hematopoiesis. that are hijacked specifically by cells metastasizing to bone and not other sites. This data supports ongoing clinical efforts to inhibit breast cancer bone metastasis with E-selectin-blocking agents. The complexity of E-selectin ligand biology may also play a role in these discrepant "in vitro" and "in vivo" results. At least 15 different glycoprotein and glycolipid substrates for E-selectin have been described on various cancer cells, while only n-glycan Glg1 (Esl1) was shown to mediate bone metastasis. Other ligands or combinations thereof may result in distinct mechanisms during cancer metastasis.