Metastasis of cancer cells is a complex process involving multiple steps including invasion, angiogenesis, and trafficking of cancer cells through blood vessels, extravasations, organ-specific homing, and growth. While matrix metalloproteinases, urokinase-type plasminogen activator, and cytokines play a major role in invasion and angiogenesis, chemokines such as stromal derived factor-1␣ (SDF-1␣) and their receptors such as CXCR4 are thought to play a critical role in motility, homing, and proliferation of cancer cells at specific metastatic sites. We and others have previously reported that the extracellular signal-activated transcription factor NF-B up-regulates the expression of matrix metalloproteinases, urokinase-type plasminogen activator, and cytokines in highly metastatic breast cancer cell lines. In this report, we demonstrate that NF-B regulates the motility of breast cancer cells by directly up-regulating the expression of CXCR4. Overexpression of the inhibitor of B (IB) in breast cancer cells with constitutive NF-B activity resulted in reduced expression of CXCR4 and a corresponding loss of SDF-1␣-mediated migration in vitro. Introduction of CXCR4 cDNA into IB-expressing cells restored SDF-1␣-mediated migration. Electrophoretic mobility shift assays and transient transfection assays revealed that the NF-B subunits p65 and p50 bind directly to sequences within the ؊66 to ؉7 region of the CXCR4 promoter and activate transcription. We also show that the cell surface expression of CXCR4 and the SDF-1␣-mediated migration are enhanced in breast cancer cells isolated from mammary fat pad xenografts compared with parental cells grown in culture. A further increase in CXCR4 cell surface expression and SDF-1␣-mediated migration was observed with cancer cells that metastasized to the lungs. Taken together, these results implicate NF-B in the migration and the organ-specific homing of metastatic breast cancer cells.Morbidity and mortality in cancer are mainly due to organspecific metastasis and the failure of chemotherapeutic drugs to selectively kill cancer cells at the sites of metastasis. Metastasis is a non-random process, and each cancer type has its own preferred sites of metastasis (1). For example, breast cancer cells preferentially metastasize to the regional lymph nodes, lungs, liver, and bone (1, 2). Prostate cancers usually metastasize to bone. While there has been considerable progress in identifying genes that promote the metastasis of cancer cells, little is known about the genes that enable cancer cells to seed, survive, and proliferate at sites of metastasis. Three models of organ-specific metastasis are currently under consideration: 1) selective survival and proliferation of cancer cells in a particular organ due to local production of appropriate growth factors, 2) organ-specific endothelial cells trapping circulating tumor cells by expressing appropriate adhesion molecules on their surface, and 3) organ-specific attractant molecules helping in homing cancer cells to specific sites (3). While...

Hematopoietic stem cell homing and engraftment are crucial to transplantation efficiency, and clinical engraftment is severely compromised when donor-cell numbers are limiting. The peptidase CD26 (DPPIV/dipeptidylpeptidase IV) removes dipeptides from the amino terminus of proteins. We present evidence that endogenous CD26 expression on donor cells negatively regulates homing and engraftment. By inhibition or deletion of CD26, it was possible to increase greatly the efficiency of transplantation. These results suggest that hematopoietic stem cell engraftment is not absolute, as previously suggested, and indicate that improvement of bone marrow transplant efficiency may be possible in the clinic.

CD26/dipeptidylpeptidase IV (DPPIV) is a membrane-bound extracellular peptidase that cleaves dipeptides from the N terminus of polypeptide chains. The N terminus of chemokines is known to interact with the extracellular portion of chemokine receptors, and removal of these amino acids in many instances results in significant changes in functional activity. CD26/DPPIV has the ability to cleave the chemokine CXCL12/stromal cell-derived factor 1α (SDF-1α) at its position two proline. CXCL12/SDF-1α induces migration of hemopoietic stem and progenitor cells, and it is thought that CXCL12 plays a crucial role in homing/mobilization of these cells to/from the bone marrow. We found that CD26/DPPIV is expressed by a subpopulation of CD34+ hemopoietic cells isolated from cord blood and that these cells have DPPIV activity. The involvement of CD26/DPPIV in CD34+ hemopoietic stem and progenitor cell migration has not been previously examined. Functional studies show that the N-terminal-truncated CXCL12/SDF-1α lacks the ability to induce the migration of CD34+ cord blood cells and acts to inhibit normal CXCL12/SDF-1α-induced migration. Finally, inhibiting the endogenous CD26/DPPIV activity on CD34+ cells enhances the migratory response of these cells to CXCL12/SDF-1α. This process of CXCL12/SDF-1α cleavage by CD26/DPPIV on a subpopulation of CD34+ cells may represent a novel regulatory mechanism in hemopoietic stem and progenitor cells for the migration, homing, and mobilization of these cells. Inhibition of the CD26/DPPIV peptidase activity may therefore represent an innovative approach to increasing homing and engraftment during cord blood transplantation.