Introduction A subpopulation (CD44 + /CD24 -) of breast cancer cells has been reported to have stem/progenitor cell properties. The aim of this study was to investigate whether this subpopulation of cancer cells has the unique ability to invade, home, and proliferate at sites of metastasis.

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...

PTEN is a tumor suppressor gene mutated in many human cancers, and its expression is reduced or absent in almost half of hepatoma patients. We used the Cre-loxP system to generate a hepatocyte-specific null mutation

PTEN is a tumor suppressor gene mutated in many human cancers, and its expression is reduced or absent in almost half of hepatoma patients. We used the Cre-loxP system to generate a hepatocyte-specific null mutation

At the site of contact between T cells and antigen-presenting cells (APCs), T cell receptor (TCR)–peptide–major histocompatibility complex (MHC) interaction is intensified by interactions between other molecules, notably by CD28 and lymphocyte function-associated antigen 1 (LFA-1) on T cells interacting with B7 (B7-1 and B7-2), and intracellular adhesion molecule 1 (ICAM-1), respectively, on APCs. Here, we show that during T cell–APC interaction, T cells rapidly absorb various molecules from APCs onto the cell membrane and then internalize these molecules. This process is dictated by at least two receptors on T cells, namely CD28 and TCR molecules. The biological significance of T cell uptake of molecules from APCs is unclear. One possibility is that this process may allow activated T cells to move freely from one APC to another and eventually gain entry into the circulation.