E- and N-cadherin are calcium-dependent cell adhesion molecules that mediate cell–cell adhesion and also modulate cell migration and tumor invasiveness. The loss of E-cadherin–mediated adhesion has been shown to play an important role in the transition of epithelial tumors from a benign to an invasive state. However, recent evidence indicates that another member of the cadherin family, N-cadherin, is expressed in highly invasive tumor cell lines that lacked E-cadherin expression. These findings have raised the possibility that N-cadherin contributes to the invasive phenotype. To determine whether N-cadherin promotes invasion and metastasis, we transfected a weakly metastatic and E-cadherin–expressing breast cancer cell line, MCF-7, with N-cadherin and analyzed the effects on cell migration, invasion, and metastasis. Transfected cells expressed both E- and N-cadherin and exhibited homotypic cell adhesion from both molecules. In vitro, N-cadherin–expressing cells migrated more efficiently, showed an increased invasion of Matrigel, and adhered more efficiently to monolayers of endothelial cells. All cells produced low levels of the matrix metalloproteinase MMP-9, which was dramatically upregulated by treatment with FGF-2 only in N-cadherin–expressing cells. Migration and invasion of Matrigel were also greatly enhanced by this treatment. When injected into the mammary fat pad of nude mice, N-cadherin–expressing cells, but not control MCF-7 cells, metastasized widely to the liver, pancreas, salivary gland, omentum, lung, lymph nodes, and lumbar spinal muscle. The expression of both E- and N-cadherin was maintained both in the primary tumors and metastatic lesions. These results demonstrate that N-cadherin promotes motility, invasion, and metastasis even in the presence of the normally suppressive E-cadherin. The increase in MMP-9 production by N-cadherin–expressing cells in response to a growth factor may endow them with a greater ability to penetrate matrix protein barriers, while the increase in their adherence to endothelium may improve their ability to enter and exit the vasculature, two properties that may be responsible for metastasis of N-cadherin–expressing cells.

The loss of E-cadherin expression or function in epithelial carcinomas has long been thought as a primary reason for disruption of tight epithelial cell-cell contacts and release of invasive tumor cells from the primary tumor. Indeed, E-cadherin serves as a widely acting suppressor of invasion and growth of epithelial cancers, and its functional elimination represents a key step in the acquisition of the invasive phenotype for many tumors. Recent evidence indicates, however, that in addition to the loss of the "invasion-suppressor" E-cadherin, another adhesion molecule, N-cadherin, becomes upregulated in invasive tumor cell lines. N-cadherin was shown to be present in the most invasive and dedifferentiated breast cancer cell lines, and its exogenous expression in tumor cells induces a scattered morphology and heightened motility, invasion, and metastasis. N-cadherin cooperates with the FGF receptor, resulting in signals that lead to the up-modulation of MMP-9 and, hence, cellular invasion. In addition to a signaling function in metastasis, N-cadherin probably also supports the systemic dissemination of tumor cells by enabling circulating tumor cells to associate with the stroma and the endothelium at distant sites. Here, we summarize the various aspects of the E- to N-cadherin switching in epithelial carcinomas and its potential impact on metastatic progression.

Prostate cancer is a leading cause of cancer death in men. Risk prognostication, treatment stratification, and the development of rational therapeutic strategies lag because the molecular mechanisms underlying the initiation and progression from primary to metastatic disease are unknown. Multiple lines of evidence now suggest that KLF6 is a key prostate cancer tumor suppressor gene including loss and/or mutation in prostate cancer tumors and cell lines and decreased KLF6 expression levels in recurrent prostate cancer samples. Most recently, we identified a common KLF6 germ line single nucleotide polymorphism that is associated with an increased relative risk of prostate cancer and the increased production of three alternatively spliced, dominant-negative KLF6 isoforms. Here we show that although wild-type KLF6 (wtKLF6) acts as a classic tumor suppressor, the single nucleotide polymorphismincreased splice isoform, KLF6 SV1, displays a markedly opposite effect on cell proliferation, colony formation, and invasion. In addition, whereas wtKLF6 knockdown increases tumor growth in nude mice >2-fold, short interfering RNAmediated KLF6 SV1 inhibition reduces growth by f50% and decreases the expression of a number of growth-and angiogenesis-related proteins. Together, these findings begin to highlight a dynamic and functional antagonism between wtKLF6 and its splice variant KLF6 SV1 in tumor growth and dissemination. (Cancer Res 2005; 65(13): 5761-8)

We apply smoothed dissipative particle dynamics (SDPD) [Español and Revenga, Phys. Rev. E 67, 026705 (2003)] to model solid particles in suspension. SDPD is a thermodynamically consistent version of smoothed particle hydrodynamics (SPH) and can be interpreted as a multiscale particle framework linking the macroscopic SPH to the mesoscopic dissipative particle dynamics (DPD) method. Rigid structures of arbitrary shape embedded in the fluid are modeled by frozen particles on which artificial velocities are assigned in order to satisfy exactly the no-slip boundary condition on the solid-liquid interface. The dynamics of the rigid structures is decoupled from the solvent by solving extra equations for the rigid body translational/angular velocities derived from the total drag/torque exerted by the surrounding liquid. The correct scaling of the SDPD thermal fluctuations with the fluid-particle size allows us to describe the behavior of the particle suspension on spatial scales ranging continuously from the diffusion-dominated regime typical of sub-micron-sized objects towards the non-Brownian regime characterizing macro-continuum flow conditions. Extensive tests of the method are performed for the case of two/three dimensional bulk particle-system both in Brownian/non-Brownian environment showing numerical convergence and excellent agreement with analytical theories. Finally, to illustrate the ability of the model to couple with external boundary geometries, the effect of confinement on the diffusional properties of a single sphere within a micro-channel is considered, and the dependence of the diffusion coefficient on the wall-separation distance is evaluated and compared with available analytical results.