Raf-1 oncogenic signaling is linked to activation of mesenchymal to epithelial transition pathway in metastatic breast cancer cells.

Aberrant activation of the Raf/MEK/MAPK pathway plays a key role in breast cancer development and progression. Dysregulation of Raf/MEK/MAPK oncogenic signaling often results from overexpression of the HER-2/Neu tyrosine kinase receptor leading to chemoendocrine resistance, development of distant metastases and ultimately poor prognosis in breast cancer patients. HER-2/Neu overexpression is also linked to activation of the epithelial to mesenchymal transition (EMT) pathway, loss of adhesion molecules and metastasis.

Abrogation of p53 function leads to metastatic transcriptome networks that typify tumor progression in human breast cancer xenografts.

Development of chromosomal instability (CIN) and consequent phenotypic heterogeneity represent common events during breast cancer progression. Breast carcinomas harboring extensive chromosomal aberrations display a more aggressive behavior characterized by chemoresistance and the propensity to give rise to distant metastases. The tumor suppressor p53 plays a key role in the maintenance of chromosomal stability and tissue homeostasis through activation of cell cycle checkpoints following DNA damage and control of centrosome duplication that ensures equal chromosome segregation during cell division.

Role of active drug transporters in refractory multiple myeloma.

Drug resistance is a major drawback for cancer chemotherapy protocols and previous studies have demonstrated the overexpression of the P-glycoprotein (P-gp) as mechanism by which myeloma cells develop multidrug resistance (MDR). However, other molecules may apparently promote MDR in multiple myeloma (MM). They include both lung resistance-related protein (LRP) and p53 activation.

Glomerular accumulation of plasmacytoid dendritic cells in active lupus nephritis: role of interleukin-18.

Objective: Defective circulating dendritic cells (DCs) have been described in systemic lupus erythematosus (SLE) and correlated with high levels of interferon-alpha (IFNalpha). DCs are differentiated as being either myeloid or plasmacytoid, according to chemokine expression and the tendency to migrate toward inflamed tissue. We investigated the potential role of interleukin-18 (IL-18) in driving the glomerular migration of DCs in lupus nephritis (LN) and in affecting the ability of DCs to induce an imbalance in the Th1:Th2 ratio.

Increased IL-18 production by dendritic cells in active inflammatory myopathies.

Inflammatory myopathies (IM) are chronic disorders characterized by muscular accumulation of inflammatory cells that promote cytotoxicity and tissue damage. Overexpression of chemokines and cytokines as well as imbalance of dendritic cells (DC) homeostasis have been postulated to exert a role in both dermatomyositis (DM) and polymyositis (PM). We studied the T helper (Th)-1 and Th2 cytokine levels by enzyme linked immunosorbent assay (ELISA) and the muscular expression of IL-18 and its receptor by both histochemistry (HIC) and in situ hybridization (ISH) in both patients and normal controls.

Expression and function of the calcitonin receptor by myeloma cells in their osteoclast-like activity in vitro.

Malignant plasma cells exert osteoclast-like activity in vitro. We investigated the function of the calcitonin (CT) receptor (R) on myeloma cells from patients and in myeloma cell lines. Primary myeloma cells expressed high CTR levels whereas the cell lines uniformly exposed the CTR-2 variant expressed by osteoclasts.

Deregulated expression of monocyte chemoattractant protein-1 (MCP-1) in arterial hypertension: role in endothelial inflammation and atheromasia.

Objective: Arterial hypertension is recurrently associated with inflammation of the endothelium as an effect of the upregulation of functional molecules, including cytokines, adhesion molecules and chemokines. However, the role of monocyte chemoattractant protein-1 (MCP-1) in maintaining the inflammatory state of endothelial cells (EC) that leads to the progressive cardiovascular damage is unclear.

Design: Here, we investigated the expression of MCP-1, its major cell source as well as recurrence of a defined polymorphism (-2518 MCP-1) apparently linked to endothelial damage in several diseases.

The interplay of chemokines and dendritic cells in the pathogenesis of lupus nephritis.

Lupus nephritis (LN) occurs in more that one-third of patients with systemic lupus erythematosus. Production of nephritogenic autoantibodies, glomerular immune complex deposition, and cytokine overproduction have been postulated to contribute to the pathogenesis of LN. However, overexpression of chemokines and imbalance of dendritic cell (DC) homeostasis may contribute to the development of nephritis in SLE.

Recent advances in understanding the pathogenesis of anemia in multiple myeloma.

Anemia is a prominent feature of multiple myeloma (MM) and is commonly associated with clinical progression of MM. In addition to being affected by a number of pathogenetic events, including imbalance of the cytokine network, inappropriate erythropoietin (EPO) levels, blood loss, and hemolysis, the erythroid matrix is chronically deteriorated by the malignant plasma cell clone that activates a cytotoxic mechanism directed at the erythroid progenitors. In particular, malignant plasma cells express very high levels of apoptogenic receptors, including both Fas ligand and tumor necrosis factor-related apoptosis-inducing ligand, which trigger apoptosis of immature erythroblasts by stimulating specific death receptors, namely Fas and the complex DR4/DR5.