The Emerging Role of c-Met in Carcinogenesis and Clinical Implications as a Possible Therapeutic Target.

BACKGROUND: c-MET is a receptor tyrosine kinase receptor (RTK) for the hepatocyte growth factor (HGF). The binding of HGF to c-MET regulates several cellular functions: differentiation, proliferation, epithelial cell motility, angiogenesis, and epithelial-mesenchymal transition (EMT). Moreover, it is known to be involved in carcinogenesis. Comprehension of HGF-c-MET signaling pathway might have important clinical consequences allowing to predict prognosis, response to treatment, and survival rates based on its expression and dysregulation. Discussion. c-MET represents a useful molecular target for novel engineered drugs. Several clinical trials are underway for various solid tumors and the development of new specific monoclonal antibodies depends on the recent knowledge about the definite c-MET role in each different malignance. Recent clinical trials based on c-MET molecular targets result in good safety profile and represent a promising therapeutic strategy for solid cancers, in monotherapy or in combination with other target drugs. CONCLUSION: The list of cell surface receptors crosslinking with the c-MET signaling is constantly growing, highlighting the importance of this pathway for personalized target therapy. Research on the combination of c-MET inhibitors with other drugs will hopefully lead to discovery of new effective treatment options.

Wide gene expression profiling of ischemia-reperfusion injury in human liver transplantation.

Ischemia-reperfusion injury (IRI) causes up to 10% of early liver failures in humans and can lead to a higher incidence of acute and chronic rejection. So far, very few studies have investigated wide gene expression profiles associated with the IRI process. The discovery of novel genes activated by IRI might lead to the identification of potential target genes for the prevention or treatment of the injury. In our study, we compared gene expression levels in reperfused livers (RL group) vs. the basal values before retrieval from the donor (basal liver [BL] group) using oligonucleotide array technology. We examined 10 biopsies from 5 livers, analyzing approximately 33,000 genes represented on the Affymetrix HG-U133APlus 2.0 oligonucleotide arrays (Affymetrix, Santa Clara, CA). About 13,000 individual genes were considered expressed in at least 1 condition. A total of 795 genes whose expression is significantly modified by ischemia-reperfusion in human liver transplantation were identified in this study. Some of them are likely to be completely activated by IRI, as they are not expressed in basal livers. The supervised gene expression analysis revealed that at least 12% of the genes involved in the apoptotic process, 12.5% of the genes involved in inflammatory processes, and 22.5% of the genes encoding for heat shock proteins are differentially expressed in RL samples vs. BL samples. Furthermore, IRI induces the upregulation of some genes' coding for adhesion molecules and integrins. In conclusion, we have identified a relevant amount of early genes regulated in the human liver after 7-9 hours of cold ischemia and 2 hours from reperfusion, many of them not having been described before in this process. Their analyses may help us to better understand the pathophysiology of IRI and to characterize potential target genes for the prevention or treatment of the liver injury in order to increase the number of patients that successfully undergo transplantation.

Expression of HOX homeobox genes in the adult human colonic mucosa (and colorectal cancer?).

We studied the expression of several homeobox genes of the HOX family in the adult human intestinal mucosa. HOX genes are regulatory genes homologous to the homeotic genes controlling the body plan of the fruit fly Drosophila melanogaster. The HOX genes are distributed in four homologous HOX loci termed HOX-A, B, C and D, located on four different chromosomes. They have been found to be expressed in many embryonic tissues and axial structures like the central nervous system, the spine and in selected adult cells. The expression of 39 HOX genes belonging to HOX-A, B, C and D was studied by in situ hybridization on specimens of mucosa from normal adult colon. All the genes studied were shown to be expressed in these tissues, but the genes belonging to the four loci showed different localization within the colonic mucosa: HOX-A genes are expressed in undifferentiated proliferating cells at the base of the crypts, HOX-C genes in differentiated cells at the apex of the crypts and HOX-B and HOX-D genes are weakly expressed along the entire crypt length. Expression of some of these genes was also studied in differentiating CaCo-2 cells and tumoral tissues. In particular, in colonic adenocarcinomatous cells, some HOX-A genes appear to be abundantly expressed confirming the presence of these gene products in normal.

Non-allelic heterogeneity in familial unilateral renal adysplasia.

We report three families with dominant unilateral renal adysplasia without vesico-ureteral reflux. No dysmorphia or anomalies were evident in the reproductive system. Ophthalmological examination excluded the presence of optic nerve coloboma or other ocular anomalies. No mutations were detected in the EMX(2) and in PAX(2) genes of affected members. Other homeobox genes could be responsible for this anomaly in these three families.