P M Comoglio

..Deregulated activation of PRGF or semaphorin ligands or receptors, by mutation or overexpression, confers to cancer cells invasive and metastatic properties...

..Here we discuss how alterations of these receptors or of their signal transduction pathways are responsible for cancer onset and progression towards metastasis...

....

..These data suggest that HGF/SF promotes cell adhesion and invasiveness by increasing the avidity of integrins for their specific ligands...

..These data show that, while specific for their ligands, scatter factor receptors cross-talk and cooperate in intracellular signaling...

..This review is focused on how, and to what extent, scatter factors can behave 'well' or 'badly' according to their molecular structure, the way they are activated, and the way they interact with cell surface receptors and coreceptors...

....

..Activation of signal transducers that directly control transcription is therefore required for morphogenesis...

..We conclude that plexin signaling uncouples cell substrate-adhesion from cytoskeletal dynamics required for cell migration and axon extension...

..Such findings invoke an unexpected role for alpha6beta4 in cancer invasion as a functional amplifier of biochemical outputs rather than a mechanical adhesive device...

..Consistently, Arhgap12 silencing by RNA interference selectively increased the scatter and adhesion responses. These data show that HGF-driven invasive growth involves transcriptional regulation of a Rac1-specific GAP...

..Significantly, nonphosphorylated HGF receptor prevents FAP68 from stimulating p70S6K. These data suggest a role for FAP68 in coupling HGF receptor signaling to the p70S6K pathway...

..Since simple receptor dimerization is not sufficient to trigger full biological responses, we propose that the region on the ss chain of the receptor recognized by the full agonist mAb is crucial for optimal receptor activation...

..Together, these data suggest that MSP is a novel neurotrophic factor for cranial motoneurons and, by regulating the production of NO, may have a role in brain plasticity and regeneration...

..Notably, silencing MET in already established metastases led to their almost complete regression. This indicates that persistent expression of the MET oncogene is mandatory until the advanced phases of cancer progression...

..The flexibility and efficiency of the GFNR-based trap screening procedure make it suitable for wide surveys of transcriptionally regulated genes...

....

..The role of HGF as putative therapeutical agent in pathologies characterized by massive cell loss or deregulated cell proliferation is under investigation...

..We conclude that plexins are receptors for multiple (and perhaps all) classes of semaphorins, either alone or in combination with neuropilins, and trigger a novel signal transduction pathway controlling cell repulsion...

..It is concluded that sustained recruitment of PLCgamma to Gab1 plays an important role in branching tubulogenesis...

..These data (i) provide a novel molecular mechanism for posttranscriptional activation of a tyrosine kinase receptor protein and (ii) suggest a role for the Ron receptor in progression toward malignancy...

..By using the MET oncogene as a model this review focuses on the strategies that can be applied to therapeutically target RTKs...

..After RT-PCR analysis we were able to attribute a more advanced stage to 10 out of 20 HNSCC cases, including 5 cases classified as tumor-free after routine histopathology...

..These data show that Nef enhances programmed cell death in different cell types by affecting multiple critical components of the apoptotic machinery independently from the Fas pathway...

..The finding of a link between growth factor receptors and the anti-apoptotic machinery fills a gap in the understanding of the molecular events regulating programmed cell death...

..These findings show that the Ron receptor and its ligand are involved in the development of epithelial tissues, bones, and neuroendocrine derivatives driving cells towards the proliferation program...

..In vivo analysis showed that both proteins support the thrombohaemorrhagic phenotype, thus providing direct genetic evidence for the long-sought-after link between oncogene activation and haemostasis...

..These results unravel an in-built mechanism of negative feedback regulation in which Met activation leads to transcriptional induction of Notch function, which in turn limits HGF activity through repression of the Met oncogene...

..These data show that proteolytic activation of pro-SF is a limiting step in tumor progression, thus suggesting a new strategy for the treatment or prevention of the malignant conversion of neoplastic lesions...

....

..Interfering with Met activation is thus a new and challenging approach to hamper tumorigenic and metastatic processes...

..We conclude that p190-RhoGAP is crucially involved in semaphorin signalling to the actin cytoskeleton, via interaction with plexins...

..These findings reveal a long-sought mechanistic link between coagulation and cancer, highlighting a clinically important perspective on malignant invasion and metastasis...

..Interestingly, the "decoy effect" generated by the shed ectodomain, acting as a dominant negative molecule, enhanced the inhibitory effect of the Ab...

..As we suggest possible directions for drug development, we propose the receptor for the hepatocyte growth factor, Met, as an ideal target for tackling cancer progression...

..Here we discuss recent progress in the development of molecules that inhibit MET function and consider their application in a subset of human tumours that are potentially responsive to MET-targeted therapies...

..Among those soluble factors a major position is exerted by hepatocyte growth factor (HGF) together with its receptor MET and macrophage-stimulating protein (MSP) in cooperation with its receptor RON...

..Several approaches have been recently developed to interfere with the tumorigenic and metastatic processes triggered by Met...

..In conclusion, we report that SEMA3B exerts unexpected functions in cancer progression by fostering a prometastatic environment through elevated IL-8 secretion and recruitment of macrophages coupled to the suppression of tumor growth...

..Although the IPT-HGF-alpha interaction provides binding strength, the Sema-HGF-beta contact confers selective sensitivity to the active form of the ligand...

..CONCLUSION: These data suggest that MF-1 is as effective as HGF at preventing liver injury and at promoting hepatocyte regeneration, but therapeutically safer than HGF because it lacks proangiogenic and prometastatic activity...

..Here we discuss the different biological facets of invasive growth and analyze the intracellular signals which lead to its execution...

..Altogether, these data show that expression of a naturally occurring, constitutively active truncated RON kinase results in loss of epithelial phenotype and aggressive behavior and, thus, it might contribute to tumor progression...

....

..These data suggest that MET might be one of the long sought oncogenes controlling progression of primary cancers to metastasis...

..Thus, we conclude that cleavage by proprotein convertases is a novel regulatory step for semaphorin receptors localized at the cell surface...

..These data show that hypoxia promotes tumor invasion by sensitizing cells to HGF stimulation, providing a molecular basis to explain Met overexpression in cancer...

..This explains why mutant met provides an oncogenic predisposition but needs a second activating "hit," provided by sustained ligand stimulation or receptor overexpression, to achieve a fully transformed phenotype...

..What are the differences between physiological and pathological activation of these signalling molecules, and can we exploit them therapeutically to prevent metastasis?..

..These data suggest that coexpression of the MET and RON receptors confer a selective advantage to ovarian cancer cells and might promote ovarian cancer progression...

..In an in vivo murine model of drug-induced nephrotoxicity, intravenous injection of recombinant Metron factor 1 prevented renal damage and preserved tubular integrity...

..This work identifies a novel biological function of semaphorins and suggests the involvement of an unexpected signalling mechanism, namely, the coupling of a plexin to a tyrosine kinase receptor...

..These data provide further evidence of a relationship between receptor-mediated signalling and endocytosis, and disclose a novel functional role for Cbl in HGF receptor signalling...

....

..Our findings identify HGF and MET as potential targets for new approaches to malaria prevention...

..This suggests that integration of cell-restricted expression of receptor partners that modulate kinase outputs with the intrinsic signalling features of receptors is required for specification of biological responses...

....

..This review focuses on the mechanisms whereby semaphorins are thought to regulate cell migration...

....

..We thus conclude that Sema5A is able to elicit multiple functional responses through its receptor plexin-B3...

....

..These data show that MET overexpression is oncogenic and that it is essential for the maintenance of the cancer phenotype...

..Therefore, the p38 MAPK pathway might be a suitable target to improve response to conventional chemotherapy in human ovarian cancer...

....

..This suggests that HGF may be used to improve response to chemotherapy in a set of human ovarian carcinomas molecularly classified based on the MET oncogene expression...

..These results unravel a novel pathway whereby beta4 directs tyrosine kinase-based signals toward adhesion-unrelated outcomes...