K252a inhibits the oncogenic properties of Met, the HGF receptor

Morotti, Alessandro; Mila, Silvia; Accornero, Paolo; Tagliabue, E.; Ponzetto, Carola

doi:10.1038/sj.onc.1205622

Cited by 133 publications

(93 citation statements)

References 49 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…Very few HGFR tyrosine kinase inhibitors are currently available, and they are not highly specific for this kinase (41)(42)(43). Here, we describe an anti-HGFR mAb (DN30) inducing receptor down-regulation.…”

Section: Discussionmentioning

confidence: 99%

Ab-induced ectodomain shedding mediates hepatocyte growth factor receptor down-regulation and hampers biological activity

Petrelli

Circosta

Granziero

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

151

152

View full text Add to dashboard Cite

Targeting tyrosine kinase receptors (RTKs) with specific Abs is a promising therapeutic approach for cancer treatment, although the molecular mechanism(s) responsible for the Abs' biological activity are not completely known. We targeted the transmembrane RTK for hepatocyte growth factor (HGF) with a monoclonal Ab (DN30). In vitro, chronic treatment of carcinoma cell lines resulted in impairment of HGF-induced signal transduction, anchorage-independent growth, and invasiveness. In vivo, administration of DN30 inhibited growth and metastatic spread to the lung of neoplastic cells s.c. transplanted into immunodeficient nu͞nu mice. This Ab efficiently down-regulates HGF receptor through a molecular mechanism involving a double proteolytic cleavage: (i) cleavage of the extracellular portion, resulting in ''shedding'' of the ectodomain, and (ii) cleavage of the intracellular domain, which is rapidly degraded by the proteasome. Interestingly, the ''decoy effect'' generated by the shed ectodomain, acting as a dominant negative molecule, enhanced the inhibitory effect of the Ab.Ab ͉ metastasis ͉ tyrosine kinase ͉ receptor degradation ͉ proteolytic cleavage

show abstract

Section: Discussionmentioning

confidence: 99%

Ab-induced ectodomain shedding mediates hepatocyte growth factor receptor down-regulation and hampers biological activity

Petrelli

Circosta

Granziero

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

151

152

View full text Add to dashboard Cite

show abstract

“…As was pointed out by Cristini et al (2005), another approach to therapy is to use anti-invasive drugs such as Met inhibitors (Boccaccio et al, 1998;Bardelli et al, 1999;Morotti et al, 2002) or hepatocyte growth factor antagonists (Date et al, 1998;Michieli et al, 1999) in addition to anti-angiogenic therapies. Such therapies affect the cell-cell and cell-ECM adhesive properties of the tumor.…”

Section: Discussion and Future Workmentioning

confidence: 99%

Nonlinear simulation of the effect of microenvironment on tumor growth

Macklin

Lowengrub

2007

Journal of Theoretical Biology

176

190

View full text Add to dashboard Cite

In this paper, we present and investigate a model for solid tumor growth that incorporates features of the tumor microenvironment. Using analysis and nonlinear numerical simulations, we explore the effects of the interaction between the genetic characteristics of the tumor and the tumor microenvironment on the resulting tumor progression and morphology. We find that the range of morphological responses can be placed in three categories that depend primarily upon the tumor microenvironment: tissue invasion via fragmentation due to a hypoxic microenvironment; fingering, invasive growth into nutrient-rich, biomechanically unresponsive tissue; and compact growth into nutrient-rich, biomechanically responsive tissue. We found that the qualitative behavior of the tumor morphologies was similar across a broad range of parameters that govern the tumor genetic characteristics. Our findings demonstrate the importance of the impact of microenvironment on tumor growth and morphology and have important implications for cancer therapy. In particular, if a treatment impairs nutrient transport in the external tissue (e.g., by anti-angiogenic therapy), increased tumor fragmentation may result, and therapy-induced changes to the biomechanical properties of the tumor or the microenvironment (e.g., antiinvasion therapy) may push the tumor in or out of the invasive fingering regime.

show abstract

“…As pointed out by [55], another approach to therapy is to use anti-invasive drugs such as Met inhibitors [30,20,146] or hepatocyte growth factor (HGF) antagonists [60,144] in addition to anti-angiogenic therapies. Such therapies affect cell-cell and cell-ECM adhesive properties of the tumor.…”

Section: Discussionmentioning

confidence: 99%