A UK study provides evidence of a direct link between the absorption of receptor tyrosine (RTK) into cells and the development of cancer, reports the journal "Nature Cell Biology".

The compartmentalisation of signals generated by the absorption of growth factors (the process known as endocytosis) is known to be a key determinant of various cells functions. In the "signalling endosome concept," the endosome (the membrane-bound compartment of the endocytic membrane transport pathway) represents a platform that integrates signalling pathways to determine characteristics such as cell migration and cell survival. One suggestion has been that by controlling these functions and pathways, endocytosis could contribute to the development of cancer.

In the current study Carine Joffre and colleagues, from the Spatial Signalling Team at Queen Mary University (London, UK), set out to investigate the theory using oncogenic mutations in Met, the receptor for HCF (hepatocyte growth factor) implicated in the growth, survival and spread of human cancers. NIH3T3 cells, which produce small amounts of HCF, were transfected with murine wild-type Met or Met with two mutations (M1268T and D1246N) in the kinase domain. The mutations had originally been identified in human papillary renal carcinomas. The authors were able to show that Met mutants increased endocytosis/recycling activity and decreased levels of degradation, leading to accumulation on endosomes, activation of GTPase Rac1, loss of actin stress fibres and increased levels of cell migration.

In the second part of the study the investigators were able to show that the transformation capacity of the D1246N and M1268T Met mutations was decreased when the process of endocytosis was inhibited through various manipulations.

"Thus, oncogenicity of Met mutants results not only from activation but also from their altered endocytic trafficking, indicating that endosomal signalling may be a crucial mechanism regulating RTK-dependent tumorigenesis," wrote the authors.

Strategies to inhibit Met-dependent tumorigenesis based on interference with Met localization or endosome-specific targeting, they suggest, could be considered as a new approach to cancer treatment. The approach, they add, might impact on TKI –resistant cancers.

Reference

C Joffre, R Barrow, L Ménard et al. A direct role for Met endocytosis in tumorigenesis, Nature Cell Biology, Doi 10.1038/nbc2257