The role of HGF and met in Wilms tumour.
Published: 2004
Language: eng
Number of pages: 178
Description: The pathobiological mechanism of Wilms tumour invasiveness and metastasis is unknown. Autocrine/paracrine regulation of hepatocyte growth factor (HGF) and its tyrosine kinase receptor met have been shown in many adult cancers to play a key role in tumour invasion and metastasis. HGF/met were studied in a series of homotypic and heterotypic Wilms tumours and showed high levels of expression in both phenotypes with higher levels in metastatic tumours as compared to normal kidney. Investigation of a number of intrinsic target proteins of met, important in cell-cell adhesion such as E-cadherin, beta-catenin, gamma-catenin and ezrin, revealed aberrant expression with significantly lower levels of E-cadherin and gamma-catenin with nuclear localization of beta-catenin in metastatic tumours compared to cytoplasmic localization in primary tumours. These results suggested that aberrant expression of adhesion proteins correlated with acquisition of an invasive and metastatic phenotype in Wilms tumour. The isolation of a novel Wilms tumour cell line, WiT49, from a Wilms tumour lung metastasis allowed us to investigate the role of HGF/met in Wilms tumour cells. WiT49 showed expression of an intact WT1, overexpression of IGF2 and harbored a common p53 missense mutation, 248Arg, previously documented in metastatic Wilms tumours. Importantly, WiT49 expressed high levels of HGF and met, with co-localization of met and beta-catenin at the cell membrane and showed a notable loss of E-cadherin protein, similar to that found in the parent tumour. The MAPK and PKB mediated signaling pathways, associated with growth and motility and activated through HGF binding to met, were expressed in WiT 49. Addition of recombinant HGF to WiT9 cultures induced an increase in met expression, recruitment of adapter protein Gab-1, and release of beta-catenin bound to met. Analysis of matrix metalloproteinases MMP9 and MMP2, indicated constitutive expression in WiT49 supporting the notion of possible beta-catenin mediated transcriptional activation. The studies presented here have identified new players in the pathobiology of Wilms tumour, supporting a role for HGF/met in regulation of the invasive and metastatic phenotype in Wilms tumour.
Notes: Adviser:  Herman Yeger.

Thesis (Ph.D.)--University of Toronto, 2004.

Electronic version licensed for access by U. of T. users.

Source: Dissertation Abstracts International, Volume: 65-05, Section: B, page: 2234.