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FRIMEDBIO-Fri prosj.st. med.,helse,biol

Hepatocyte Growth Factor in the Pathogenesis of Multiple Myeloma

Awarded: NOK 3.3 mill.

Since our publications in 1996 showing that malignant plasma cells (MM cells) usually express both HGF and its receptor c-Met, a growing number of reports have implicated HGF/c-Met in the biology of MM. For instance, high levels of HGF in serum of MM pati ents predict a bad prognosis and correlate with increased angiogenesis in the bone marrow. HGF supports growth of MM cells, often in an autocrine way. HGF stimulates adhesion of MM cells to fibronectin and promotes MM cell migration. HGF is not expressed by normal plasma cells, but is aberrantly expressed in a majority of MM cells. We hypothesize that HGF expression is a basic oncogenic event in the cases of MM where it is expressed, and that it induces expression of cyclin-D1 and other molecules importan t for cell growth. Consequently, we think that HGF/c-Met will be an important therapeutic target in MM. The project is a continuation of project ES389125, which was funded by the Research Council from 2006. In the first 2,5 years of the project, we did th e important discovery that HGF can be expressed in MM cells due to mutations in the HGF promoter, creating novel binding sites for transcription factors. This mode of oncogene activation is not commonly recognized in the literature. To elucidate whether t his is a common way of deregulating HGF and other genes we will: 1) Sequence HGF promoters from MM cell lines as well as from purified primary MM cells, identify mutations in the promoter, and check whether these mutations create novel transcription bin ding sites. Other subprojects to elucidate the role of HGF/c-Met include: 2) examination of the crosstalk between the signals from c-Met and the IL-6 receptor; 3) identification of molecular targets downstream of c-Met by gene expression profiling; 4) fu nctional studies of the intracellular fate of c-Met and syndecan-1 upon internalization into MM cells

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FRIMEDBIO-Fri prosj.st. med.,helse,biol

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