Hepatocyte Growth Factor in the Pathogenesis of Multiple Myeloma

Since our original 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 o f an MM patient 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 an aberrantly expressed gene in over 50 % of cases with MGUS, the premalignancy often preceding MM. MM is now subclassified in 8 groups based on molecular ethiology and on differential expression of cyclin-D. Inte restingly, the HGF gene is expressed in 4 of these groups and largely silent in the remaining 4, whereas c-Met is always expressed. In 2 of the groups where HGF is highly expressed, the primary oncogenic event leading to malignancy is unknown. We hypothes ise 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 important for cell growth. Consequently, we think that HGF/c-Met will be an important therapeutic target in MM. To elucidate this we will: 1) examine the HGF gene in MM cells by interphase FISH, Southern blots and direct sequencing to detect gene aberrations; 2) map molecular targets downstream of c-Met by gene expression profiling; 3) treat mice wi th MM with a novel pharmacological inhibitor of c-Met; and 4) examine expression of HGF and c-Met (including activated c-Met) in biopsies from patients with MM. The project is collaboration with a leading MM research center in the US, UAMS in Little Rock, Arkansas. Erming Tian, BS MBA, Laboratory Director in Dr. John Shaughnessy's at UAMS, wants to do a Ph.D. at NTNU and will work in Trondheim for longer periods.