Multiple myeloma : the interplay between malignant plasma cells and the bonemarrow microenvironment

Abstract

The overall objective of this work was to study how myeloma cells influence the bone marrow microenvironment in which they reside, focusing on the cells that resorb or synthesize bone. More specifically we wanted to study:

Do myeloma cells secrete or express factors that disturb the OPG/RANKL balance? RANKL and OPG are key regulators of osteoclastogenesis. Our group found that myeloma patients with osteolytic lesions have less OPG in serum as compared to patients without bone disease308. Others had shown reduced OPG- and enhanced RANKL-expression in the BM of myeloma patients 181,182. We aimed to study mechanisms behind the disturbance of the OPG/RANKL balance at the cellular level (paper I).

What is the role of HGF in the pathogenesis of multiple myeloma? Our group was the first to show that HGF is produced by myeloma cells309, and, furthermore, that high serum concentration of HGF in myeloma patients is indicative of a poor prognosis80. The JJN-3 mouse model established in our laboratory indicated that HGF might be an inhibitor of osteoblastogenesis310, and we aimed to study the effect of HGF on osteoblastogenesis in vitro (paper V). Furthermore, as HGF stimulates angiogenesis, we wanted to investigate whether HGF is involved in angiogenesis induced by myeloma cells (paper IV).

Can we identify new cytokines possibly involved in multiple myeloma? And do measurements of already known “myeloma-factors” give information about disease outcome? By measuring the concentrations of cytokines/growth factors in patient samples and comparing them to the concentrations in healthy persons or correlating them to other disease variables, the relevance of the cytokine in multiple myeloma can possibly be found. IGF-1 was known to be a growth factor for myeloma cells, and thus it was of interest to correlate serum levels of this growth factor to disease progression (paper II). Furthermore, osteopontin was known to be involved in other cancers, and also known to exhibit osteoclast-activating potential243. It was therefore of interest to investigate if OPN serves a function in disease progression of multiple myeloma (paper III).