Bone marrow endothelial cells as active players in the pathobiology of multiple myeloma

Multiple myeloma (MM) is the second most prevalent haematological cancer, characterised by the accumulation of monoclonal plasma cells in the bone marrow (BM), overproduction of monoclonal immunoglobulins, renal failure, bone lesions and neovascularisation. One of the key features of MM cells is their predominant localisation in the BM. The latter plays a pivotal role in the pathogenesis of MM providing a sanctuary for the MM cells to survive, proliferate and evade drug-induced cell death due to the existence of functional, mutual interactions between the MM cells and the BM compartments. One of the cellular components of this BM microenvironment is the BM endothelial cells (BMEC), lining the BM sinusoids. It has been well established that MM cells activate the endothelial compartment resulting in angiogenesis, which is correlated to disease outcome.
Besides being gatekeepers between the vascular and extravascular compartments, BMEC also play an active role in the pathobiology of MM. It has recently been demonstrated that BMEC, in addition to the BMSC,
are involved in autocrine and paracrine interactions with the MM cells, by secretion of factors like SDF-1?, IL6, VEGF, IGF-1, Ang-1 and Ang-2 and thereby support survival and proliferation of the MM cells. Another key process of the MM disease is the selective homing of the MM cells towards the BM extravascular compartment. This results in a sequence of specific interactions, making the transendothelial migration highly selective. Upon arrival in the BM compartment MM cells are arrested
and adhere to the BMEC. Using the 5TMM syngeneic murine models,we have demonstrated (both in vitro and in vivo) that the interaction of the MM cells with the BMEC not only induces increased angiogenesis but
also alters gene and protein expression in the MM cells (CD44v6, IGF-1R, MMP9, CD9, HGF, ...), resulting in better adhesion, migration and proteolytic activity of theMM cells and thereby increasing their homing capacity to the BM. It has furthermore been demonstrated by Okada T et al. (2003) that MM cells promote osteoclastogenesis by inducing RANKL on BMEC. Upon binding to RANK, the BMEC do not only stimulate osteoclastogenesis but also secrete IL6 and IL11, thereby further supporting MM growth (Giuliani, 2004).
In conclusion, it has been clearly demonstrated that BMEC are actively involved in the BM pathogenesis and this forms the rationale for several anti-angiogenic therapies currently investigated

Jaar van publicatie:2011

Trefwoorden:multiple myeloma