Extravasation and homing mechanisms in multiple myeloma

Abstract

Multiple myeloma (MM) is a malignant B-cell disorder characterized by a monoclonal expansion of plasma cells (PC) in the bone marrow (BM). During the main course of disease evolution, MM cells depend on the BM microenvironment for their growth and survival. Reciprocal interactions between MM cells and the BM mediate not only MM cell growth, but also protect them against apoptosis and cause bone disease and angiogenesis. A striking feature of MM represents the predominant localization and retention of MM cells in the BM. Although BM PC indeed represent the main neoplastic cell type, small numbers of MM cells can also be detected in the peripheral blood circulation. It can be assumed that these circulating cells represent the tumour-spreading component of the disease. This implicates that MM cells have the capacity to (re)circulate, to extravasate and to migrate to the BM (homing). In analogy to the migration and homing of normal leucocytes, the BM homing of MM cells is mediated by a multistep process of extravasation with adhesion to the endothelium, invasion of the subendothelial basement membrane, followed by further migration within the stroma, mediated by chemotactic factors. At the end stage of disease, MM cells are thought to develop autocrine growth supporting loops that enable them to survive and proliferate in the absence of the BM microenvironment and to become stroma-independent. In this stage, the number of circulating cells increases and growth at extramedullary sites can occur, associated with alteration in adhesion molecule and chemokine receptor expression. This review summarizes the recent progress in the study of the extravasation and homing mechanisms of MM cells.

Syndecan-1 Is Required for Robust Growth, Vascularization, and Metastasis of Myeloma Tumors in Vivo

“…Thus circulating, mature plasma cells in patients likely contribute to establishing new tumor foci leading to widely disseminated disease, a hallmark of myeloma (34). Although the mechanisms mediating metastasis of myeloma tumors are not well understood, they likely involve participation of a number of adhesion molecules, cytokines and proteases (34). Our results indicate that syndecan-1 plays a critical role in ensuring that tumor cells form metastatic foci following their intravasation into the circulation.…”

“…It has been demonstrated that these mature (CD38 ϩ /CD45 Ϫ ) syndecan-1-positive plasma cells isolated from the blood of myeloma patients can populate a nonmyelomatous human bone and produce disease that is typical of human myeloma (32,33). Thus circulating, mature plasma cells in patients likely contribute to establishing new tumor foci leading to widely disseminated disease, a hallmark of myeloma (34). Although the mechanisms mediating metastasis of myeloma tumors are not well understood, they likely involve participation of a number of adhesion molecules, cytokines and proteases (34).…”

Vesiculovirus Neutralization by Natural IgM and Complement

“…e are interested in developing an oncolytic therapy for systemic treatment of multiple myeloma (MM), an incurable disseminated cancer of antibody-secreting plasma cells primarily localized in the bone marrow, which is characterized by the development of progressive and destructive osteolytic bone disease (1)(2)(3)(4). Despite advances in diagnosis and treatment and improvements in patient survival, MM remains an incurable disease (2,(5)(6)(7)(8)(9).…”

Angiogenesis and Multiple Myeloma

“…HGF is involved in tumoral angiogenesis and metastasis [80,81]. In addition, HGF is synthesized by myeloma cells [82] and enhances MMP-9 secretion by myeloma cells [83]. HGF activity and signaling in myeloma cells is enhanced by syndecan-1, a cell surface heparan sulfate-bearing proteoglycan highly expressed by myeloma cells [84,85].…”