Part of the multiple myeloma-associated microvessels is functionally connected to the systemic circulation: a study in the murine 5T33MM model

Abstract

It is now well established that angiogenesis in multiple myeloma (MM) is associated with poor prognosis. The exact function of the newly formed vessels in MM is, however, a matter of debate. It is believed that, in contrast to solid tumor growth, the bone marrow (BM) is a sufficiently vascularized organ to support expansion of the MM clone with no need for additional blood vessels. From this point of view, it could be that MM-associated angiogenesis is rather an epiphenomenon and that the newly formed microvessels form a chaotic network that does not contribute to the blood flow. We investigated whether these newly formed microvessels in MM are connected to the blood circulation. The intravenously injected ferritin 30 min prior to sacrifice was detected in 100% of the BM vessels of control mice. In MM-bearing mice, the ferritin tracer was found in 31% of the MM-associated vessels, indicating a connection with the peripheral blood circulation in these vessels. We conclude that, comparable to the situation in solid tumors, at least part of the tumor-associated microvessels in MM is functionally connected to the blood circulation and, therefore, can participate in the transport of nutrients and in the dissemination of MM cells.

Endothelial cell-driven regulation of CD9 or motility-related protein-1 expression in multiple myeloma cells within the murine 5T33MM model and myeloma patients

“…Moreover, the size and perimeter of the microvessels decreases during myeloma progression. 30 Both observations result in an increase in the proportion of myeloma cells to BMEC during myeloma progression. As such, as disease progresses, the percentage of myeloma cells in contact with BMEC declines, leading to a reduced number of myeloma cells that express CD9.…”

“…injection of the tumor cells, a time point when they are first detectable by flow cytometry (intermediate stage, tumor load between 5 and 20%). 29,30 Isolation and purification of the myeloma cells in the BM was performed as described previously. 31 The murine 5T33MMvt cell line is a clonally identical, but in vitro stroma-independent growing variant of the 5T33MMvv cell line.…”

A multiscale model of the bone marrow and hematopoiesis

“…The microvessel density was reported to be 75 microvessels/mm 2 for animal models (De Raeve et al, 2004), and 59.5 (ranging from 17–140) and 25.1 (ranging from 0–60) microcvessels/mm 2 for patients with multiple myeloma before and after treatment, respectively (Sezer et al, 2001). Biopsies in asymptomatic patients showed on average a microvessel density of 5 microvessels/mm 2 (Watchman et al, 2007).…”

Myeloma Cells and Their Interactions With the Bone Marrow Endothelial Cells

“…It is assumed that MGUS and non-active MM represent the prevascular phase, while active MM represents the vascular phase [66,76]. Comparable to the situation in solid tumors, at least part of the tumor-associated microvessels in MM is functionally connected to the circulation and, therefore, can contribute to the growth and dissemination of the MM cells [79]. VEGF, bFGF, HGF, platelet derived growth factor (PDGF), Ang-1 and osteopontin (OPN) are some examples of pro-angiogenic factors expressed by the MM cells and/or BMSC and BMEC [66,80,81].…”