Mesangiogenic progenitor cells are forced toward the angiogenic fate, in multiple myeloma.

Simone Pacini,Mario Petrini,Giovanni Battista Previti,Francesca M Panvini,Gabriele Buda,Francesco Mazziotta,Marina Montali,Claudia P Schifone,Vittoria Carnicelli,Laura Notarfranchi,Lucia Macchia,Serena Barachini

doi:10.18632/oncotarget.27285

Abstract

Multiple myeloma (MM) progresses mainly in the bone marrow where the involvement of a specific microenvironment plays a critical role in maintaining plasma cell growth, spread, and survival. In active disease, the switch from a pre-vascular/non-active phase to a vascular phase is coupled with the impairment of bone turnover. Previously, we have isolated Mesangiogenic Progenitor Cells (MPCs), a bone marrow population that showed mesengenic and angiogenic potential, both in vitro and in vivo. MPC differentiation into musculoskeletal tissue and their ability of sprouting angiogenesis are mutually exclusive, suggesting a role in the imbalancing of the microenvironment in multiple myeloma.MPCs from 32 bone marrow samples of multiple myeloma and 23 non-hematological patients were compared in terms of frequency, phenotype, mesengenic/angiogenic potential, and gene expression profile. Defective osteogenesis was recorded for MM-derived MPCs that showed longer angiogenic sprouting distances respect to non-hematological MPCs, retaining this capability after mesengenic induction. This altered MPCs differentiation potential was not detected in asymptomatic myelomatous disease.These in vitro experiments are suggestive of a forced angiogenic fate in MPCs isolated from MM patients, which also showed increased sprouting activity. Taking together our results suggest a possible role of these cells in the “angiogenic switch” in the MM micro-environment.

Highlights

Tumor microenvironment contributes to disease progression in most haematological malignancies [1]
Absolute count of Pop#8 cells resulted not significantly different (52.5 ± 8.6 cells/μl, n=20 in NH vs 41.6 ± 10.2 cells/μl, n=21 in MM, p=0.424) and its percentage negatively correlated with the percentage of CD138brightCD45dim/neg (Spearman R = -0.569, p
In recent years impairment of bone turnover and angiogenesis have been described as two hallmarks of tumor microenvironment in MM [22]; [23]

Summary

Introduction

Tumor microenvironment contributes to disease progression in most haematological malignancies [1]. In Multiple Myeloma (MM) the interactions between malignant plasma cells (PCs) and the bone marrow (BM) niche sustain and promote tumor growth [2]. Cross-talks between neoplastic www.oncotarget.com cells and BM create a suitable microenvironment for disease development and are responsible for the hallmarks of MM progression: osteolysis and angiogenesis [3]. MM cells develop complex interactions with BMmesenchymal stromal cells (BM-MSCs) supporting tumor survival and chemoresistance [4]. BMMSCs appear to have reduced osteogenic potential and to stimulate proliferation/activity of osteoclasts, contributing to osteolysis [5]. Osteoclasts establish a feed-forward relationship with PCs, which further supports tumor growth [6]. The role of osteoblasts and osteocytes is yet to be clarified some authors showed MM cells to inhibit osteoblast proliferation, differentiation, and activity through different molecular pathways while promoting osteocyte apoptosis [6]

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