Modifications of the mouse bone marrow microenvironment favor angiogenesis and correlate with disease progression from asymptomatic to symptomatic multiple myeloma

Arianna Calcinotto, Maurilio Ponzoni, Roberto Ria, Matteo Grioni, Elena Cattaneo, Isabella Villa, Maria Teresa Sabrina Bertilaccio, Marta Chesi, Alessandro Rubinacci, Giovanni Tonon, P. Leif Bergsagel, Angelo Vacca, Matteo Bellone

Research output: Contribution to journalArticle

Abstract

While multiple myeloma (MM) is almost invariably preceded by asymptomatic monoclonal gammopathy of undetermined significance (MGUS) and/or smoldering MM (SMM), the alterations of the bone marrow (BM) microenvironment that establish progression to symptomatic disease are circumstantial. Here we show that in Vk*MYC mice harboring oncogene-driven plasma cell proliferative disorder, disease appearance associated with substantial modifications of the BM microenvironment, including a progressive accumulation of both CD8+ and CD4+ T cells with a dominant T helper type 1 (Th1) response. Progression from asymptomatic to symptomatic MM was characterized by further BM accrual of T cells with reduced Th1 and persistently increased Th2 cytokine production, which associated with accumulation of CD206+Tie2+ macrophages, and increased pro-angiogenic cytokines and microvessel density (MVD). Notably, MVD was also increased at diagnosis in the BM of MGUS and SMM patients that subsequently progressed to MM when compared with MGUS and SMM that remained quiescent. These findings suggest a multistep pathogenic process in MM, in which the immune system may contribute to angiogenesis and disease progression. They also suggest initiating a large multicenter study to investigate MVD in asymptomatic patients as prognostic factor for the progression and outcome of this disease.

Original languageEnglish
JournalOncoImmunology
Volume4
Issue number6
DOIs
Publication statusPublished - Jan 1 2015

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Keywords

  • Angiogenesis
  • Macrophages
  • Multiple myeloma
  • Smoldering multiple myeloma
  • T cells

ASJC Scopus subject areas

  • Immunology and Allergy
  • Oncology
  • Immunology

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