title: Modifications of the mouse bone marrow microenvironment favor angiogenesis and correlate with disease progression from asymptomatic to symptomatic multiple myeloma.
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.
authors.affiliation: Cellular Immunology Unit; IRCCS San Raffaele Scientific Institute ; Milan, Italy ; Università Vita-Salute San Raffaele ; Milan, Italy.
authors.forename: Arianna
authors.initials: A
authors.lastname: Calcinotto
authors.affiliation: Pathology and Myeloma Units; IRCCS San Raffaele Scientific Institute ; Milan, Italy.
authors.forename: Maurilio
authors.initials: M
authors.lastname: Ponzoni
authors.affiliation: Department of Biomedical Sciences and Human Oncology; Internal Medicine and Clinical Oncology Unit; University of Bari Medical School ; Bari, Italy.
authors.forename: Roberto
authors.initials: R
authors.lastname: Ria
authors.affiliation: Cellular Immunology Unit; IRCCS San Raffaele Scientific Institute ; Milan, Italy.
authors.forename: Matteo
authors.initials: M
authors.lastname: Grioni
authors.affiliation: Cellular Immunology Unit; IRCCS San Raffaele Scientific Institute ; Milan, Italy.
authors.forename: Elena
authors.initials: E
authors.lastname: Cattaneo
authors.affiliation: Bone Metabolic Unit; Division of Cardiovascular Science; IRCCS San Raffaele Scientific Institute ; Milan, Italy.
authors.forename: Isabella
authors.initials: I
authors.lastname: Villa
authors.affiliation: Division of Molecular Oncology; IRCCS San Raffaele Scientific Institute ; Milan, Italy.
authors.forename: Maria Teresa
authors.initials: MT
authors.lastname: Sabrina Bertilaccio
authors.affiliation: Comprehensive Cancer Center; Mayo Clinic Arizona ; Scottsdale, AZ, USA.
authors.forename: Marta
authors.initials: M
authors.lastname: Chesi
authors.affiliation: Bone Metabolic Unit; Division of Cardiovascular Science; IRCCS San Raffaele Scientific Institute ; Milan, Italy.
authors.forename: Alessandro
authors.initials: A
authors.lastname: Rubinacci
authors.affiliation: Division of Molecular Oncology; IRCCS San Raffaele Scientific Institute ; Milan, Italy.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Tonon
authors.affiliation: Comprehensive Cancer Center; Mayo Clinic Arizona ; Scottsdale, AZ, USA.
authors.forename: P Leif
authors.initials: PL
authors.lastname: Bergsagel
authors.affiliation: Department of Biomedical Sciences and Human Oncology; Internal Medicine and Clinical Oncology Unit; University of Bari Medical School ; Bari, Italy.
authors.forename: Angelo
authors.initials: A
authors.lastname: Vacca
authors.affiliation: Cellular Immunology Unit; IRCCS San Raffaele Scientific Institute ; Milan, Italy.
authors.forename: Matteo
authors.initials: M
authors.lastname: Bellone
keywords: BM, bone marrow; BMb, BM biopsies; M-spike, monoclonal (M) protein; MGUS, monoclonal gammopathy of undetermined significance; MM, multiple myeloma; MVD, microvessel density; SMM, smoldering multiple myeloma; T cells; TAMs, M2 tumor associated macrophages; TEMs, Tie2-expressing macrophages; angiogenesis; macrophages; multiple myeloma; smoldering multiple myeloma