title: Bone marrow fibroblasts parallel multiple myeloma progression in patients and mice: in vitro and in vivo studies.
abstract: The role of cancer-associated fibroblasts (CAFs) has not been previously studied in multiple myeloma (MM). Here, cytofluorimetric analysis revealed higher proportions of bone marrow (BM) CAFs in patients with active MM (both at diagnosis and relapse) compared with patients in remission or those with monoclonal gammopathy of undetermined significance or deficiency anemia (controls). CAFs from MM patients produced increased levels of transforming growth factor-β, interleukin-6, stromal cell-derived factor-1α, insulin-like growth factor-1, vascular endothelial growth factor and fibroblast growth factor-2 and displayed an activated and heterogeneous phenotype, which supported their origin from resident fibroblasts, endothelial cells and hematopoietic stem and progenitor cells via the endothelial-mesenchymal transition as well as mesenchymal stem cells via the mesenchymal transition, as both of these processes are induced by MM cells and CAFs. Active MM CAFs fostered chemotaxis, adhesion, proliferation and apoptosis resistance in MM cells through cytokine signals and cell-to-cell contact, which were inhibited by blocking CXCR4, several integrins and fibronectin. MM cells also induced the CAFs proliferation. In syngeneic 5T33MM and xenograft mouse models, MM cells induced the expansion of CAFs, which, in turn, promoted MM initiation and progression as well as angiogenesis. In BM biopsies from patients and mice, nests of CAFs were found in close contact with MM cells, suggesting a supportive niche. Therefore, the targeting of CAFs in MM patients may be envisaged as a novel therapeutic strategy.
authors.affiliation: Department of Biomedical Sciences and Human Oncology (DIMO), General Pathology Section, Bari, Italy.
authors.forename: M A
authors.initials: MA
authors.lastname: Frassanito
authors.affiliation: Internal Medicine Section, University of Bari Medical School, Bari, Italy.
authors.forename: L
authors.initials: L
authors.lastname: Rao
authors.affiliation: Internal Medicine Section, University of Bari Medical School, Bari, Italy.
authors.forename: M
authors.initials: M
authors.lastname: Moschetta
authors.affiliation: Internal Medicine Section, University of Bari Medical School, Bari, Italy.
authors.forename: R
authors.initials: R
authors.lastname: Ria
authors.affiliation: Internal Medicine Section, University of Bari Medical School, Bari, Italy.
authors.forename: L
authors.initials: L
authors.lastname: Di Marzo
authors.affiliation: Internal Medicine Section, University of Bari Medical School, Bari, Italy.
authors.forename: A
authors.initials: A
authors.lastname: De Luisi
authors.affiliation: Internal Medicine Section, University of Bari Medical School, Bari, Italy.
authors.forename: V
authors.initials: V
authors.lastname: Racanelli
authors.affiliation: Internal Medicine Section, University of Bari Medical School, Bari, Italy.
authors.forename: I
authors.initials: I
authors.lastname: Catacchio
authors.affiliation: Internal Medicine Section, University of Bari Medical School, Bari, Italy.
authors.forename: S
authors.initials: S
authors.lastname: Berardi
authors.affiliation: Internal Medicine Section, University of Bari Medical School, Bari, Italy.
authors.forename: A
authors.initials: A
authors.lastname: Basile
authors.affiliation: Department of Hematology and Immunology, Myeloma Center Brussels, Vrije Universiteit Brussel (VUB), Brussels, Belgium.
authors.forename: E
authors.initials: E
authors.lastname: Menu
authors.affiliation: Department of Basic Medical Sciences, Neurosciences and Sensory Organs, University of Bari Medical School, Bari, Italy.
authors.forename: S
authors.initials: S
authors.lastname: Ruggieri
authors.affiliation: Department of Basic Medical Sciences, Neurosciences and Sensory Organs, University of Bari Medical School, Bari, Italy.
authors.forename: B
authors.initials: B
authors.lastname: Nico
authors.affiliation: 1] Department of Basic Medical Sciences, Neurosciences and Sensory Organs, University of Bari Medical School, Bari, Italy [2] National Cancer Institute "Giovanni Paolo II", Bari, Italy.
authors.forename: D
authors.initials: D
authors.lastname: Ribatti
authors.affiliation: Department of Biomedical Sciences and Human Oncology (DIMO), General Pathology Section, Bari, Italy.
authors.forename: R
authors.initials: R
authors.lastname: Fumarulo
authors.affiliation: Internal Medicine Section, University of Bari Medical School, Bari, Italy.
authors.forename: F
authors.initials: F
authors.lastname: Dammacco
authors.affiliation: Department of Hematology and Immunology, Myeloma Center Brussels, Vrije Universiteit Brussel (VUB), Brussels, Belgium.
authors.forename: K
authors.initials: K
authors.lastname: Vanderkerken
authors.affiliation: Internal Medicine Section, University of Bari Medical School, Bari, Italy.
authors.forename: A
authors.initials: A
authors.lastname: Vacca
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D000818:Animals; D017209:Apoptosis; D001854:Bone Marrow Cells / Q000502:physiology*; D049109:Cell Proliferation; D002478:Cells, Cultured; D054377:Chemokine CXCL12 / Q000502:physiology; D018450:Disease Progression; D058750:Epithelial-Mesenchymal Transition; D005260:Female; D005347:Fibroblasts / Q000502:physiology*; D006801:Humans; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008875:Middle Aged; D009101:Multiple Myeloma / Q000473:pathology*; D010641:Phenotype
chemical_list: D054377:Chemokine CXCL12