N-cadherin-mediated interaction with multiple myeloma cells inhibits osteoblast differentiation

Richard W J Groen, Martin F M de Rooij, Kinga A Kocemba, Rogier M Reijmers, Anneke de Haan-Kramer, Marije B Overdijk, Linda Aalders, Henk Rozemuller, Anton C M Martens, P Leif Bergsagel, Marie José Kersten, Steven T Pals, Marcel Spaargaren

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

BACKGROUND: Multiple myeloma is a hematologic malignancy characterized by a clonal expansion of malignant plasma cells in the bone marrow, which is accompanied by the development of osteolytic lesions and/or diffuse osteopenia. The intricate bi-directional interaction with the bone marrow microenvironment plays a critical role in sustaining the growth and survival of myeloma cells during tumor progression. Identification and functional analysis of the (adhesion) molecules involved in this interaction will provide important insights into the pathogenesis of multiple myeloma.

DESIGN AND METHODS: Multiple myeloma cell lines and patients' samples were analyzed for expression of the adhesion molecule N-cadherin by immunoblotting, flow cytometry, immunofluorescence microscopy, immunohistochemistry and expression microarray. In addition, by means of blocking antibodies and inducible RNA interference we studied the functional consequence of N-cadherin expression for the myeloma cells, by analysis of adhesion, migration and growth, and for the bone marrow microenvironment, by analysis of osteogenic differentiation.

RESULTS: The malignant plasma cells in approximately half of the multiple myeloma patients, belonging to specific genetic subgroups, aberrantly expressed the homophilic adhesion molecule N-cad-herin. N-cadherin-mediated cell-substrate or homotypic cell-cell adhesion did not contribute to myeloma cell growth in vitro. However, N-cadherin directly mediated the bone marrow localization/retention of myeloma cells in vivo, and facilitated a close interaction between myeloma cells and N-cadherin-positive osteoblasts. Furthermore, this N-cadherin-mediated interaction contributed to the ability of myeloma cells to inhibit osteoblastogenesis.

CONCLUSIONS: Taken together, our data show that myeloma cells frequently display aberrant expression of N-cadherin and that N-cadherin mediates the interaction of myeloma cells with the bone marrow microenvironment, in particular the osteoblasts. This N-cadherin-mediated interaction inhibits osteoblast differentiation and may play an important role in the pathogenesis of myeloma bone disease.

Original languageEnglish
Pages (from-to)1653-61
Number of pages9
JournalHaematologica
Volume96
Issue number11
DOIs
Publication statusPublished - Nov 2011

Cite this

Groen, R. W. J., de Rooij, M. F. M., Kocemba, K. A., Reijmers, R. M., de Haan-Kramer, A., Overdijk, M. B., ... Spaargaren, M. (2011). N-cadherin-mediated interaction with multiple myeloma cells inhibits osteoblast differentiation. Haematologica, 96(11), 1653-61. https://doi.org/10.3324/haematol.2010.038133
Groen, Richard W J ; de Rooij, Martin F M ; Kocemba, Kinga A ; Reijmers, Rogier M ; de Haan-Kramer, Anneke ; Overdijk, Marije B ; Aalders, Linda ; Rozemuller, Henk ; Martens, Anton C M ; Bergsagel, P Leif ; Kersten, Marie José ; Pals, Steven T ; Spaargaren, Marcel. / N-cadherin-mediated interaction with multiple myeloma cells inhibits osteoblast differentiation. In: Haematologica. 2011 ; Vol. 96, No. 11. pp. 1653-61.
@article{2d0185d83ae8429ebf50fb88b1edd333,
title = "N-cadherin-mediated interaction with multiple myeloma cells inhibits osteoblast differentiation",
abstract = "BACKGROUND: Multiple myeloma is a hematologic malignancy characterized by a clonal expansion of malignant plasma cells in the bone marrow, which is accompanied by the development of osteolytic lesions and/or diffuse osteopenia. The intricate bi-directional interaction with the bone marrow microenvironment plays a critical role in sustaining the growth and survival of myeloma cells during tumor progression. Identification and functional analysis of the (adhesion) molecules involved in this interaction will provide important insights into the pathogenesis of multiple myeloma.DESIGN AND METHODS: Multiple myeloma cell lines and patients' samples were analyzed for expression of the adhesion molecule N-cadherin by immunoblotting, flow cytometry, immunofluorescence microscopy, immunohistochemistry and expression microarray. In addition, by means of blocking antibodies and inducible RNA interference we studied the functional consequence of N-cadherin expression for the myeloma cells, by analysis of adhesion, migration and growth, and for the bone marrow microenvironment, by analysis of osteogenic differentiation.RESULTS: The malignant plasma cells in approximately half of the multiple myeloma patients, belonging to specific genetic subgroups, aberrantly expressed the homophilic adhesion molecule N-cad-herin. N-cadherin-mediated cell-substrate or homotypic cell-cell adhesion did not contribute to myeloma cell growth in vitro. However, N-cadherin directly mediated the bone marrow localization/retention of myeloma cells in vivo, and facilitated a close interaction between myeloma cells and N-cadherin-positive osteoblasts. Furthermore, this N-cadherin-mediated interaction contributed to the ability of myeloma cells to inhibit osteoblastogenesis.CONCLUSIONS: Taken together, our data show that myeloma cells frequently display aberrant expression of N-cadherin and that N-cadherin mediates the interaction of myeloma cells with the bone marrow microenvironment, in particular the osteoblasts. This N-cadherin-mediated interaction inhibits osteoblast differentiation and may play an important role in the pathogenesis of myeloma bone disease.",
keywords = "Bone Marrow/metabolism, Bone Marrow Cells/metabolism, Cadherins/genetics, Cell Adhesion/genetics, Cell Communication, Cell Differentiation, Cell Line, Tumor, Humans, Multiple Myeloma/genetics, Neoplasm Proteins/genetics, Osteoblasts/metabolism, Tumor Microenvironment",
author = "Groen, {Richard W J} and {de Rooij}, {Martin F M} and Kocemba, {Kinga A} and Reijmers, {Rogier M} and {de Haan-Kramer}, Anneke and Overdijk, {Marije B} and Linda Aalders and Henk Rozemuller and Martens, {Anton C M} and Bergsagel, {P Leif} and Kersten, {Marie Jos{\'e}} and Pals, {Steven T} and Marcel Spaargaren",
year = "2011",
month = "11",
doi = "10.3324/haematol.2010.038133",
language = "English",
volume = "96",
pages = "1653--61",
journal = "Haematologica",
issn = "0390-6078",
publisher = "Ferrata Storti Foundation",
number = "11",

}

Groen, RWJ, de Rooij, MFM, Kocemba, KA, Reijmers, RM, de Haan-Kramer, A, Overdijk, MB, Aalders, L, Rozemuller, H, Martens, ACM, Bergsagel, PL, Kersten, MJ, Pals, ST & Spaargaren, M 2011, 'N-cadherin-mediated interaction with multiple myeloma cells inhibits osteoblast differentiation' Haematologica, vol. 96, no. 11, pp. 1653-61. https://doi.org/10.3324/haematol.2010.038133

N-cadherin-mediated interaction with multiple myeloma cells inhibits osteoblast differentiation. / Groen, Richard W J; de Rooij, Martin F M; Kocemba, Kinga A; Reijmers, Rogier M; de Haan-Kramer, Anneke; Overdijk, Marije B; Aalders, Linda; Rozemuller, Henk; Martens, Anton C M; Bergsagel, P Leif; Kersten, Marie José; Pals, Steven T; Spaargaren, Marcel.

In: Haematologica, Vol. 96, No. 11, 11.2011, p. 1653-61.

Research output: Contribution to journalArticleAcademicpeer-review

TY - JOUR

T1 - N-cadherin-mediated interaction with multiple myeloma cells inhibits osteoblast differentiation

AU - Groen, Richard W J

AU - de Rooij, Martin F M

AU - Kocemba, Kinga A

AU - Reijmers, Rogier M

AU - de Haan-Kramer, Anneke

AU - Overdijk, Marije B

AU - Aalders, Linda

AU - Rozemuller, Henk

AU - Martens, Anton C M

AU - Bergsagel, P Leif

AU - Kersten, Marie José

AU - Pals, Steven T

AU - Spaargaren, Marcel

PY - 2011/11

Y1 - 2011/11

N2 - BACKGROUND: Multiple myeloma is a hematologic malignancy characterized by a clonal expansion of malignant plasma cells in the bone marrow, which is accompanied by the development of osteolytic lesions and/or diffuse osteopenia. The intricate bi-directional interaction with the bone marrow microenvironment plays a critical role in sustaining the growth and survival of myeloma cells during tumor progression. Identification and functional analysis of the (adhesion) molecules involved in this interaction will provide important insights into the pathogenesis of multiple myeloma.DESIGN AND METHODS: Multiple myeloma cell lines and patients' samples were analyzed for expression of the adhesion molecule N-cadherin by immunoblotting, flow cytometry, immunofluorescence microscopy, immunohistochemistry and expression microarray. In addition, by means of blocking antibodies and inducible RNA interference we studied the functional consequence of N-cadherin expression for the myeloma cells, by analysis of adhesion, migration and growth, and for the bone marrow microenvironment, by analysis of osteogenic differentiation.RESULTS: The malignant plasma cells in approximately half of the multiple myeloma patients, belonging to specific genetic subgroups, aberrantly expressed the homophilic adhesion molecule N-cad-herin. N-cadherin-mediated cell-substrate or homotypic cell-cell adhesion did not contribute to myeloma cell growth in vitro. However, N-cadherin directly mediated the bone marrow localization/retention of myeloma cells in vivo, and facilitated a close interaction between myeloma cells and N-cadherin-positive osteoblasts. Furthermore, this N-cadherin-mediated interaction contributed to the ability of myeloma cells to inhibit osteoblastogenesis.CONCLUSIONS: Taken together, our data show that myeloma cells frequently display aberrant expression of N-cadherin and that N-cadherin mediates the interaction of myeloma cells with the bone marrow microenvironment, in particular the osteoblasts. This N-cadherin-mediated interaction inhibits osteoblast differentiation and may play an important role in the pathogenesis of myeloma bone disease.

AB - BACKGROUND: Multiple myeloma is a hematologic malignancy characterized by a clonal expansion of malignant plasma cells in the bone marrow, which is accompanied by the development of osteolytic lesions and/or diffuse osteopenia. The intricate bi-directional interaction with the bone marrow microenvironment plays a critical role in sustaining the growth and survival of myeloma cells during tumor progression. Identification and functional analysis of the (adhesion) molecules involved in this interaction will provide important insights into the pathogenesis of multiple myeloma.DESIGN AND METHODS: Multiple myeloma cell lines and patients' samples were analyzed for expression of the adhesion molecule N-cadherin by immunoblotting, flow cytometry, immunofluorescence microscopy, immunohistochemistry and expression microarray. In addition, by means of blocking antibodies and inducible RNA interference we studied the functional consequence of N-cadherin expression for the myeloma cells, by analysis of adhesion, migration and growth, and for the bone marrow microenvironment, by analysis of osteogenic differentiation.RESULTS: The malignant plasma cells in approximately half of the multiple myeloma patients, belonging to specific genetic subgroups, aberrantly expressed the homophilic adhesion molecule N-cad-herin. N-cadherin-mediated cell-substrate or homotypic cell-cell adhesion did not contribute to myeloma cell growth in vitro. However, N-cadherin directly mediated the bone marrow localization/retention of myeloma cells in vivo, and facilitated a close interaction between myeloma cells and N-cadherin-positive osteoblasts. Furthermore, this N-cadherin-mediated interaction contributed to the ability of myeloma cells to inhibit osteoblastogenesis.CONCLUSIONS: Taken together, our data show that myeloma cells frequently display aberrant expression of N-cadherin and that N-cadherin mediates the interaction of myeloma cells with the bone marrow microenvironment, in particular the osteoblasts. This N-cadherin-mediated interaction inhibits osteoblast differentiation and may play an important role in the pathogenesis of myeloma bone disease.

KW - Bone Marrow/metabolism

KW - Bone Marrow Cells/metabolism

KW - Cadherins/genetics

KW - Cell Adhesion/genetics

KW - Cell Communication

KW - Cell Differentiation

KW - Cell Line, Tumor

KW - Humans

KW - Multiple Myeloma/genetics

KW - Neoplasm Proteins/genetics

KW - Osteoblasts/metabolism

KW - Tumor Microenvironment

U2 - 10.3324/haematol.2010.038133

DO - 10.3324/haematol.2010.038133

M3 - Article

VL - 96

SP - 1653

EP - 1661

JO - Haematologica

JF - Haematologica

SN - 0390-6078

IS - 11

ER -