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Tumor-associated macrophages and extracellular matrix metalloproteinase inducer in prognosis of multiple myeloma

Leukemia volume 30, pages 951–954 (2016)Cite this article

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Multiple myeloma (MM) largely remains incurable and despite therapeutic advances in the last decade, patients eventually relapse or develop resistance to therapies.1 The interaction of MM cells with different cell components of the tumor microenvironment has a significant role in conferring resistance to therapy and in the maintenance of residual disease, ultimately dictating the clinical behavior and prognosis.2

Tumor-associated macrophages (TAMs) arise from in situ maturation of recruited circulating monocytes and constitute a significant part of myeloma tumor microenvironment. Once recruited to microenvironment, they are exposed to tumor- and stroma-secreted factors leading to macrophage activation.3 Activated macrophages can be grouped as M1 TAMs (M1ϕ, classically activated) and M2 TAMs (M2ϕ, alternatively activated) subtypes, which are extremes of a dynamic continuum rather than mutually exclusive cell states and display plasticity in both phenotype and function. The hallmarks of M1 activation are iNOS expression, high level of interleukin (IL)-12, low level of IL-10 production and thus they have immuno-stimulatory functions.2 M2ϕ are formed under selective pressure because of the bidirectional interactions of macrophages with myeloma cells and mesenchymal stromal cells, which effectively educate these macrophages to perform pro-tumoral functions. The hallmarks of M2 activation are increased amounts of IL-10 and low amounts of IL-12 and tumor necrosis factor-α, thus orchestrating a locally immunosuppressive environment and allowing the tumor to progress.3 Myelomas are highly vascularized tumors and increased neovascularization imparts poor prognosis. Traditionally, plasma cells and mesenchymal stromal cells are assumed to be major sources of vascular endothelial growth factor (VEGF).2 Current findings additionally suggest, M2ϕ as another major contributors of VEGF and the central orchestrators of the angiogenic switch observed during progression from MGUS to MM. This is attributed to increased secretion of VEGF by M2ϕ, which in turn is enhanced also by a paracrine loop between myeloma and stromal cells as the tumor expands.4, 5 In addition to promoting an immunosuppressive environment, a pro-tumoral role of M2ϕ is ascribed to secretion of factors such as IL-6 and IL-10. IL-10 secreted mainly by the M2ϕ is a myeloma growth factor6 and was recently shown to enhance angiogenesis in MM through VEGF secretion.7 In addition to the cytokines, CD147, which is an extracellular matrix metalloproteinase inducer (EMMPRIN), is also implicated in MM tumor progression with levels increasing from benign to malignant disease.8 CD147 functions to stimulate tumor cells and adjacent fibroblasts to produce matrix metalloproteinase and also stimulates expression of VEGF, which leads to angiogenesis.9, 10 As induction of angiogenesis through VEGF is the common theme for both M2ϕ and CD147, the primary aim of this study is to evaluate the degree of M2ϕ infiltration and CD147 expression in the bone marrow of patients with different stages of MM ranging in spectrum from MGUS to relapsed MM.

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Acknowledgements

We would like to acknowledge Carol Viso and Tammy-Brehm Gibson for help with the flow cytometry (Mayo Clinic Arizona), Cheryl Prothoroe from Jamie Lee lab in helping us set the immunohistochemistry protocol for tissue microarray staining (Mayo Clinic Arizona). We would also like to thank Anthony Blahnik from Pathology Imaging services for scanning the tissue microarray slides (Mayo Clinic Rochester). RF is a clinical investigator of the Damon Runyon Cancer Research Fund. This work is supported by grants R01 CA83724, ECOG CA 21115 T, Predolin Foundation, Mayo Clinic Cancer Center and the Mayo Foundation.

Author contributions

SP and RF contributed to the conception and design of the study. SP performed research and analyzed the data. KK provided the histopathological diagnosis of myeloma patients for analysis and independently counted the number of macrophages in random cores. GA, JM and SS contributed to the acquisition of data. SP drafted the article and all authors read, revised the article critically for important intellectual content, gave final approval of the version to be published and contributed to the interpretation of the data.

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Authors and Affiliations

  1. Division of Hematology/Oncology, Mayo Clinic, Scottsdale, AZ, USA

    S Panchabhai, G Ahmann, S Sebastian, J Mantei & R Fonseca

  2. Department of Laboratory Medicine and Pathology, Mayo Clinic, Scottsdale, AZ, USA

    K Kelemen

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  1. S Panchabhai
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Correspondence to R Fonseca.

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Competing interests

FR has sponsored research from AMGEN, Celgene, Onyx and Sanofi. He has received consulting fees from Bayer, Novartis, Onyx, Pharmacyclics, Sanofi and serves on the advisory committee of Applied Biosciences. He has received a patent for the prognostication of MM based on genetic categorization of the disease The remaining authors declare no competing financial interests.

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Panchabhai, S., Kelemen, K., Ahmann, G. et al. Tumor-associated macrophages and extracellular matrix metalloproteinase inducer in prognosis of multiple myeloma. Leukemia 30, 951–954 (2016). https://doi.org/10.1038/leu.2015.191

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