Mesenchymal stromal cells revert multiple myeloma cells to less differentiated phenotype by the combined activities of adhesive interactions and interleukin-6

Dezorella, Nili; Pevsner‐Fischer, Meirav; Deutsch, Varda; Kay, Sigi; Baron, Shoshana; Stern, Ruth; Tavor, Sigal; Nagler, Arnon; Naparstek, Elizabeth; Zipori, Dov; Katz, Ben Z.

doi:10.1016/j.yexcr.2009.03.016

Cited by 26 publications

(24 citation statements)

References 42 publications

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“…These cells underwent de-differentiation when subjected to fibroblast nemosis and gained phenotype reminiscent to less differentiated plasma cells. Our results are in accordance with observation made by the group of Dezorella et al [36]. They showed that incubation of multiple myeloma cells with bone marrow-derived mesenchymal stromal cells led to reduction of expression of plasma cell differentiation markers CD38 and CD138, as well [36].…”

Section: Discussionsupporting

confidence: 93%

“…Our results are in accordance with observation made by the group of Dezorella et al [36]. They showed that incubation of multiple myeloma cells with bone marrow-derived mesenchymal stromal cells led to reduction of expression of plasma cell differentiation markers CD38 and CD138, as well [36]. Moreover, we also observed significant increase of CD45 expression after exposure of these cells to nemosis.…”

Section: Discussionsupporting

confidence: 93%

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Inflammatory environment created by fibroblast aggregates induces growth arrest and phenotypic shift of human myeloma cells

K¹,

I²,

Mistrík³

et al. 2015

neo

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Multiple myeloma (MM) is characterized by accumulation of clonal plasma cells (PCs) predominantly in the bone marrow but tumor cells appear in the circulation in significant numbers as the disease progress. The occurrence of circulating multiple myeloma cells raises question concerning interactions between these cells and stroma of peripheral organs specifically under certain pathophysiological conditions, e.g., inflammation. Therefore, in the present study we exposed three human multiple myeloma cell lines to sterile inflammation produced in a culture dish by clusters of cell-cell contact-activated dermal fibroblasts. We now observed that myeloma cells responded differently to this particular type of stromal cell activation, nemosis. Two cell lines U-266 and LP-1 were minimally affected by the proinflammatory signalling, while the third cell line RPMI 8226 responded with growth arrest and altered expression of three phenotypic markers CD38, CD45, and CD138, indicating dedifferentiation shift of these cells to less mature PC-like phenotype. In a preliminary study we identified a subclone of cells having similar phenotype in 14 out of 23 analysed specimens of MM patients. This set of data indicates that the observed phenomenon might be clinically relevant. Our results emphasize the potential role of activated stromal fibroblasts and subsequent inflammation in altering phenotype of PCs and directing myeloma progression towards dormancy. Given the significant implication of dormant myeloma cells that might serve as a major cellular basis for the relapse, understanding their unique biology and precise elucidation of the underlying molecular mechanisms for the maintenance of quiescence is important. Therefore, we consider this study as a particular contribution to development of experimental model for in vitro studies of cancer dormancy.

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Section: Discussionsupporting

confidence: 93%

Section: Discussionsupporting

confidence: 93%

Inflammatory environment created by fibroblast aggregates induces growth arrest and phenotypic shift of human myeloma cells

K¹,

I²,

Mistrík³

et al. 2015

neo

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“…In that connection, we note that oncogenes in the poorly differentiated type A cells were highly expressed, a finding that is compatible with previous data showing that MM M4 patients with poor prognoses are characterized by gene expression profiles clustered with tonsil B cells that are poorly differentiated in nature (43). Our recent study showed that on removal from their microenvironment (ex vivo cultivation), primary MM cells significantly upregulate their differentiation markers (44). These cells do not attach to fibronectin and grow as floating cells in a similar manner to type F cells (data not shown).…”

Section: Discussionsupporting

confidence: 92%

“…These cells do not attach to fibronectin and grow as floating cells in a similar manner to type F cells (data not shown). This observation supports the hypothesis that microenvironmental factors (e.g., cell adhesion) can maintain low level of cellular differentiation in MM cells (44). MM cell that may display the type A phenotype should be isolated from the solid textures of the BM (e.g., BM biopsies, ongoing study).…”

Section: Discussionsupporting

confidence: 76%

Adhesive Interactions Regulate Transcriptional Diversity in Malignant B Cells

Nadav-Dagan

Shay

Dezorella

et al. 2010

Molecular Cancer Research

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The genetic profiling of B-cell malignancies is rapidly expanding, providing important information on the tumorigenic potential, response to treatment, and clinical outcome of these diseases. However, the relative contributions of inherent gene expression versus microenvironmental effects are poorly understood. The regulation of gene expression programs by means of adhesive interactions was studied here in ARH-77 human malignant B-cell variants, derived from the same cell line by selective adhesion to a fibronectin matrix. The populations included cells that adhere to fibronectin and are highly tumorigenic (designated "type A" cells) and cells that fail to adhere to fibronectin and fail to develop tumors in vivo ("type F" cells). To identify genes directly affected by cell adhesion to fibronectin, type A cells deprived of an adhesive substrate (designated "AF cells") were also examined. Bioinformatic analyses revealed a remarkable correlation between cell adhesion and both B-cell differentiation state and the expression of multiple myeloma (MM)-associated genes. The highly adherent type A cells expressed higher levels of NFκB-regulated genes, many of them associated with MM. Moreover, we found that the transcription of several MM-related proto-oncogenes is stimulated by adhesion to fibronectin. In contrast, type F cells, which display poor adhesive and tumorigenic properties, expressed genes associated with higher levels of B-cell differentiation. Our findings indicate that B-cell differentiation, as manifested by gene expression profiles, is attenuated by cell adhesion to fibronectin, leading to upregulation of specific genes known to be associated with the pathogenesis of MM. Mol Cancer Res; 8(4); 482-93. ©2010 AACR.

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“…BI 2536 induces MM cell cytotoxicity in the presence of ECM components, IL-6, and bone marrow stromal cells As the activity of MM cells is known to be regulated by the bone marrow microenvironment [8,9], we sought to determine the effect of this environment on the response of MM cells to BI 2536. We used ECM, laminin, and fibronectin as cell culture substrates.…”

Section: Plk Genes Are Present In MM Cellsmentioning

confidence: 99%

The polo-like kinase inhibitor BI 2536 exhibits potent activity against malignant plasma cells and represents a novel therapy in multiple myeloma

Stewart

Kishikova

Powell

et al. 2011

Experimental Hematology

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Objective. Polo-like kinase 1 (Plk1) is a regulator of the cell cycle that has been implicated in the pathology of many cancers. We have investigated whether this kinase plays a role in multiple myeloma (MM) using the Plk1 inhibitor BI 2536. Materials and Methods. We have used six MM cell lines and six patient-derived samples to determine the effects of the Plk1 inhibitor, BI 2536, on cell viability, apoptosis, and cytokinesis. We have also examined the effect of the microenvironment on these parameters and the effects of BI 2536 in combination with other antimyeloma agents. Results. We show that MM cell lines and patient samples express PLK1 and that cell death by apoptosis occurs when Plk1 is inhibited. Cells treated with BI 2536 accumulate in the G 2 /M phase of the cell cycle causing endoduplication. The effects of BI 2536 are not abrogated when cells are cultured on extracellular matrix components, in the presence of interleukin-6, or with bone marrow stromal cells. Conclusions. Plk1 inhibition leads to cell death in MM cell lines and patient myeloma samples. Our data suggest that inhibition of Plk1 may have potential use as a therapeutic strategy in multiple myeloma. Ó

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Mesenchymal stromal cells revert multiple myeloma cells to less differentiated phenotype by the combined activities of adhesive interactions and interleukin-6

Cited by 26 publications

References 42 publications

Inflammatory environment created by fibroblast aggregates induces growth arrest and phenotypic shift of human myeloma cells

Inflammatory environment created by fibroblast aggregates induces growth arrest and phenotypic shift of human myeloma cells

Adhesive Interactions Regulate Transcriptional Diversity in Malignant B Cells

The polo-like kinase inhibitor BI 2536 exhibits potent activity against malignant plasma cells and represents a novel therapy in multiple myeloma

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