Transcriptomic profile induced in bone marrow mesenchymal stromal cells after interaction with multiple myeloma cells: implications in myeloma progression and myeloma bone disease

García-Gómez, Antonio; Rivas, Javier De Las; Ocio, Enrique M.; Dı́az-Rodrı́guez, Elena; Montero, Juan Carlos; Martín, Montserrat; Blanco, Juan F.; Sánchez‐Guijo, Fermín; Pandiella, Atanasio; Miguel, Jesús F. San; Garayoa, Mercedes

doi:10.18632/oncotarget.2058

Cited by 45 publications

(51 citation statements)

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“…Stromal cells isolated from MM patients display lower proliferative capacity, a premature senescence profile, and reduced ability to differentiate in osteoblasts compared to healthy MSC [61,86,87,88,89,90,91,92,93]. These features are usually associated with higher secretion of pro-angiogenic factors and modulated ability to impair T cell proliferation compared to healthy donors [58,66,94,95,96,97,98].…”

Section: Msc Cross-talk With Tumor Cellsmentioning

confidence: 99%

Mesenchymal Stromal Cells Can Regulate the Immune Response in the Tumor Microenvironment

Poggi

Giuliani

2016

Vaccines

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The tumor microenvironment is a good target for therapy in solid tumors and hematological malignancies. Indeed, solid tumor cells’ growth and expansion can influence neighboring cells’ behavior, leading to a modulation of mesenchymal stromal cell (MSC) activities and remodeling of extracellular matrix components. This leads to an altered microenvironment, where reparative mechanisms, in the presence of sub-acute inflammation, are not able to reconstitute healthy tissue. Carcinoma cells can undergo epithelial mesenchymal transition (EMT), a key step to generate metastasis; these mesenchymal-like cells display the functional behavior of MSC. Furthermore, MSC can support the survival and growth of leukemic cells within bone marrow participating in the leukemic cell niche. Notably, MSC can inhibit the anti-tumor immune response through either carcinoma-associated fibroblasts or bone marrow stromal cells. Experimental data have indicated their relevance in regulating cytolytic effector lymphocytes of the innate and adaptive arms of the immune system. Herein, we will discuss some of the evidence in hematological malignancies and solid tumors. In particular, we will focus our attention on the means by which it is conceivable to inhibit MSC-mediated immune suppression and trigger anti-tumor innate immunity.

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Section: Msc Cross-talk With Tumor Cellsmentioning

confidence: 99%

Mesenchymal Stromal Cells Can Regulate the Immune Response in the Tumor Microenvironment

Poggi

Giuliani

2016

Vaccines

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“…However, genes associated with ribosome function, the ubiquitin-proteasome pathway, and the noncanonical WNT pathway were modulated only in patient-derived MSCs. 59 These results suggest that myeloma cells exert a major role in influencing the function of MSCs, but that healthy and cancer-derived MSCs also respond differently to this interaction.The osteoblastic niche. OBs are the bone cellular component responsible for apposition of new bone, thus counterbalancing the function of OCs, the bone-resorbing cells.…”

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confidence: 95%

Pathogenesis beyond the cancer clone(s) in multiple myeloma

Bianchi

Munshi

2015

Blood

234

224

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Over the past 4 decades, basic research has provided crucial information regarding the cellular and molecular biology of cancer. In particular, the relevance of cancer microenvironment (including both cellular and noncellular elements) and the concept of clonal evolution and heterogeneity have emerged as important in cancer pathogenesis, immunologic escape, and resistance to therapy. Multiple myeloma (MM), a cancer of terminally differentiated plasma cells, is emblematic of the impact of cancer microenvironment and the role of clonal evolution. Although genetic and epigenetic aberrations occur in MM and evolve over time under the pressure of exogenous stimuli, they are also largely present in premalignant plasma cell dyscrasia such as monoclonal gammopathy of undetermined significance (MGUS) and smoldering multiple myeloma (SMM), suggesting that genetic mutations alone are necessary, but not sufficient, for myeloma transformation. The role of bone marrow microenvironment in mediating survival, proliferation, and resistance to therapy in myeloma is well established; and although an appealing speculation, its role in fostering the evolution of MGUS or SMM into MM is yet to be proven. In this review, we discuss MM pathogenesis with a particular emphasis on the role of bone marrow microenvironment. (Blood. 2015;125(20):3049-3058) Characteristics of the myeloma cancer clone Ontogenesis of myelomaMultiple myeloma (MM) represents the far end of the spectrum of B cell-derived neoplasms. It is the neoplastic counterpart of terminally differentiated, immunoglobulin-producing, long-lived plasma cells (PCs). Long-lived PCs are a subset of PCs characterized by long-term (months to years) survival within the bone marrow (BM) and thought to be key for immunologic memory.1,2 Based on the sequencing of the immunoglobulin heavy chain (IgH) variable region of MM cells (MMCs), the first oncogenic events in MM appear to occur in the germinal center, likely during the processes of isotype class switching and somatic hypermutation, which are, by nature, mutation prone. 3 The observation that patients with premalignant PC dyscrasia monoclonal gammopathy of undetermined significance (MGUS) and/or smoldering MM (SMM) also carry these initial mutations suggests that they are necessary, but not sufficient, in MM pathogenesis. Late oncogenic events are thought to occur in the BM, after the founder cancer clone is completely differentiated into a long-lived PC (Figure 1). 4 There is ongoing debate regarding the identity of the MM stem cells. Different groups have shown that both CD138 1 and CD192 cells are capable of tumorigenesis in mouse models.However, CD138 1 tends to lose self-renewing potential after a few cycles of serial transplantation, whereas the putative B-cell stem clone was never proved to be clonally related to its putative CD138 1 progeny.Overall, modification in the cytokine composition of the media used to maintain CD138 1 ex vivo successfully overcame the first issue, suggesting that the MM stem cell may be CD1381 . 5Ev...

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“…The active NF-κβ transcription factor promotes the expression of over 150 target genes. [38][39][40][41] The finding of the western blotting showed that phosphorylated p65 increased through the co-culturing of U266 cells with UCB-MSCs, although amount of p65 in U266 cells and U266 cells on UCB-MSC did not indicate significant change. Studies have documented that IKKB is a crucial component in the phosphorylation of p65 and may ignite the NF-κβ pathway activity, modulate the entry of phosphorylated p65 into the nucleus and activate gene transcription.…”

Section: Discussionmentioning

confidence: 94%