Under one roof

Nair, Jayakumar; Rozanski, Cheryl; Lee, Kelvin P.

doi:10.4161/onci.18746

Cited by 16 publications

(9 citation statements)

References 9 publications

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“…Normal and malignant PCs rely on their niche within the BM for survival and proliferation, respectively [5], [9], [25], [26]. We have identified a novel component of this niche – the eosinophils – that contributes to the enhanced proliferation of MM cells.…”

Section: Discussionmentioning

confidence: 97%

Induction of Malignant Plasma Cell Proliferation by Eosinophils

et al. 2013

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The biology of the malignant plasma cells (PCs) in multiple myeloma (MM) is highly influenced by the bone marrow (BM) microenvironment in which they reside. More specifically, BM stromal cells (SCs) are known to interact with MM cells to promote MM cell survival and proliferation. By contrast, it is unclear if innate immune cells within this same space also actively participate in the pathology of MM. Our study shows for the first time that eosinophils (Eos) can contribute to the biology of MM by enhancing the proliferation of some malignant PCs. We first demonstrate that PCs and Eos can be found in close proximity in the BM. In culture, Eos were found to augment MM cell proliferation that is predominantly mediated through a soluble factor(s). Fractionation of cell-free supernatants and neutralization studies demonstrated that this activity is independent of Eos-derived microparticles and a proliferation-inducing ligand (APRIL), respectively. Using a multicellular in vitro system designed to resemble the native MM niche, SCs and Eos were shown to have non-redundant roles in their support of MM cell growth. Whereas SCs induce MM cell proliferation predominantly through the secretion of IL-6, Eos stimulate growth of these malignant cells via an IL-6-independent mechanism. Taken together, our study demonstrates for the first time a role for Eos in the pathology of MM and suggests that therapeutic strategies targeting these cells may be beneficial.

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Section: Discussionmentioning

confidence: 97%

Induction of Malignant Plasma Cell Proliferation by Eosinophils

et al. 2013

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“…Plasma cells also reside within the BM and depend on signals provided by the surrounding environment enabling quiescence, and regulating proliferation or differentiation. 4 Oncogenic transformation of plasma cells results in multiple myeloma. Myeloma cells utilize and alter the surrounding BM microenvironment, 5 to support tumor proliferation, resistance to therapy, cancer cell trafficking and homing.…”

Section: Introductionmentioning

confidence: 99%

Cellular immunotherapy on primary multiple myeloma expanded in a 3D bone marrow niche model

et al. 2018

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Bone marrow niches support multiple myeloma, providing signals and cell-cell interactions essential for disease progression. A 3D bone marrow niche model was developed, in which supportive multipotent mesenchymal stromal cells and their osteogenic derivatives were co-cultured with endothelial progenitor cells. These co-cultured cells formed networks within the 3D culture, facilitating the survival and proliferation of primary CD138+ myeloma cells for up to 28 days. During this culture, no genetic drift was observed within the genomic profile of the primary myeloma cells, indicating a stable outgrowth of the cultured CD138+ population.The 3D bone marrow niche model enabled testing of a novel class of engineered immune cells, so called TEGs (αβT cells engineered to express a defined γδTCR) on primary myeloma cells. TEGs were engineered and tested from both healthy donors and myeloma patients. The added TEGs were capable of migrating through the 3D culture, exerting a killing response towards the primary myeloma cells in 6 out of 8 donor samples after both 24 and 48 hours. Such a killing response was not observed when adding mock transduced T cells. No differences were observed comparing allogeneic and autologous therapy. The supporting stromal microenvironment was unaffected in all conditions after 48 hours. When adding TEG therapy, the 3D model surpassed 2D models in many aspects by enabling analyses of specific homing, and both on- and off-target effects, preparing the ground for the clinical testing of TEGs. The model allows studying novel immunotherapies, therapy resistance mechanisms and possible side-effects for this incurable disease.

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“…Further, the transformation of the BM into a tumor supportive niche leaves a less viable milieu for the mesenchymal stem cell population (MSC) that are critical for tissue regeneration, and hematopoietic stem cells (HSC) central to hematopoiesis and myelopoiesis (11, 15). …”

Section: Introductionmentioning

confidence: 99%

Low intensity vibration mitigates tumor progression and protects bone quantity and quality in a murine model of myeloma

Pagnotti

Chan

Adler

et al. 2016

Bone

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Myeloma facilitates destruction of bone and marrow. Since physical activity encourages musculoskeletal preservation we evaluated whether low-intensity vibrations (LIV), a component of mechanical signaling, could protect bone and marrow during myeloma progression. Immunocompromised-mice (n=25) were injected with human-myeloma cells, while 8 (AC) were saline-injected. Myeloma-injected mice (LIV; n=13) were subjected to daily-mechanical loading (15min/d; 0.3g @ 90Hz) while 12 (MM) were sham-handled. At 8w, femurs had 85% less trabecular bone volume (BV) fraction in MM versus AC, yet only a 21% decrease in LIV as compared to as compared to AC, reflecting a 76% increase versus MM. Cortical BV was 21% and 15% lower in MM and LIV, respectively, than AC; LIV showing 30% improvement over MM. Similar outcomes were observed in the axial skeleton, showing a 35% loss in MM with a 27% improved retention of bone in L5 of LIV-treated mice as compared to MM. Transcortical-perforations in the femur from myeloma-induced osteolysis were 9× higher in MM versus AC, reduced by 57% in LIV. Serum-TRACP5b, 61% greater in MM versus AC, rose by 33% in LIV compared to AC, a 45% reduction in activity when compared to MM. Histomorphometric analyses of trabecular bone demonstrated a 70% elevation in eroded surfaces of MM versus AC, while measures in LIV were 58% below those in MM. 72% of marrow in the femur of MM mice contained tumor, contrasted by a 31% lower burden in LIV. MM mice (42%) presented advanced-stage necrosis of marrow in the tibia while present in just 8% of LIV. Myeloma infiltration inversely correlated to measures of bone quality, while LIV slowed systemic myeloma-associated decline in bone quality and inhibited tumor progression through the hindlimbs.

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Under one roof

Cited by 16 publications

References 9 publications

Induction of Malignant Plasma Cell Proliferation by Eosinophils

Induction of Malignant Plasma Cell Proliferation by Eosinophils

Cellular immunotherapy on primary multiple myeloma expanded in a 3D bone marrow niche model

Low intensity vibration mitigates tumor progression and protects bone quantity and quality in a murine model of myeloma

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