Increased CCL2 and IL‐8 in the bone marrow microenvironment in acute lymphoblastic leukemia

Vasconcellos, Jaira F. de; Laranjeira, Angelo Brunelli Albertoni; Zanchin, Nilson Ivo Tonin; Otubo, Rosemary; Vaz, Thais Haline; Cardoso, Angelo A.; Brandalise, Sílvia Regina; Yunes, José Andrés

doi:10.1002/pbc.22941

Cited by 51 publications

(43 citation statements)

References 47 publications

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“…The M+REH-CM showed the same effect as the LN on this adhesive phenotype, suggesting that soluble factors in the LN are responsible for these alterations. This situation is similar to the phenotype described for MSC from ALL patients having increased adhesion induced by soluble factors [23]. The specific molecules responsible for the higher cell adhesion to MSC should be further explored.…”

Section: Discussionsupporting

confidence: 78%

“…The fact that some soluble factors (CCL2, IL-6, IL8, CXCL1, and RANTES) are synergistically increased in the LN argues in favor that the phenotypic and functional alterations observed in the CD34+ cells is either directly through soluble factors secreted from the REH cell and/or indirectly through REH-CM-induced secretion by MSC. In particular the role of CCL2, IL-6, and IL-8 merits further study; the fact that IL-8 and CCL2 are upregulated in MSC from ALL patients [23], and that plasma levels of CCL2, IL-8, and IL-6 are increased in children at ALL diagnosis [23,31], show their relevance in vivo and validates in part our in vitro LN. The leukemic-induced alterations of the HSPC found here could be equated with the observed reduced hematopoiesis, increased progenitors and differentiated cells, and, in general, bone marrow failure in patients with ALL [6,20,32].…”

Section: Discussionmentioning

confidence: 73%

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Phenotypic and Functional Alterations of Hematopoietic Stem and Progenitor Cells in an In Vitro Leukemia-Induced Microenvironment

Vernot

Bonilla

Rodríguez-Pardo

et al. 2017

IJMS

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An understanding of the cell interactions occurring in the leukemic microenvironment and their functional consequences for the different cell players has therapeutic relevance. By co-culturing mesenchymal stem cells (MSC) with the REH acute lymphocytic leukemia (ALL) cell line, we have established an in vitro leukemic niche for the functional evaluation of hematopoietic stem/progenitor cells (HSPC, CD34+ cells). We showed that the normal homeostatic control exerted by the MSC over the HSPC is considerably lost in this leukemic microenvironment: HSPC increased their proliferation rate and adhesion to MSC. The adhesion molecules CD54 and CD44 were consequently upregulated in HSPC from the leukemic niche. Consequently, with this adhesive phenotype, HSPC showed less Stromal derived factor-1 (SDF-1)-directed migration. Interestingly, multipotency was severely affected with an important reduction in the absolute count and the percentage of primitive progenitor colonies. It was possible to simulate most of these HSPC alterations by incubation of MSC with a REH-conditioned medium, suggesting that REH soluble factors and their effect on MSC are important for the observed changes. Of note, these HSPC alterations were reproduced when primary leukemic cells from an ALL type B (ALL-B) patient were used to set up the leukemic niche. These results suggest that a general response is induced in the leukemic niche to the detriment of HSPC function and in favor of leukemic cell support. This in vitro leukemic niche could be a valuable tool for the understanding of the molecular events responsible for HSPC functional failure and a useful scenario for therapeutic evaluation.

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Section: Discussionsupporting

confidence: 78%

Section: Discussionmentioning

confidence: 73%

Phenotypic and Functional Alterations of Hematopoietic Stem and Progenitor Cells in an In Vitro Leukemia-Induced Microenvironment

Vernot

Bonilla

Rodríguez-Pardo

et al. 2017

IJMS

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“…It is widely known that MCP-1 is a chemokine with suppressive effects on normal hematopoiesis, which attracts monocytes to leukemic cells without the promotion of positive effects on monocyte cytotoxicity. Its upregulation as a consequence of TLR ligation could possibly promote survival, proliferation, and adhesiveness of leukemia cells and may represent a possible explanation of microenvironmental imbalances in hematological malignancies [35]. Furthermore, during chemotherapy, MCP-1 is upregulated in cerebrospinal fluid, suggesting that cell destruction and DAMPs release may activate the TLR program, resulting in critical MCP-1 release [36].…”

Section: Resultsmentioning

confidence: 99%

TLR Stimulation of Bone Marrow Lymphoid Precursors from Childhood Acute Leukemia Modifies Their Differentiation Potentials

Dorantes-Acosta

Vadillo

Contreras-Quiroz

et al. 2013

BioMed Research International

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Acute leukemias are the most frequent childhood malignancies worldwide and remain a leading cause of morbidity and mortality of relapsed patients. While remarkable progress has been made in characterizing genetic aberrations that may control these hematological disorders, it has also become clear that abnormalities in the bone marrow microenvironment might hit precursor cells and contribute to disease. However, responses of leukemic precursor cells to inflammatory conditions or microbial components upon infection are yet unexplored. Our previous work and increasing evidence indicate that Toll-like receptors (TLRs) in the earliest stages of lymphoid development in mice and humans provide an important mechanism for producing cells of the innate immune system. Using highly controlled co-culture systems, we now show that lymphoid precursors from leukemic bone marrow express TLRs and respond to their ligation by changing cell differentiation patterns. While no apparent contribution of TLR signals to tumor progression was recorded for any of the investigated diseases, the replenishment of innate cells was consistently promoted upon in vitro TLR exposure, suggesting that early recognition of pathogen-associated molecules might be implicated in the regulation of hematopoietic cell fate decisions in childhood acute leukemia.

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“…In solid tumors CCL2 can be produced by both cancer and stromal cells, including monocytes, fibroblasts, and endothelial cells (Strieter et al, 1989;Lazennec and Richmond, 2010), and its expression in each compartment is dynamically regulated by crosstalk between the tumor and the niche. For example, increased expression of CCL2 is detected in bone marrow MSCs following stimulation by leukemia cells resulting in enhanced cancer-promoting capacity of MSCs (de Vasconcellos et al, 2011). Co-culture with MSCs, in turn, induces CCL2 expression in cancer cells (Molloy et al, 2009).…”

Section: Ccl2 (Mcp-1)mentioning

confidence: 99%

Cytokines driving breast cancer stemness

Chin

Wang

2014

Molecular and Cellular Endocrinology

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a b s t r a c tThere is increasing evidence for the cancer stem cell model in which a subset of cancer cells possessing stem cell properties, referred to as tumor-initiating or cancer stem-like cells (CSCs), play crucial roles in multiple aspects of cancer. Recent studies have started to characterize the crucial role of various cytokines in the tumor microenvironment in regulating the fate of CSCs. In this review, we summarized some of the latest findings on cytokines that drive breast cancer stemness and their mechanisms of action. These cytokines, including IL-6, IL-8, CCL2 and TGF-b, are frequently elevated in breast tumors and may hold promise as potential therapeutic targets to eradicate CSCs. In combination with conventional chemotherapy and radiotherapy targeting rapidly proliferating cancer cells, intervention of the cancer stemness-driving cytokines may achieve additional benefits for breast cancer patients by suppressing CSC-promoted cancer progression, recurrence, and drug refractoriness.

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Increased CCL2 and IL‐8 in the bone marrow microenvironment in acute lymphoblastic leukemia

Cited by 51 publications

References 47 publications

Phenotypic and Functional Alterations of Hematopoietic Stem and Progenitor Cells in an In Vitro Leukemia-Induced Microenvironment

Phenotypic and Functional Alterations of Hematopoietic Stem and Progenitor Cells in an In Vitro Leukemia-Induced Microenvironment

TLR Stimulation of Bone Marrow Lymphoid Precursors from Childhood Acute Leukemia Modifies Their Differentiation Potentials

Cytokines driving breast cancer stemness

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