Abnormal bone remodelling and increased levels of macrophage inflammatory protein‐1 alpha (MIP‐1<i>α</i>) in Waldenström macroglobulinaemia

Terpos, Evangelos; Anagnostopoulos, Athanasios; Kastritis, Efstathios; Bamias, Aristotelis; Tsionos, Konstantinos; Dimopoulos, Meletios Α.

doi:10.1111/j.1365-2141.2006.06017.x

Cited by 22 publications

(13 citation statements)

References 12 publications

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“…32 Levels of MIP-1␣ were also found to be elevated in WM patient sera. 33 Angiogenic cytokines including vascular endothelial growth factor (VEGF), VEFG-A, angiogenin, angiopoetin-1, angiopoetin-2, and basic fibroblast growth factor (bFGF) have also been studied in WM and found to be elevated in patient sera. 34 In this study, we measured the levels of 30 different cytokines in sera obtained from WM patients and identified several cytokines, one of which was CCL5, that are dysregulated compared with healthy controls.…”

Section: Discussionmentioning

confidence: 99%

Comprehensive analysis of tumor microenvironment cytokines in Waldenstrom macroglobulinemia identifies CCL5 as a novel modulator of IL-6 activity

Elsawa

Novak

Ziesmer

et al. 2011

Blood

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Although proinflammatory and chemotactic cytokines can profoundly affect the tumor microenvironment, and many of them have been shown to have therapeutic efficacy in preclinical models, the role of these molecules in Waldenströ m macroglobulinemia (WM) remains poorly understood. In this study, simultaneous analysis of WM patient sera and bone marrow biopsies identified a set of dysregulated cytokines including CCL5, G-CSF, and soluble IL-2 receptor, that were significantly elevated in WM patients whereas IL-8 and EGF levels were significantly lower in these patients compared with healthy controls. Interestingly, CCL5 levels positively correlated with features of disease aggressiveness such as elevated IgM levels and bone marrow involvement. IntroductionCytokines are protein mediators that are known to be involved in many biologic processes including cell growth, survival, inflammation, and differentiation. [1][2][3] In the malignant scenario, cytokines can profoundly affect tumor cells directly as well as the surrounding microenvironment, thereby impacting tumor cell biology. Therefore, understanding the composition of the cytokine milieu, particularly in the tumor microenvironment, is an important component of our understanding of the biology of malignant transformation. Targeting cytokines has been shown to have potent therapeutic efficacy in preclinical cancer models. 4,5 Despite the importance of cytokine networks in normal and disease states, only a limited number of studies have addressed the role of cytokines in the regulation of the tumor microenvironment in B-cell malignancies, and in particular, Waldenström macroglobulinemia (WM).WM is characterized by an infiltration of lymphoplasmacytic cells in the bone marrow accompanied by a high circulating monoclonal IgM protein that often leads to serum hyperviscosity. 6 Despite the introduction of multiple therapies, WM remains an incurable disease. Therefore, an understanding of the basic mechanisms underlying disease biology is fundamental to the development of novel therapies. In this study, we used a multiplex immunobead assay to simultaneously measure cytokines, chemokines, angiogenic factors, as well as growth factors and soluble receptors in the sera of WM patients and compared them with healthy donors. Our studies identify CCL5 (also known as regulated on activation, normal T-cell expressed, and secreted [RAN-TES]), G-CSF, and soluble IL-2 receptor ␣ (sIL-2R/CD25) as highly expressed in WM patient sera whereas IL-8 and EGF are down-regulated. Further analysis of CCL5 found that serum CCL5 levels correlated with expression of CCL5 in the bone marrow, IgM, IL-6 and bone marrow involvement by lymphoplasmacytic cells. Further analysis of the interplay between CCL5 and IL-6 indicated that CCL5 induced IL-6 secretion by WM stromal cells and identified the JAK/STAT signaling pathway as a mediator of IgM secretion in response to IL-6 stimulation. Therefore, therapies targeting CCL5 may provide therapeutic efficacy for WM patients by reducing IL-6 secretion by...

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Section: Discussionmentioning

confidence: 99%

Comprehensive analysis of tumor microenvironment cytokines in Waldenstrom macroglobulinemia identifies CCL5 as a novel modulator of IL-6 activity

Elsawa

Novak

Ziesmer

et al. 2011

Blood

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“…Post-traumatic stress disorder has been shown to modulate salivary CRP and α2-macroglobulin levels [74], and nephrotic syndrome is known to alter the serum concentration of α2-macroglobulin, thus potentially impacting salivary concentrations. Infectious disease states, such as HIV infection, are known to be associated with altered salivary MMP and TIMP levels [143] and serum MIP-1α levels are elevated in multiple myeloma and other lytic bone disorders potentially confounding its utility in salivary diagnosis of periodontal disease [60,144]. Cyclic changes in salivary ALP levels have been associated with the menstrual cycle [145] and oral lesions [146], and periodontal therapy has resulted in altered levels of inflammatory cytokines and TIMPs in saliva [89,147].…”

Section: Potential Confoundersmentioning

confidence: 99%

Current Developments in Salivary Diagnostics

et al. 2010

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Salivary diagnostics is an emerging field that has progressed through several important developments in the past decade, including the publication of the human salivary proteome and the infusion of federal funds to integrate nanotechnologies and microfluidic engineering concepts into developing compact point-of-care devices for rapid analysis of this secretion. In this article, we discuss some of these developments and their relevance to the prognosis, diagnosis and management of periodontitis, as an oral target, and cardiovascular disease, as a systemic example for the potential of these biodiagnostics. Our findings suggest that several biomarkers are associated with distinct biological stages of these diseases and demonstrate promise as practical biomarkers in identifying and managing periodontal disease, and acute myocardial infarction. The majority of these studies have progressed through biomarker discovery, with the identified molecules requiring more robust clinical studies to enable substantive validation for disease diagnosis. It is predicted that with continued advances in this field the use of a combination of biomarkers in multiplex panels is likely to yield accurate screening tools for these diagnoses in the near future. Keywordsacute myocardial infarction; lab-on-a-chip; periodontitis; salivary diagnosis Overview of the field of salivary diagnosisThe analysis of blood and its components has been the mainstay for laboratory diagnostic procedures for several decades. However, other biological fluids are also utilized frequently for the diagnosis of disease, for example urine and cerebrospinal fluid, and thus, saliva could offer some distinct advantages in select situations [1][2][3][4][5][6]. Saliva is a hypotonic fluid NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author Manuscript composed mostly of water, electrolytes and organic molecules (i.e., amino acids, proteins and lipids). The water component is derived largely from the local capillary bed via intracellular diffusion, aquaporin water channels and extracellular routes [7,8]. Small neutral molecules from the serum enter by passive diffusion from the dense beds of capillaries surrounding and bathing the salivary glands. Electrolytes enter the saliva via osmotic gradients and are regulated by the rate of secretion, nature of the stimulus and level of mineralocorticoids in the circulation. The organic components of glandular saliva are derived largely from protein synthesis and are stored as granules within the acinar cells [4]. Because serum components of saliva are derived primarily from the local vasculature that originates from the carotid arteries [9], saliva has a prodigious fluid source that provides many, if not most, of the same molecules found in the systemic circulation. This makes saliva a potentially valuable fluid for the diagnosis of various systemic diseases (Figure 1).The recent cataloguing of the salivary proteome has availed considerable information that is potentially important for diagnostic applications ...

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“…Increased levels of MIP-1α have been reported in cancer patients with multiple myeloma [8], Waldenström macroglobulinemia [25], Schwann cell tumors [26], and ATLL [13]. These tumors have the potential to develop bone metastases or bone lesions.…”

Section: Discussionmentioning

confidence: 99%

Osteolytic bone resorption in adult T-cell leukemia/lymphoma

Shu

Martin²,

Thudi³

et al. 2010

Leukemia & Lymphoma

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Adult T-cell leukemia/lymphoma (ATLL) is caused by human T lymphotropic virus type 1 (HTLV-1). Patients with ATLL frequently develop humoral hypercalcemia of malignancy (HHM) resulting from increased osteoclastic bone resorption. Our goal was to investigate the mechanisms of ATLL-induced osteoclastic bone resorption. Murine calvaria co-cultured with HTLV-1-infected cells directly or conditioned media from cell cultures had increased osteoclast activity that was dependent on RANKL, indicating that factors secreted from ATLL cells had a stimulatory effect on bone resorption. Factors released from resorbing bone stimulated proliferation of HTLV-1-infected T-cells. Parathyroid hormone-related protein (PTHrP) and macrophage inflammatory protein-1α (MIP-1α), both osteoclast stimulators, were expressed in HTLV-1-infected T-cell lines. Interestingly, when HTLV-1-infected T-cells were co-cultured with pre-osteoblasts, the expression of osteoprotegerin (OPG), an osteoclast inhibitory factor, was significantly down-regulated in the pre-osteoblasts. When OPG was added into the ex vivo osteoclastogenesis assay induced by HTLV-1-infected T-cells, osteoclastogenesis was strongly inhibited. In addition, HTLV-1-infected T-cells inhibited expression of early osteoblast genes and induced late genes. These regulators will serve as future therapeutic targets for the treatments of HHM in ATLL.

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Abnormal bone remodelling and increased levels of macrophage inflammatory protein‐1 alpha (MIP‐1α) in Waldenström macroglobulinaemia

Cited by 22 publications

References 12 publications

Comprehensive analysis of tumor microenvironment cytokines in Waldenstrom macroglobulinemia identifies CCL5 as a novel modulator of IL-6 activity

Comprehensive analysis of tumor microenvironment cytokines in Waldenstrom macroglobulinemia identifies CCL5 as a novel modulator of IL-6 activity

Current Developments in Salivary Diagnostics

Osteolytic bone resorption in adult T-cell leukemia/lymphoma

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