Edorium Journal of

Tumor Biology

 
  Table of Contents    
Original Article
 
Angiogenic cytokines: IL-6, sIL-6R, TNF-α, sVCAM-1, and PDGF-AB in multiple myeloma patients depending on the stage of the disease
Joanna Kamińska1, Olga M. Koper1, Violetta Dymicka-Piekarska2, Elżbieta Motybel3, Janusz Kłoczko4, Halina Kemona5
1PhD, Researcher, Department of Clinical Laboratory Diagnostics, Medical University of Bialystok, Poland.
2Assistant Professor, Researcher, Department of Clinical Laboratory Diagnostics, Medical University of Bialystok, Poland.
3MS, Researcher, Department of Clinical Laboratory Diagnostics, Medical University of Bialystok, Poland.
4Head of the Department, Department of Hematology, Clinical Hospital of the Medical University of Bialystok, Poland.
5Head of the Department, Department of Clinical Laboratory Diagnostics, Medical University of Bialystok, Poland.

Article ID: :100003T09JK2015
doi:10.5348/T09-2015-3-OA-2

Address correspondence to:
Joanna Kamińska
Department of Clinical Laboratory Diagnostics
Medical University of Bialystok, ul. Waszyngtona 15A
15-269 Bialystok
Poland
Tel/Fax: + 48 857468584
Mob: 508 739 863

Access full text article on other devices

  Access PDF of article on other devices

[HTML Abstract]   [PDF Full Text] [Print This Article]
[Similar article in Pumed] [Similar article in Google Scholar]

How to cite this article
Kamińska J, Koper OM, Dymicka-Piekarska V, Motybel E, Kloczko J, Kemona H. Angiogenic cytokines: IL-6, sIL-6R, TNF-α, sVCAM-1, and PDGF-AB in multiple myeloma patients depending on the stage of the disease. Edorium J Tumor Bio 2015;2:11–19.


Abstract
Aims: Angiogenesis plays an important role for growth, progression and metastasis of various cancers, including multiple myeloma (MM). Therefore, the aim of the study was the evaluation of concentrations of chosen angiogenic cytokines: interleukin 6 (IL-6), its soluble receptor (sIL-6R), tumor necrosis factor-α (TNF-α), soluble vascular cell adhesion molecule-1 (sVCAM-1), and platelet-derived growth factor-AB (PDGF-AB) in patient with newly diagnosed MM depending on the stage of the disease and as compared to the control group.
Methods: The study group consisted of newly diagnosed MM patients prior to treatment and categorized depending on the Durie and Salmon staging system. The controls consisted of healthy subjects. Angiogenic cytokines were determined with the use of ELISA method.
Results: Serum concentrations of all angiogenic cytokines analyzed were significantly higher in the whole study group as compared to the controls. Moreover, concentrations of all proteins tested significantly increasing with the stage of MM. Additionally, all cytokines tested positively correlated with the percentage of plasma cells in the bone marrow. The areas under the ROC curves (AUCs) for all cytokines analyzed were significantly higher than AUC=0.500.
Conclusion: Concentrations of angiogenic cytokines analyzed were significantly higher in MM patients as compared to the healthy subjects. Additionally, the concentrations of proteins tested were significantly increasing with the stage of the disease. Since the progression of MM proceeds at the same time as angiogenesis it allowed us to hypothesize that cytokines analyzed take part in bone marrow neovascularization. The areas under ROC curves analysis may indicate that these cytokines have potential clinical significance in MM.

Keywords: Angiogenic cytokines, Multiple myeloma, Platelet-derived growth factor-AB, Soluble vascular cell adhesion molecule-1



Introduction

Multiple myeloma (MM) accounts 1–2% of all human cancers and approximately 10 percent of all hematological malignancies. MM is associated with clonal proliferation of plasma cells in the bone marrow, the presence of monoclonal protein (a single abnormal immunoglobulin) in the serum and/or in urine, and osteolytic bone lesion [1] [2].

Angiogenesis is a multistep process of the formation of new blood vessels during embryonic growth, tissue healing, and in the female in regeneration of endometrium during menstrual cycle [3]. Angiogenenesis also occurs in growth and metastases of solid tumors. It is also important in hematological malignancies, such as MM [4] [5]. The measuring of microvessel density (MVD) is an objective method used to the evaluation of neovascularization in bone marrow [5]. In MM, angiogenesis was defined as a prognostic factor [6]. Vacca et al. revealed a high correlation between the increased bone marrow angiogenesis, estimated by measuring of MVD, and the proliferating fraction of plasma cells (estimated as labeling index) in Monoclonal Gammopathy of Undetermined Significance (MGUS) and MM patients. On the basis of obtained results authors suggested that MM is angiogenesis-dependent [4] .

It is well established that various pro-inflammatory cytokines and growth factors secreted by bone marrow microenvironment cells and malignant plasma cells play an important role in the multistep process of angiogenesis [7] [8] [9]. These proteins include interleukins (e.g.: IL-1, -6, -8, -10) and mitogenic growth factors (e.g.: vascular endothelial growth factor, VEGF; basic fibroblast growth factor, b-FGF; tumor necrosis factor-alpha, TNF-α; insulin-like growth factor 1, IGF-1; platelet derived growth factor-AB, PDGF-AB; stem cell factor, SCF) and have direct impact on growth, survival and metastasis of plasma cells [10] [11]. Studies showed positive correlations between serum concentrations of chosen pro-angiogenic cytokines and MVD [12] .

Therefore, the aim of the current study was to assess the serum concentrations of chosen angiogenic cytokines, such as: interleukin 6 (IL-6) and its soluble receptor (sIL-6R), tumor necrosis factor-α (TNFα), soluble vascular cell adhesion molecule-1 (sVCAM-1), and platelet-derived growth factor-AB (PDGF-AB) in patients with newly diagnosed MM as compared to the healthy controls. Moreover serum concentrations of above-mentioned cytokines were analyzed depending on the stage of the disease and other markers of the MM activity: β2-microglobulin (β2M), albumin (Alb) concentrations, lactate dehydrogenase activity (LDH), and the percentage of plasma cells in the bone marrow (% of plasma cells). Additionally, the areas under receiver operating characteristic (ROC) curves (AUCs) for all proteins tested were assessed.


Materials and Methods

The study group (MM) included 41 patients (18 females and 23 males, mean age 68 years, range 47–86 years) with newly diagnosed MM, prior to treatment. Patients were diagnosed at the Department of Hematology of the Clinical Hospital of the Medical University of Bialystok according to the World Health Organization (WHO) criteria, including: an increased number of abnormal, atypical or immature plasma cells in the bone marrow or histological proof of plasmocytoma; the presence of an M protein in the serum and/or in urine; bone lesions [13]. The patients were categorized depending on the stage of the disease according to the Durie and Salmon staging system [14]: I stage, II stage, and III stage. Table 1 presents the clinical characteristic of the study group. The control group (C) consisted of 30 healthy volunteers (15 F/15 M, mean age 66 years, range 45–77 years). The study was approved by the Bioethics Committee on human research of the Medical University of Bialystok (permission number: R-I-002/112/2009). All the patients gave they written informed consent to participate in the study.

Blood samples from the patients group and the controls were drawn between 6–7 o'clock in the morning following a fasting period of 10–12 hours. Tubes with the blood collected without anticoagulant were allowed to clot for 30 minutes before centrifugation for 15 minutes at 1000 xg, obtained sera were stored at –750C until further analysis.

The IL-6, sIL-6R, TNF-α, sVCAM-1, and PDGF-AB concentrations in the sera were measured with the use of commercially available ELISAs (Quantikine ELISA ® R&D Systems Inc., Abingdon, United Kingdom) according to the manufacturer's instructions.

The β2-microglobulin and albumin concentrations were measured with the use of immunonephelometry method on the BN* II (Siemens, Berlin, Germany).

The serum lactate dehydrogenase activity (LDH) was determined spectrophotometrically on the ARCHITECT c Systems™ (ABBOTT Park, IL, USA).

The percentage of plasma cells in the bone marrow was evaluated in bone marrow smears under light microscopy.

Statistical analysis
The obtained results were statistically analyzed with the use of the STATISTICA 10.0 PL software (StatSoft Inc., Tulsa, USA). The concentrations of proteins tested did not follow a normal distribution based on Shapiro-Wilk and Kolmogorov-Smirnov test. Therefore, nonparametric statistical analyses were used in the next step: Mann-Whitney's test was used in order to compare two independent samples and ANOVA rank Kruskal-Wallis test was used for the comparison of three samples. If statistical differences were found, the post-hoc test was conducted to assess which groups were different. The values for each given measured variable are given as medians and interquartile ranges. Differences were considered statistically significant for p<0.05. Correlation coefficients were obtained by applying Spearman's rank method. Receiver operator characteristic (ROC) curves were generated to calculate the areas under the ROC curves (AUCs).


Cursor on image to zoom/Click text to open image
Table 1: Clinical characteristic of multiple myeloma patients. Results are presented as medians




Results

Serum concentrations of all angiogenic cytokines tested (IL-6, sIL-6R, TNF-α, sVCAM-1, and PDGF-AB) in the whole study group were significantly higher as compared to the control group. Median PDGF-AB concentration was approximately 6-fold higher in the MM group as compared to the healthy subjects (Table 2). The analysis of median concentrations depending on the stage of the disease revealed that the highest medians were in the III stage of MM in case of all proteins tested. The post-hoc tests revealed that the statistically significant differences were not observed only between II versus III stage in case of TNF-α, sVCAM-1, and PDGF-AB and between I versus II stage in case of TNF-α (Table 3).

Table 4 presents the correlation coefficients between IL-6, sIL-6R, TNF-α, sVCAM-1, and PDGF-AB in MM patients. IL-6 and sVCAM-1 were significantly positively correlated with sIL-6R, TNF-α, sVCAM-1, and PDGF-AB. sIL-6R as well as TNF-α revealed a correlation coefficient with IL-6, sVCAM-1, and PDGF-AB (Table 4). The Spearman's rank method did not reveal correlations between angiogenic cytokines tested and β2-microglobulin as well as albumin concentrations (data not shown). The percentage of plasma cells in the bone marrow positively correlated with all cytokines analyzed, whereas the LDH activity negatively correlated with IL-6, sIL-6R, and PDGF-AB concentrations (Table 5).

Table 6 summarizes the results of diagnostic usefulness of angiogenic cytokines tested. AUCs for all proteins tested were significantly higher than AUC=0.500. Interestingly the highest sensitivity and specificity showed PDGF-AB (100%); also sVCAM-1 revealed high sensitivity and specificity (97% and 100%, respectively). Moreover the biggest AUCs were observed for PDGF-AB and sVCAM-1. The AUCs for IL-6 and sIL-6R were identical (Table 6).

Cursor on image to zoom/Click text to open image
Table 2: Statistical data of IL-6, sIL-6R, TNF-α, sVCAM-1, and PDGF-AB concentrations in the total study group of multiple myeloma patients and in the control group. Presented values are expressed as medians and interquartile ranges.


Cursor on image to zoom/Click text to open image
Table 3: Statistical data of IL-6, sIL-6R, TNF-α, sVCAM-1, and PDGF-AB concentrations in the groups of multiple myeloma patients depending on the stage of the disease and in the controls. Presented values are expressed as medians and interquartile ranges.


Cursor on image to zoom/Click text to open image
Table 4: Correlation coefficients (r) between angiogenic cytokines (IL-6, sIL-6R, TNF-α, sVCAM-1, and PDGF-AB) in multiple myeloma patients.


Cursor on image to zoom/Click text to open image
Table 5: Correlation coefficient (r) between LDH activity, % of plasma cells in the bone marrow and angiogenic cytokines (IL-6, sIL-6R, TNF-α, sVCAM-1, and PDGF-AB) in multiple myeloma patients.



Cursor on image to zoom/Click text to open image
Table 6: Diagnostic usefulness of IL-6, sIL-6R, TNF-α, sVCAM-1 and PDGF-AB in the total study group of multiple myeloma patients.



Discussion

Current study revealed that serum concentrations of IL-6, sIL-6R, TNF-α, sVCAM-1, and PDGF-AB, assessed using ELISA method, were significantly higher in MM patients as compared to the healthy subjects. Additionally, the concentrations of angiogenic cytokines were significantly increasing with the stage of the disease, which is in agreement with findings of other authors [9] [15].

IL-6 is produced by myeloma cells by both autocrine and paracrine mechanisms [16]. In MM, IL-6 takes part not only in the pathogenesis of the disease but also it is involved in the activation of angiogenic pathways [17]. The secretion of angiogenic growth factors by plasma cells is stimulated by IL-6 [15] [18] . IL-6 mediates its effect through a cell surface receptor build of the IL-6Rβ (CD 130) and the specific ligand-binding protein (IL-6Ra). IL-6Ra exists in membrane-bound form (CD126) and in soluble form (sIL-6Ra). IL-6 can bind to IL-6Ra to generate complex of IL-6/IL-6Ra/CD130, leading to the activation of the intracellular signaling cascade. Therefore, cells that express only CD130 are sensitive only to exogenous IL-6/IL-6Ra chains complex [18] [19]. CD130 is presented on the surface of most of the cells, while the cell surface receptor for IL-6 is expressed only on the membranes of a single cells, e.g.: megakaryocytes, hepatocytes, neutrophils, monocyte/macrophages, and lymphocytes [20].

In the present study, strong positive correlation coefficient between IL-6 and sIL-6R was revealed. Moreover, the concentrations of sIL-6R were 1.5-fold higher in MM patients as compared to the healthy individuals and significantly higher in the III stage of the disease as compared to the I and II stage of MM, which may indicate that both IL-6 and its soluble receptor might be recognized as a markers of poor prognosis. Our results are in line with findings of Pulkki et al., which indicated that sIL-6R was a poor prognostic factor in MM [21]. Furthermore, in the current study LDH activity significantly correlated with IL-6 and sIL-6R. It should be emphasized that increased LDH activity is a biochemical predictor of poor prognosis in MM [22]. We also revealed that the IL-6 and sIL-6R significantly correlated with the percentage of the plasma cells in the bone marrow.

TNF-α is also involved in MM angiogenesis and recognized as an important factor in a survival for human myeloma cells. In MM, TNF-α is synthesized by stromal and plasma cells [23]. Moreover, it triggers the secretion of proangiogenic cytokines, including IL-6, VEGF [15] [24]. TNF-α and IL-6 stimulate migration of endothelial cells. Synergistic common action of both mentioned cytokines cause significantly higher migration of endothelial cells than the action of each cytokine separately [10] . TNF-α also enhance the transendothelial migration of myeloma cells [25].

In the available literature only, the study of Hatjiharissi et al. concerns the evaluation of TNF-α in MM patients as compared to healthy subjects, in which no significant difference was found [26]. The result is in disagreement with our findings. The discrepancy between these two study could be explained by different number of subjects included into the patients group (in our study MM group included 41 patients; in the study of Hatjiharissi et al. 25 patients).

In the current study, the positive correlation between IL-6 and TNF-α was found, which is with agreement with the investigation of Zdzisinska et al. [27]. It allows us to hypothesize that increased secretion of IL-6 and TNF-α may influence angiogenesis because the progression of MM proceeds at the same time as angiogenesis. Therefore, the inhibition of neovascularyzation by effective chemotherapy would be especially important in the reduction of MM growth [15].

Vascular cell adhesion molecule 1 (VCAM-1) is a transmembrane glycoprotein expressed on vascular endothelial and tumor cells in response to inflammatory cytokines. In the circulation, VCAM-1 is presented in soluble form (sVCAM-1) [28]. Increased sVCAM-1 concentrations were found in various malignancies, such as breast cancer and gastric cancer [28] [29]. It is suggested that leukocyte-endothelial adhesion and neoangiogenesis are linked, because VCAM-1 expression is induced by TNF-α and VEGF, which are angiogenic cytokines [28] [30].

To the best of our knowledge the evaluation of concentrations of adhesion molecules in MM were investigated only by Scudla et al. [31]. The results of Scudla et al. are in agreement with our study, in which significantly higher sVCAM-1 concentrations in MM patients as compared to the control group was observed; sVCAM-1 concentrations were also significantly increasing with the stage of the disease. Additionally, the correlations coefficient between sVCAM-1 and all angiogenic cytokines tested were observed. Obtained results allow us to hypothesize that the increased sVCAM-1 concentrations, beside the pro-angiogenic cytokines and growth factors concentrations, may be used as a marker of angiogenesis in MM.

Growth factors also have an angiogenic potential. The platelet-derived growth factor (PDGF) family consists of four different molecules: PDGF-A,-B,-C, and -D, which may form either homodimers (AA, BB, CC, DD) or heterodimers (AB) [32] [33] . PDGF is expressed by various cells (e.g., epithelial and endothelial cells, macrophages, nervous tissue, vascular and smooth muscle cells, and bone marrow stromal cells), and released by activated platelets and megakaryocytes [34] [35] . PDGF are a major mitogens for cancer development by autocrine and paracrine signaling binding to the PDGFR-a and -β receptors [36]. PDGF-AB is considered as a potent stimulator of angiogenesis in many solid tumours and haematological malignancies, including MM [9]. PDGF-AB influences tumor angiogenesis by direct induction of VEGF production [37].

In the current study, serum PDGF-AB concentrations in MM patients were significantly higher as compared to the healthy subjects and were increasing with the stage of the disease. Furthermore, positive correlations between PDGF-AB and all cytokines tested, as well as the LDH activity and the percentage of plasma cells in the bone marrow were observed. Our study is in the line with the reports of Tsirakis et al., which also revealed positive correlation between serum PDGF-AB and IL-6 concentrations [9]. Our findings, supported by the results of Tsirakis et al., support the hypothesis that increased PDGF-AB concentrations play an important role in angiogenesis in MM [9].

It should be emphasized that this is the first study estimating the diagnostic usefulness of IL-6, sIL-6R, TNF-α, sVCAM-1, PDGF-AB in MM patients. The AUCs analysis revealed that areas under ROC curves for all angiogenic proteins tested were significantly higher than AUC=0.500, which may indicate that these cytokines have potential clinical significance in MM. Among all cytokines tested the largest area under ROC curve and thereby the greatest potential clinical usefulness in MM had sVCAM- 1 and PDGF-AB.


Conclusion

In conclusion, increased IL-6, sIL-6R, TNF-α, sVCAM-1, and PDGF-AB concentrations in MM patients as compared to the healthy subjects may support the hypothesis that these proteins play an important role MM. Additionally, the serum concentrations of all proteins tested were significantly increasing with the stage of the disease, which may indicate that above-mentioned cytokines take part in the progression of MM. It allows us to hypothesize that cytokines analyzed take part in bone marrow neovascularization because the progression of MM proceeds at the same time as angiogenesis. The largest areas under ROC curves were for sVCAM- 1 and PDGF-AB, which may indicate that these proteins have the highest potential clinical usefulness in MM. Certainly, further studies, on larger study group, are needed to explain whether IL-6, sIL-6R, TNF-α, sVCAM-1, and PDGF-AB may be utilized as potential tools for the evaluation of neoangiogenesis in MM patients.


References
  1. Korbet SM, Schwartz MM. Multiple myeloma. J Am Soc Nephrol 2006 Sep;17(9):2533–45.   [CrossRef]   [Pubmed]    Back to citation no. 1
  2. Kyle RA, Gertz MA, Witzig TE, et al. Review of 1027 patients with newly diagnosed multiple myeloma. Mayo Clin Proc 2003 Jan;78(1):21–33.   [CrossRef]   [Pubmed]    Back to citation no. 2
  3. Folkman J. Tumor angiogenesis: Therapeutic implications. N Engl J Med 1971 Nov 18;285(21):1182–6.   [CrossRef]   [Pubmed]    Back to citation no. 3
  4. Vacca A, Ribatti D, Roncali L, et al. Bone marrow angiogenesis and progression in multiple myeloma. Br J Haematol 1994 Jul;87(3):503–8.   [CrossRef]   [Pubmed]    Back to citation no. 4
  5. Sezer O, Niemöller K, Eucker J, et al. Bone marrow microvessel density is a prognostic factor for survival in patients with multiple myeloma. Ann Hematol 2000 Oct;79(10):574–7.   [CrossRef]   [Pubmed]    Back to citation no. 5
  6. Rajkumar SV, Leong T, Roche PC, et al. Prognostic value of bone marrow angiogenesis in multiple myeloma. Clin Cancer Res 2000 Aug;6(8):3111–6.   [Pubmed]    Back to citation no. 6
  7. Sezer O, Jakob C, Eucker J, et al. Serum levels of the angiogenic cytokines basic fibroblast growth factor (bFGF), vascular endothelial growth factor (VEGF) and hepatocyte growth factor (HGF) in multiple myeloma. Eur J Haematol 2001 Feb;66(2):83–8.   [CrossRef]   [Pubmed]    Back to citation no. 7
  8. Jakob C, Sterz J, Zavrski I, et al. Angiogenesis in multiple myeloma. Eur J Cancer 2006 Jul;42(11):1581–90.   [CrossRef]   [Pubmed]    Back to citation no. 8
  9. Tsirakis G, Pappa CA, Kanellou P, et al. Role of platelet-derived growth factor-AB in tumour growth and angiogenesis in relation with other angiogenic cytokines in multiple myeloma. Hematol Oncol 2012 Sep;30(3):131–6.   [CrossRef]   [Pubmed]    Back to citation no. 9
  10. Alexandrakis MG, Passam FJ, Ganotakis E, et al. Bone marrow microvascular density and angiogenic growth factors in multiple myeloma. Clin Chem Lab Med 2004;42(10):1122–6.   [CrossRef]   [Pubmed]    Back to citation no. 10
  11. Urba ska-Rys H, Wierzbowska A, Robak T. Circulating angiogenic cytokines in multiple myeloma and related disorders. Eur Cytokine Netw 2003 Jan-Mar;14(1):40–51.   [Pubmed]    Back to citation no. 11
  12. Tsirakis G, Pappa CA, Kaparou M, et al. Assessment of proliferating cell nuclear antigen and its relationship with proinflammatory cytokines and parameters of disease activity in multiple myeloma patients. Eur J Histochem 2011;55(3):e21.   [CrossRef]   [Pubmed]    Back to citation no. 12
  13. International Myeloma Working Group. Criteria for the classification of monoclonal gammopathies, multiple myeloma and related disorders: a report of the International Myeloma Working Group. Br J Haematol 2003 Jun;121(5):749–57.   [CrossRef]   [Pubmed]    Back to citation no. 13
  14. Durie BG, Salmon SE. A clinical staging system for multiple myeloma. Correlation of measured myeloma cell mass with presenting clinical features, response to treatment, and survival. Cancer 1975 Sep;36(3):842–54.   [CrossRef]   [Pubmed]    Back to citation no. 14
  15. Alexandrakis MG, Passam FH, Boula A, et.al. Relationship between circulating serum soluble interleukin-6 receptor and the angiogenic cytokines basic fibroblast growth factor and vascular endothelial growth factor in multiple myeloma. Ann Hematol 2003 Jan;82(1):19–23.   [Pubmed]    Back to citation no. 15
  16. Lauta VM. A review of the cytokine network in multiple myeloma: diagnostic, prognostic, and therapeutic implications. Cancer 2003 May 15;97(10):2440–52.   [CrossRef]   [Pubmed]    Back to citation no. 16
  17. Klein B, Zhang XG, Jourdan M, Portier M, Bataille R. Interleukin-6 is a major myeloma cell growth factor in vitro and in vivo especially in patients with terminal disease. Curr Top Microbiol Immunol 1990;166:23–31.   [CrossRef]   [Pubmed]    Back to citation no. 17
  18. Barillé S, Bataille R, Amiot M. The role of interleukin-6 and interleukin-6/interleukin-6 receptor-alpha complex in the pathogenesis of multiple myeloma. Eur Cytokine Netw 2000 Dec;11(4):546–51.   [Pubmed]    Back to citation no. 18
  19. Naka T, Nishimoto N, Kishimoto T. The paradigm of IL-6: from basic science to medicine. Arthritis Res 2002;4 Suppl 3:S233–42.   [Pubmed]    Back to citation no. 19
  20. Jones SA, Horiuchi S, Topley N, Yamamoto N, Fuller GM. The soluble interleukin 6 receptor: mechanisms of production and implications in disease. FASEB J 2001 Jan;15(1):43–58.   [CrossRef]   [Pubmed]    Back to citation no. 20
  21. Pulkki K, Pelliniemi TT, Rajamäki A, Tienhaara A, Laakso M, Lahtinen R. Soluble interleukin-6 receptor as a prognostic factor in multiple myeloma. Finnish Leukaemia Group. Br J Haematol 1996 Feb;92(2):370–4.   [Pubmed]    Back to citation no. 21
  22. Dimopoulos MA, Barlogie B, Smith TL, Alexanian R. High serum lactate dehydrogenase level as a marker for drug resistance and short survival in multiple myeloma. Ann Intern Med 1991 Dec 15;115(12):931–5.   [CrossRef]   [Pubmed]    Back to citation no. 22
  23. Jourdan M, Tarte K, Legouffe E, Brochier J, Rossi JF, Klein B. Tumor necrosis factor is a survival and proliferation factor for human myeloma cells. Eur Cytokine Netw 1999 Mar;10(1):65–70.   [Pubmed]    Back to citation no. 23
  24. Lee C, Oh JI, Park J, et al. TNF a mediated IL-6 secretion is regulated by JAK/STAT pathway but not by MEK phosphorylation and AKT phosphorylation in U266 multiple myeloma cells. Biomed Res Int 2013;2013:580135.   [Pubmed]    Back to citation no. 24
  25. Jöhrer K, Janke K, Krugmann J, Fiegl M, Greil R. Transendothelial migration of myeloma cells is increased by tumor necrosis factor (TNF)-alpha via TNF receptor 2 and autocrine up-regulation of MCP-1. Clin Cancer Res 2004 Mar 15;10(6):1901–10.   [Pubmed]    Back to citation no. 25
  26. Hatjiharissi E, Terpos E, Papaioannou M, et al. The combination of intermediate doses of thalidomide and dexamethasone reduces bone marrow micro-vessel density but not serum levels of angiogenic cytokines in patients with refractory/relapsed multiple myeloma. Hematol Oncol 2004 Dec;22(4):159–68.   [CrossRef]   [Pubmed]    Back to citation no. 26
  27. Zdzisinska B, Bojarska-Junak A, Dmoszynska A, Kandefer-Szerszen M. Abnormal cytokine production by bone marrow stromal cells of multiple myeloma patients in response to RPMI8226 myeloma cells. Arch Immunol Ther Exp (Warsz) 2008 May-Jun;56(3):207–21.   [Pubmed]    Back to citation no. 27
  28. Byrne GJ, Ghellal A, Iddon J et al. Serum soluble vascular cell adhesion molecule-1: Role as a surrogate marker of angiogenesis. J Natl Cancer Inst 2000 Aug 16;92(16):1329–36.   [CrossRef]   [Pubmed]    Back to citation no. 28
  29. Velikova G, Banks RE, Gearing A, et al. Circulating soluble adhesion molecules E-cadherin, E-selectin, intercellular adhesion molecule-1 (ICAM-1) and vascular cell adhesion molecule-1 (VCAM-1) in patients with gastric cancer. Br J Cancer 1997;76(11):1398–404.   [CrossRef]   [Pubmed]    Back to citation no. 29
  30. Jain RK, Koenig GC, Dellian M, Fukumura D, Munn LL, Melder RJ. Leukocyte-endothelial adhesion and angiogenesis in tumors. Cancer Metastasis Rev 1996 Jun;15(2):195–204.   [CrossRef]   [Pubmed]    Back to citation no. 30
  31. Scudla V, Budíková M, Bacovský J, Opíchalová D, Farbiaková V. Relation of serum levels of the soluble cytoadhesion molecules sVCAM-1 and sICAM-1 to selected factors in the cytokine network in multiple myeloma. Cas Lek Cesk 2000 Jul 5;139(13):401–6.   [Pubmed]    Back to citation no. 31
  32. Dührsen U, Martinez T, Vohwinkel G, et al. Effects of vascular endothelial and platelet-derived growth factor receptor inhibitors on long-term cultures from normal human bone marrow. Growth Factors 2001;19(1):1–17.   [Pubmed]    Back to citation no. 32
  33. Betsholtz C, Karlsson L, Lindahl P. Developmental roles of platelet-derived growth factors. Bioessays 2001 Jun;23(6):494–507.   [CrossRef]   [Pubmed]    Back to citation no. 33
  34. Andrae J, Gallini R, Betsholtz C. Role of platelet-derived growth factors in physiology and medicine. Genes Dev 2008 May 15;22(10):1276–312.   [CrossRef]   [Pubmed]    Back to citation no. 34
  35. Abboud SL. A bone marrow stromal cell line is a source and target for platelet-derived growth factor. Blood 1993 May 15;81(10):2547–53.   [Pubmed]    Back to citation no. 35
  36. Lewis NL. The platelet-derived growth factor receptor as a therapeutic target. Curr Oncol Rep 2007 Mar;9(2):89-95. 17288872, 10.1007/s11912-007-0003–6   [CrossRef]   [Pubmed]    Back to citation no. 36
  37. Wang D, Huang HJ, Kazlauskas A, Cavenee WK. Induction of vascular endothelial growth factor expression in endothelial cells by platelet-derived growth factor through the activation of phosphatidylinositol 3-kinase. Cancer Res 1999 Apr 1;59(7):1464–72.   [Pubmed]    Back to citation no. 37
[HTML Abstract]   [PDF Full Text]

Author Contributions:
Joanna Kamińska – Substantial contributions to conception and design, Acquisition of data, Analysis and interpretation of data, Drafting the article, Revising it critically for important intellectual content, Final approval of the version to be published
Olga M. Koper – Substantial contributions to conception and design, Analysis and interpretation of data, Drafting the article, Revising it critically for important intellectual content, Final approval of the version to be published
Violetta Dymicka-Piekarska – Analysis and interpretation of data, Revising it critically for important intellectual content, Final approval of the version to be published
Elżbieta Motybel – Analysis and interpretation of data, Revising it critically for important intellectual content, Final approval of the version to be published
Janusz Kłoczko – Analysis and interpretation of data, Revising it critically for important intellectual content, Final approval of the version to be published
Halina Kemona – Analysis and interpretation of data, Revising it critically for important intellectual content, Final approval of the version to be published
Guarantor of submission
The corresponding author is the guarantor of submission.
Source of support
None
Conflict of interest
Authors declare no conflict of interest.
Copyright
© 2015 Joanna Kamińska et al. This article is distributed under the terms of Creative Commons Attribution License which permits unrestricted use, distribution and reproduction in any medium provided the original author(s) and original publisher are properly credited. Please see the copyright policy on the journal website for more information.



About The Authors

Joanna Kamińska is a Researcher at the Department of Clinical Laboratory Diagnostic of the Medical University of Bialystok (Poland). She earned undergraduate degree PhD from the Department of Clinical Laboratory Diagnostic of the Medical University of Bialystok (Poland). The aim of her doctoral thesis was the evaluation of the chosen thrombocytopoiesis parameters in multiple myeloma patients depending on the sex and the stage of the disease. She has published 15 research papers in national and international academic journals and authored three chapters in books. Her research interests include the angiogenesis, thrombopoiesis and the role of the platelets in multiple myeloma, the significance of chemokines-mediated inflammation in chosen diseases of the central nervous system and novels in laboratory examination of cerebrospinal fluid and other fluids from body cavities. In future, she intends to pursue the clinical significance of sCD40L in multiple myeloma and the role of platelet-monocyte aggregates as well as chosen chemokines in myocardial infarction. Moreover, she intends to pursue the role of blood brain barrier (BBB) in the diseases concerning the central nervous system in future.



Olga M. Koper is a Researcher at the Department of Clinical Laboratory Diagnostics of the Medical University of Bialystok, Poland. She earned undergraduate degree PhD from the Department of Clinical Laboratory Diagnostic of the Medical University of Bialystok (Poland). The aim of her doctoral thesis was the evaluation of the chosen thrombocytopoiesis parameters in type 2 diabetes patients depending on the glycosylated hemoglobin. She has published 13 research papers in national and international academic journals. She is the author of microscopic cells photos (these photos were presented on pages from 28 to 118 in the monographic book entitled "Body fluids- assay and interpretation" which is recommended by the Polish National Chamber of Laboratory Diagnosticians). Her areas of scientific interests include chosen thrombopoiesis parameters, markers of platelets activation and platelet morphology in type 2 diabetes depending on glycemic control as well as in multiple myeloma depending on the sex and the stage of the disease advancement. She intends to pursue the role of blood brain barrier (BBB) and chemokines in the diseases concerning the central nervous system in future.



Violetta Dymicka-Piekarska is Associate Professor, and is a Researcher at Department of Clinical Laboratory Diagnostics, Medical University of Bialystok, Poland. She earned the undergraduate degree PhD from Department of Clinical Laboratory Diagnostics, Medical University of Bialystok, Poland and postgraduate degree form Associate Professor from Department of Clinical Laboratory Diagnostics, Medical University of Bialystok, Poland. She has published 40 research papers in national and international academic journals and authored three books. Her research interests include platelet activation and function in colorectal cancer and myocardial infarction and inflammation, searching for new biomarkers in colorectal cancer. She intends to pursue platelet-monocyte aggregates assessed by flow cytometry and role of chemokines in MI in future.



Elzbieta Motybel is a researcher at Department of Clinical Laboratory Diagnostics of Medical University of Bialystok, Poland. She earned the undergraduate degree MSc from the Department of Clinical Laboratory Diagnostics of Medical University of Bialystok, Poland. She has published 5 research papers in national and international academic journals. Her research interests include novel biomarkers in coronary heart disease. She intends to pursue the role of adhesion molecules in the prognosis of myocardial infarction in future.



Janusz Kloczko is received MD degree in 1973, PhD degree in 1979 and the title of professor in 1995, all from Medical Academy of Bialystok. He has published 206 research papers in national and international academic journals. Impact Factor of full papers is 271.057; H-index: 21; quotation: 2674. He is co-author of 6 books. The main research interest include blood coagulation and hematoproliferative disorders.



Halina Kemona is Professor Halina Kemona is Head of the Department of Clinical Laboratory Diagnostics of the Medical University of Bialystok, Poland. She earned the undergraduate degree PhD from Department of Clinical Laboratory Diagnostics of the Medical University of Bialystok, Poland and postgraduate degree form Associate Professor from Department of Clinical Laboratory Diagnostics of the Medical University of Bialystok, Poland. She has published 192 research papers in national and international academic journals and authored 5 books. Her research interests include trombocytopoiesis, the role of platelets in non-specific immune response, activation and reactivity of platelets in the diseases of the circulatory system, neoplastic and parasitic diseases as well as the evaluation of the concentrations of adhesion molecules in different types of pathologic conditions. She intends to pursue platelet-monocyte aggregates assessed by flow cytometry and role of chemokines in MI in future.




  Home line About the Journal line Aim and Scope line Open Access line Archives
Apply as Editor line Apply as Reviewer line Submit Reviews - Editors line Submit Reviews - Reviewers
Instructions for Authors line Templates to Use line Copyright Form line Author Checklist
Online Submission line Email Submission line Submit Revision line Submit All Forms line Submit Page Proofs
Terms of Service line Privacy policy line Disclaimer line FAQ line Contact: Journal line Contact: Edorium Journals line Site Map
 
  Copyright © 2017. Edorium. All rights reserved.