- Email: [email protected]
The role of nuclear factor κB on angiogenesis regulation through monocyte chemotactic protein-1 in myeloma
Medical Hypotheses (2006) 66, 384–386
http://intl.elsevierhealth.com/journals/mehy
The role of nuclear factor jB on angiogenesis regulation through monocyte chemotactic protein-1 in myeloma Sanja Stifter
*
Pathology Department, School of medicine, Brac´e Branchetta 20, 51000 Rijeka, Croatia Received 2 August 2005; accepted 30 August 2005
Summary Multiple myeloma is malignant proliferation of plasma cells and plasmacytoid cells. Vascular endothelial growth factor (VEGF) is known to be one of the most important if not the main regulator of physiologic and pathologic angiogenesis which triggers growth, survival and migration of myeloma cells. It has been shown that circulating mature or bone marrow driven endothelial precursor cells play an important role in neovascularisation. In accordance with these observations, current therapeutic approaches to myeloma include VEGF inhibitors. Since angiogenesis inhibitors are heterogeneous in origin and potency, and their growing list includes many products with a different function it would be of benefit to determine the key molecule produced by transformed plasma cells which stimulates bone marrow environment to produce their homing ‘‘milieu’’ secreting different cytokines such as VEGF, IL-6, and monocyte chemotactic protein-1 (MCP-1). This molecule could be nuclear factor kappa B (NF-jB). It has been confirmed that myeloma cells express and produce NF-jB. It has been established recently that by blocking NF-jB production MCP-1 secretion is reduced up to 60%. If so, this would also reduce production of IL-6 and VEGF, since MCP-1 upregulates VEGF and IL-6 production. This way one could make bone marrow bad environment for myeloma cells to settle, followed with no disease progression. Targeting to NF-jB intended to inhibits its activation with receptor antagonist would possibly significantly inhibit lipopolysaccharide-induced IL-6, MCP-1 and TNF-a. All of them being stimulators for VEGF secretion and indirectly activation of angiogenesis. To conclude, angiogenesis could be induced by myeloma cells themselves through NF-jB activation pathway and by inhibiting its activation we might prevent myeloma expansion in bone marrow and progression of the disease by decreased MCP-1 secretion. c 2005 Elsevier Ltd. All rights reserved.
Introduction The myeloma is B-cell neoplasm characterised by bone marrow infiltration with malignant plasma cells which produce and secrete fragments of * Tel.: +385 51 325 813; fax: +385 51 325 810. E-mail address: [email protected].
monoclonal Ig despite improved understanding of MM biology molecular basis of the disease remaining unclear [1]. Transformation has been occurring in the postgerminal centre of B-cells carrying somatic hypermutated gene of Ig heavy chain. These plasmablastic precursor cells colonise the bone marrow, clonally propagate and differentiate into
0306-9877/$ - see front matter c 2005 Elsevier Ltd. All rights reserved. doi:10.1016/j.mehy.2005.08.048
The role of nuclear factor jB on angiogenesis regulation slowly proliferating population of the myeloma cells, under the influence of the various cytokines [2]. Angiogenesis, the biological phenomenon of new blood vessel formation, increases significantly in the bone marrow along the spectrum of plasma cell disorders and becomes a prominent feature in active MM [3]. Angiogenesis is a multi-step process that includes endothelial cell (EC) proliferation, migration, basement membrane degradation, and new lumen organisation [4,5]. Within a given microenvironment, a net balance between pro- and antiangiogenic regulators released from activated endothelial cells (ECs), monocytes, smooth muscle cells and platelets determines the angiogenic response [6]. The principal growth factors driving angiogenesis are vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), and hepatocyte growth factor. Other positive regulators are angiotropin, angiogenin, epidermal growth factor, granulocyte colony-stimulating factor, interleukin-1 (IL-1), IL-6, IL-8, platelet-derived growth factor (PDGF), tumor necrosis factor-a (TNF-a), and matrix protein [7]. The mechanism of angiogenesis in the induction of MM primarily goes through VEGF production. VEGF starts Flt-1 phosphorylation (VEGFR-1) and the activation of MEK/ERK and PI-3K/PKalpha signal cascade, by promoting slow proliferation and marked migration of the myeloma. The myeloma cells in minor part produce VEGF in autocrine fashion, while more pronounced is the production mediated by stromal cells (paracrine stimulation) [8]. It is known that besides VEGF, stromal cells and osteoblasts produce other numerous cytokines like MCP-1 and IL-6 which are essential for growth of the myeloma cells [9]. MCP-1 is the member of the Chemokine family (chemotactic cytokines) with the main role in the initiation and progression of the inflammation. Its binding of specific receptor sites (CCR2) activates secretion of numerous pro inflammatory signals and monocyte chemotactic activity [10]. Almost any growth of tumour is to some extent associated with an inflammatory reaction that may be protumorigenic by inducing tumour-associated angiogenesis [9]. MCP-1 is also known as potent proangiogenic chemokine [11]. According to these findings, one could conclude that the main or dominant factor in bone marrow neovascularisation is produced by matrix cells as ECs. It is my belief that myeloma cells that overexpress NF-jB promote its regulatory pathway and its
385
activation directly stimulates secretion of cytokines like MCP-1.
Hypotheses Since angiogenesis inhibitors are heterogeneous in origin and potency, and their growing list includes many products with a different function it would be of benefit to determine the key molecule produced by transformed plasma cells which stimulate bone marrow environment to produce their homing ‘‘milieu’’ secreting different cytokines such as VEGF, IL-6 and MCP-1. This molecule could be activated nuclear factor kappaB (NF-jB).
Discussion In the myeloma, which is by definition B-cell neoplasm associated with clonal proliferation of malignant plasma cells, the presence of somatic hypermutations of the immunoglobulin variable region genes of the plasma cells suggests that malignant transformation occurs in a B cell that has traversed the germinal centres of lymph nodes. However, the hypoproliferative nature of the myeloma has led to the hypothesis that the bulk of the tumour arises from a transformed B cell with the capacity for both self-renewal and production of terminally differentiated progeny [2]. Unfortunately, it remains fatal despite advances in highdose chemotherapy and transplantation with the median survival of the patients’ aged 3–4 years. Recent therapeutic approaches target mostly to molecules responsible for the maintenance and the tumour growth control. Yet, the problem of specificity of treatment with the intention of minimising undesirable toxicity remains. For the treatment of the MM, it is of critical importance to develop specific agents that target the required molecules. Some authors have included in their research NF-jB and shown its connection with multiple processes of oncogenesis, including cell cycle, apoptosis, differentiation and migration. The therapeutic strategy aims towards molecules responsible for maintaining and growth of the tumoural cells. Lately, one of the most important molecules in this strategy represents NF-jB, related to the multiple processes of oncogenesis, including apoptosis control, cell cycle, differentiation and migration [12]. It has been described that NF-jB upregulates secretions of some cytokines like VEGF, MCP-1 and IL-6 [13,14]. It has been
386 shown that blocking NF-jB reduces MCP-1 secretion up to 60% and increases IL-6 production [14]. The importance of NF-jB in MM has till now been investigated through its contribution in apoptosis and cell cycle control, while its role in the activation and regulation of angiogenesis through chemokine activation of VEGF and MCP-1 has not been researched yet [15,16]. The bone marrow angiogenesis is progressively increasing with progression of myeloma. This observation is well known, but the exact mechanism of the bone marrow angiogenesis is still in some aspects obscure. The idea of VEGF being regulated by NF-jB has been proposed by Watanabe et al., but the additional missing link could be cytokine MCP-1. Targeting to NF-jB intended to inhibit its activation with receptor antagonist would possibly significantly inhibit lipopolysaccharide-induced IL-6, MCP-1 and TNF-a. In the bone marrow, this should be taken into consideration and aimed with NF-jB like cysteinyl leukotriene 1 receptor antagonist known as Montelukast [17].
Acknowledgements I thank Prof. Dr. S.C. Nives Jonjic ´ for mentoring and guidance. This work was supported by Grant No. 0062060, from the Ministry of Science, Education and Sport of the Republic of Croatia.
References [1] Kastrinakis NG, Gorgoulis VG, Foukas PG, Dimopoulos MA, Kittas C. Molecular aspects of multiple myeloma. Ann Oncol 2000;11(10):1217–28. [2] Chesi M, Bergsagel PL, Kuehl WM. The enigma of ectopic expression of FGFR3 in multiple myeloma:a critical initiating event or just a target for mutational activation during tumor progression. Curr Opin Hematol 2002;9:288–93. [3] Rajkumar SV, Mesa RA, Fonseca R, et al. Bone marrow angiogenesis in 400 patients with monoclonal gammapathy of undetermined significance, multiple myeloma, and primary amyloidosis. Clin Cancer Res 2002;8:2210–6.
Stifter [4] Giuliani N, Colla S, Morandi F, Rizzoli V. Angiopoietin-1 and myeloma-induced angiogenesis. Leuk Lymphoma 2005; 46(1):29–33. [5] Andersen NF, Standal T, Nielsen JL, Heickendorff L, Borset M, Sorensen FB, et al. Syndecan-1 and angiogenic cytokines in multiple myeloma: correlation with bone marrow angiogenesis and survival. Br J Haematol 2005;128(2): 210–7. [6] Hideshima T, Bergsagel PL, Kuehl WM, Anderson KC. Advances in biology of multiple myeloma: clinical applications. Blood 2004;104(3):607–18. [7] Harousseau JL, Shaughnessy Jr J, Richardson P. Multiple myeloma. Hematology (Am Soc Hematol Educ Program) 2004:237–56. [8] Verheul HMW, Voest EE, Schlingemann RO. Are tumors angiogenesis-dependent? J Pathol 2004;202:5–13. [9] Goede V, Brogelli L, Ziche M, Augustin HG. Induction of inflammatory angiogenesis by monocyte chemoattractant protein-1. Int J Cancer 1999;82(5):765–70. [10] Vande Broek I, Asosingh K, Vanderkerken K, Straetmans N, Van Camp B, Van Riet I. Chemokine receptor CCR2 is expressed by human multiple myeloma cells and mediates migration to bone marrow stromal cell-produced monocyte chemotactic proteins MCP-1, -2 and -3. Br J Cancer 2003;88(6):855–62. [11] Hee Hong K, Ryu J, Hoon Han K. Monocytechemoattractant protein-1-induced angiogenesis is mediated by vascular endothelial growth factor-A. Blood 2005;105(4):1405–7. [12] Dai Y, Rahmani M, Dent P, Grant S. Blockade of histone deacetylase inhibitor-induced RelA/p65 acetylation and NF-jB activation potentiates apoptosis in leukemia cells through a process mediated by oxidative damage, XIAP downregulation, and c-Jun N-terminal kinase 1 activation. Mol Cell Biol 2005;25(13):5429–44. [13] Sengul S, Zwizinski C, Simon EE, Kapasi A, Singhal PC, Batuman V. Endocytosis of light chains induces cytokines through activation of NF-jB in human proximal tubule cells. Kidney Int 2002;62(6):1977–88. [14] Fain JN, Madan AK. Regulation of monocyte chemoattractant protein 1 (MCP-1) release by explants of human visceral adipose tissue. Int J Obes Relat Metab Disord 2005(Jul 5) [Epub ahead of print]. [15] Mancuso P, Calleri A, Cassi C, Gobbi A, Capillo M, Pruneri G, et al. Circulating endothelial cells as a novel marker of angiogenesis. Adv Exp Med Biol 2003;522:83–97. [16] Watanabe M, Dewan MZ, Okamura T, et al. A novel NF-jB inhibitor DHMEQ selectively targets constitutive NF-jB activity and induces apoptosis of multiple myeloma cells in vitro and in vivo. Int J Cancer 2005;114:32–8. [17] Maeba S, Ichiyama T, Ueno Y, Makata H, Matsubara T, Furukawa S. Effect of montelukast on nuclear factor jB activation and proinflammatory molecules. Ann Allergy Asthma Immunol 2005;94(6):670–4.
http://intl.elsevierhealth.com/journals/mehy
The role of nuclear factor jB on angiogenesis regulation through monocyte chemotactic protein-1 in myeloma Sanja Stifter
*
Pathology Department, School of medicine, Brac´e Branchetta 20, 51000 Rijeka, Croatia Received 2 August 2005; accepted 30 August 2005
Summary Multiple myeloma is malignant proliferation of plasma cells and plasmacytoid cells. Vascular endothelial growth factor (VEGF) is known to be one of the most important if not the main regulator of physiologic and pathologic angiogenesis which triggers growth, survival and migration of myeloma cells. It has been shown that circulating mature or bone marrow driven endothelial precursor cells play an important role in neovascularisation. In accordance with these observations, current therapeutic approaches to myeloma include VEGF inhibitors. Since angiogenesis inhibitors are heterogeneous in origin and potency, and their growing list includes many products with a different function it would be of benefit to determine the key molecule produced by transformed plasma cells which stimulates bone marrow environment to produce their homing ‘‘milieu’’ secreting different cytokines such as VEGF, IL-6, and monocyte chemotactic protein-1 (MCP-1). This molecule could be nuclear factor kappa B (NF-jB). It has been confirmed that myeloma cells express and produce NF-jB. It has been established recently that by blocking NF-jB production MCP-1 secretion is reduced up to 60%. If so, this would also reduce production of IL-6 and VEGF, since MCP-1 upregulates VEGF and IL-6 production. This way one could make bone marrow bad environment for myeloma cells to settle, followed with no disease progression. Targeting to NF-jB intended to inhibits its activation with receptor antagonist would possibly significantly inhibit lipopolysaccharide-induced IL-6, MCP-1 and TNF-a. All of them being stimulators for VEGF secretion and indirectly activation of angiogenesis. To conclude, angiogenesis could be induced by myeloma cells themselves through NF-jB activation pathway and by inhibiting its activation we might prevent myeloma expansion in bone marrow and progression of the disease by decreased MCP-1 secretion. c 2005 Elsevier Ltd. All rights reserved.
Introduction The myeloma is B-cell neoplasm characterised by bone marrow infiltration with malignant plasma cells which produce and secrete fragments of * Tel.: +385 51 325 813; fax: +385 51 325 810. E-mail address: [email protected].
monoclonal Ig despite improved understanding of MM biology molecular basis of the disease remaining unclear [1]. Transformation has been occurring in the postgerminal centre of B-cells carrying somatic hypermutated gene of Ig heavy chain. These plasmablastic precursor cells colonise the bone marrow, clonally propagate and differentiate into
0306-9877/$ - see front matter c 2005 Elsevier Ltd. All rights reserved. doi:10.1016/j.mehy.2005.08.048
The role of nuclear factor jB on angiogenesis regulation slowly proliferating population of the myeloma cells, under the influence of the various cytokines [2]. Angiogenesis, the biological phenomenon of new blood vessel formation, increases significantly in the bone marrow along the spectrum of plasma cell disorders and becomes a prominent feature in active MM [3]. Angiogenesis is a multi-step process that includes endothelial cell (EC) proliferation, migration, basement membrane degradation, and new lumen organisation [4,5]. Within a given microenvironment, a net balance between pro- and antiangiogenic regulators released from activated endothelial cells (ECs), monocytes, smooth muscle cells and platelets determines the angiogenic response [6]. The principal growth factors driving angiogenesis are vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), and hepatocyte growth factor. Other positive regulators are angiotropin, angiogenin, epidermal growth factor, granulocyte colony-stimulating factor, interleukin-1 (IL-1), IL-6, IL-8, platelet-derived growth factor (PDGF), tumor necrosis factor-a (TNF-a), and matrix protein [7]. The mechanism of angiogenesis in the induction of MM primarily goes through VEGF production. VEGF starts Flt-1 phosphorylation (VEGFR-1) and the activation of MEK/ERK and PI-3K/PKalpha signal cascade, by promoting slow proliferation and marked migration of the myeloma. The myeloma cells in minor part produce VEGF in autocrine fashion, while more pronounced is the production mediated by stromal cells (paracrine stimulation) [8]. It is known that besides VEGF, stromal cells and osteoblasts produce other numerous cytokines like MCP-1 and IL-6 which are essential for growth of the myeloma cells [9]. MCP-1 is the member of the Chemokine family (chemotactic cytokines) with the main role in the initiation and progression of the inflammation. Its binding of specific receptor sites (CCR2) activates secretion of numerous pro inflammatory signals and monocyte chemotactic activity [10]. Almost any growth of tumour is to some extent associated with an inflammatory reaction that may be protumorigenic by inducing tumour-associated angiogenesis [9]. MCP-1 is also known as potent proangiogenic chemokine [11]. According to these findings, one could conclude that the main or dominant factor in bone marrow neovascularisation is produced by matrix cells as ECs. It is my belief that myeloma cells that overexpress NF-jB promote its regulatory pathway and its
385
activation directly stimulates secretion of cytokines like MCP-1.
Hypotheses Since angiogenesis inhibitors are heterogeneous in origin and potency, and their growing list includes many products with a different function it would be of benefit to determine the key molecule produced by transformed plasma cells which stimulate bone marrow environment to produce their homing ‘‘milieu’’ secreting different cytokines such as VEGF, IL-6 and MCP-1. This molecule could be activated nuclear factor kappaB (NF-jB).
Discussion In the myeloma, which is by definition B-cell neoplasm associated with clonal proliferation of malignant plasma cells, the presence of somatic hypermutations of the immunoglobulin variable region genes of the plasma cells suggests that malignant transformation occurs in a B cell that has traversed the germinal centres of lymph nodes. However, the hypoproliferative nature of the myeloma has led to the hypothesis that the bulk of the tumour arises from a transformed B cell with the capacity for both self-renewal and production of terminally differentiated progeny [2]. Unfortunately, it remains fatal despite advances in highdose chemotherapy and transplantation with the median survival of the patients’ aged 3–4 years. Recent therapeutic approaches target mostly to molecules responsible for the maintenance and the tumour growth control. Yet, the problem of specificity of treatment with the intention of minimising undesirable toxicity remains. For the treatment of the MM, it is of critical importance to develop specific agents that target the required molecules. Some authors have included in their research NF-jB and shown its connection with multiple processes of oncogenesis, including cell cycle, apoptosis, differentiation and migration. The therapeutic strategy aims towards molecules responsible for maintaining and growth of the tumoural cells. Lately, one of the most important molecules in this strategy represents NF-jB, related to the multiple processes of oncogenesis, including apoptosis control, cell cycle, differentiation and migration [12]. It has been described that NF-jB upregulates secretions of some cytokines like VEGF, MCP-1 and IL-6 [13,14]. It has been
386 shown that blocking NF-jB reduces MCP-1 secretion up to 60% and increases IL-6 production [14]. The importance of NF-jB in MM has till now been investigated through its contribution in apoptosis and cell cycle control, while its role in the activation and regulation of angiogenesis through chemokine activation of VEGF and MCP-1 has not been researched yet [15,16]. The bone marrow angiogenesis is progressively increasing with progression of myeloma. This observation is well known, but the exact mechanism of the bone marrow angiogenesis is still in some aspects obscure. The idea of VEGF being regulated by NF-jB has been proposed by Watanabe et al., but the additional missing link could be cytokine MCP-1. Targeting to NF-jB intended to inhibit its activation with receptor antagonist would possibly significantly inhibit lipopolysaccharide-induced IL-6, MCP-1 and TNF-a. In the bone marrow, this should be taken into consideration and aimed with NF-jB like cysteinyl leukotriene 1 receptor antagonist known as Montelukast [17].
Acknowledgements I thank Prof. Dr. S.C. Nives Jonjic ´ for mentoring and guidance. This work was supported by Grant No. 0062060, from the Ministry of Science, Education and Sport of the Republic of Croatia.
References [1] Kastrinakis NG, Gorgoulis VG, Foukas PG, Dimopoulos MA, Kittas C. Molecular aspects of multiple myeloma. Ann Oncol 2000;11(10):1217–28. [2] Chesi M, Bergsagel PL, Kuehl WM. The enigma of ectopic expression of FGFR3 in multiple myeloma:a critical initiating event or just a target for mutational activation during tumor progression. Curr Opin Hematol 2002;9:288–93. [3] Rajkumar SV, Mesa RA, Fonseca R, et al. Bone marrow angiogenesis in 400 patients with monoclonal gammapathy of undetermined significance, multiple myeloma, and primary amyloidosis. Clin Cancer Res 2002;8:2210–6.
Stifter [4] Giuliani N, Colla S, Morandi F, Rizzoli V. Angiopoietin-1 and myeloma-induced angiogenesis. Leuk Lymphoma 2005; 46(1):29–33. [5] Andersen NF, Standal T, Nielsen JL, Heickendorff L, Borset M, Sorensen FB, et al. Syndecan-1 and angiogenic cytokines in multiple myeloma: correlation with bone marrow angiogenesis and survival. Br J Haematol 2005;128(2): 210–7. [6] Hideshima T, Bergsagel PL, Kuehl WM, Anderson KC. Advances in biology of multiple myeloma: clinical applications. Blood 2004;104(3):607–18. [7] Harousseau JL, Shaughnessy Jr J, Richardson P. Multiple myeloma. Hematology (Am Soc Hematol Educ Program) 2004:237–56. [8] Verheul HMW, Voest EE, Schlingemann RO. Are tumors angiogenesis-dependent? J Pathol 2004;202:5–13. [9] Goede V, Brogelli L, Ziche M, Augustin HG. Induction of inflammatory angiogenesis by monocyte chemoattractant protein-1. Int J Cancer 1999;82(5):765–70. [10] Vande Broek I, Asosingh K, Vanderkerken K, Straetmans N, Van Camp B, Van Riet I. Chemokine receptor CCR2 is expressed by human multiple myeloma cells and mediates migration to bone marrow stromal cell-produced monocyte chemotactic proteins MCP-1, -2 and -3. Br J Cancer 2003;88(6):855–62. [11] Hee Hong K, Ryu J, Hoon Han K. Monocytechemoattractant protein-1-induced angiogenesis is mediated by vascular endothelial growth factor-A. Blood 2005;105(4):1405–7. [12] Dai Y, Rahmani M, Dent P, Grant S. Blockade of histone deacetylase inhibitor-induced RelA/p65 acetylation and NF-jB activation potentiates apoptosis in leukemia cells through a process mediated by oxidative damage, XIAP downregulation, and c-Jun N-terminal kinase 1 activation. Mol Cell Biol 2005;25(13):5429–44. [13] Sengul S, Zwizinski C, Simon EE, Kapasi A, Singhal PC, Batuman V. Endocytosis of light chains induces cytokines through activation of NF-jB in human proximal tubule cells. Kidney Int 2002;62(6):1977–88. [14] Fain JN, Madan AK. Regulation of monocyte chemoattractant protein 1 (MCP-1) release by explants of human visceral adipose tissue. Int J Obes Relat Metab Disord 2005(Jul 5) [Epub ahead of print]. [15] Mancuso P, Calleri A, Cassi C, Gobbi A, Capillo M, Pruneri G, et al. Circulating endothelial cells as a novel marker of angiogenesis. Adv Exp Med Biol 2003;522:83–97. [16] Watanabe M, Dewan MZ, Okamura T, et al. A novel NF-jB inhibitor DHMEQ selectively targets constitutive NF-jB activity and induces apoptosis of multiple myeloma cells in vitro and in vivo. Int J Cancer 2005;114:32–8. [17] Maeba S, Ichiyama T, Ueno Y, Makata H, Matsubara T, Furukawa S. Effect of montelukast on nuclear factor jB activation and proinflammatory molecules. Ann Allergy Asthma Immunol 2005;94(6):670–4.