Next Article in Journal
Inhibition of Heme Oxygenase-1 Activity Enhances Wilms Tumor-1-Specific T-Cell Responses in Cancer Immunotherapy
Next Article in Special Issue
A Transcriptomic Insight into the Impact of Colon Cancer Cells on Mast Cells
Previous Article in Journal
Sphingolipid Metabolism: New Insight into Ceramide-Induced Lipotoxicity in Muscle Cells
 
 
Search for Articles:
Title / Keyword
Author / Affiliation / Email
Journal
Article Type
 
 
Advanced Search
 
Section
Special Issue
Volume
Issue
Number
Page
 
Journals
IJMS
Volume 20
Issue 3
10.3390/ijms20030481
ijms-logo
Submit to this Journal Review for this Journal Propose a Special Issue
► Article Menu

Article Menu

share Share announcement Help format_quote Cite question_answer Discuss in SciProfiles thumb_up
...
Endorse textsms
...
Comment
first_page
settings
Order Article Reprints
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:
Background:
Review

Mast Cells and Angiogenesis in Human Plasma Cell Malignancies

by
Domenico Ribatti
1,*,
Roberto Tamma
1 and
Angelo Vacca
2,*
1
Department of Basic Medical Sciences, Neurosciences and Sensory Organs, University of Bari Medical School, 70124 Bari, Italy
2
Department of Biomedical Sciences, and Human Oncology, Section of Internal Medicine and Clinical Oncology, University of Bari Medical School, 70124 Bari, Italy
*
Authors to whom correspondence should be addressed.
Int. J. Mol. Sci. 2019, 20(3), 481; https://doi.org/10.3390/ijms20030481
Submission received: 13 December 2018 / Revised: 18 January 2019 / Accepted: 21 January 2019 / Published: 23 January 2019
(This article belongs to the Special Issue Mast Cells in Health and Disease)
Browse Figures
Versions Notes

Abstract

:
Bone marrow angiogenesis plays an important role in the pathogenesis and progression of hematological malignancies. It is well known that tumor microenvironment promotes tumor angiogenesis, proliferation, invasion, and metastasis, and also mediates mechanisms of therapeutic resistance. An increased number of mast cells has been demonstrated in angiogenesis associated with hematological tumors. In this review we focused on the role of mast cells in angiogenesis in human plasma cell malignancies. In this context, mast cells might act as a new target for the adjuvant treatment of these tumors through the selective inhibition of angiogenesis, tissue remodeling and tumor-promoting molecules, permitting the secretion of cytotoxic cytokines and preventing mast cell-mediated immune suppression.

1. Mast Cells in Human Plasma Cell Malignancies

Multiple myeloma (MM), solitary plasmocytoma of bone, and solitary extramedullary plasmocytoma belong to a spectrum of disorders referred to as plasma cell dyscrasias [1]. Solitary plasmocytoma of the bone represent an early stage of MM and patients with an apparent solitary lesion may have an occult MM [2], and solitary plasmocytoma of the skull base tend to progress to MM [3].
Mast cells represent a dominant infiltrate in human plasma cell malignancies, and the degree of mast cell infiltration parallels the severity of disease. Mast cells are a source of different cytokines, including interleukin-1, -2 and -6 (IL-1, IL-2, IL-6) and stem cells factor (SCF), all of which can induce plasma cell proliferation. IL-6 is the major plasma cell growth factor acting through both a paracrine and autocrine growth stimulation mechanism [4]. Addition of SCF to MM cell lines enhances the proliferation of myeloma cells and the response to IL-6 [5].

2. Mast Cells and Tumor Growth

Mast cells attracted in the tumor microenvironment by SCF are secreted by tumor cells, and produce matrix metalloproteinases (MMPs) [6]. Moreover, mast cells are a major source of histamine, which modulates tumor growth through H1 and H2 receptors [7]. H1 receptor antagonists significantly improved overall survival rates and suppressed tumor growth through the inhibition of hypoxia inducible factor-1 alpha (HIF-1α) expression in B16F10 melanoma-bearing mice [8]. Mast cells exert immunosuppression, releasing tumor necrosis factor alpha (TNF-α) and IL-10, which are essential in promoting the immune tolerance mediated by regulatory T (Treg) cells, and stimulate immune tolerance and tumor promotion [9,10].
Mast cells may promote inflammation, inhibition of tumor cell growth, and tumor cell apoptosis by releasing cytokines, such as IL-1, IL-4, IL-6, IL-8, monocyte chemotactic protein-3 and -4 (MCP-3 and MCP-4), transforming growth factor beta (TGF-β), and chymase. Finally, chondroitin sulphate may inhibit tumor cells diffusion and tryptase causes both tumor cell disruption and inflammation through activation of protease-activated receptors (PAR-1 and -2) [11].

3. Mast Cells and Tumor Angiogenesis

Mast cells release several pro-angiogenic factors, including fibroblast growth factor-2 (FGF-2), vascular endothelial growth factor (VEGF), IL-8, TNF-α, TGF-β, and nerve growth factor (NGF) [12,13,14,15,16,17,18,19,20,21]. Mast cells migrate in vivo and in vitro in response to VEGF and placental growth factor-1 (PlGF-1) [22,23,24]. In this context, VEGF may act both as an angiogenic factor and as an attractant factor for mast cells activating an autocrine loop of mast cell growth.
Human lung mast cells express VEGF-A, VEGF-B, VEGF-C and VEGF-D, and supernatants of activated lung mast cells induced angiogenic response in the chick embryo chorioallantoic membrane (CAM) assay that was inhibited by an anti-VEGF-A antibody [23]. Murine mast cells and their granules stimulate an angiogenic reaction in the CAM assay, partly inhibited by anti-FGF-2 and anti-VEGF antibodies [25]. Intraperitoneal injection of the compound 48/80 causes an angiogenic response in the rat mesentery window angiogenic assay and in mice [26,27]. Histamine and heparin stimulate proliferation of endothelial cells in vitro and are angiogenic in the CAM assay [28,29]. Mast cells store pre-formed active serine proteases in their secretory granules, including tryptase and chymase [30]. Tryptase stimulates the proliferation of endothelial cells, promotes vascular tube formation in vitro, and activates proteases, which in turn degrade the extracellular matrix with consequent release of VEGF or FGF-2 [31]. The expression of mast cell chymase and tryptase correlated with mast cell maturation and angiogenesis during tumor progression in chemically induced tumor growth in Bagg Albino (BALB)/c mouse [32]. Mast cells contain tissue inhibitors of metalloproteinases (TIMPs), [33,34] which intervene in regulation of extracellular matrix degradation, modulating the activation of angiogenic factors which is promoted by MMPs released by mast cells. Mast cell-deficient W/Wv mice exhibit a decreased rate of tumor angiogenesis [35]. Development of squamous cell carcinoma in a human papilloma virus (HPV) 16 infected transgenic mouse model of epithelia carcinogenesis provided support for the participation of mast cells in tumor growth and angiogenesis [36,37].
An increased number of mast cells have been demonstrated in angiogenesis associated with vascular tumors, as well as a number of haematological and solid tumors (Table 1), in which mast cell accumulation correlate with increased neovascularization, mast cell VEGF and FGF-2 expression, tumor aggressiveness and poor prognosis [38,39,40].

4. The Role of Mast Cells in Angiogenesis in Plasmocytoma

Kumar et al. [69] demonstrated a high grade microvascular density in bone marrow samples of patients with solitary plasmocytomas and these patients were more likely to progress to MM and had a shorter progression-free survival compared with patients with low-grade angiogenesis. Naganuma et al. [70] demonstrated in two cases of solitary plasmocytoma of the skull that tumor cells express both VEGF and FGF-2. Nakayama et al. [71] demonstrated that plasmocytoma cells inoculated s.c. in nu/nuBALC/c mice gave rise to tumors that were significantly more rapidly and highly vascularized when inoculated together with mast cells, as compared to tumor cells alone. Double staining demonstrated co-localization of toluidine blue and angiopoietin-1 (Ang-1) providing evidence that mast cells within tumors are the source of Ang-1. Antibodies anti VEGF-A and anti-Tie-2/Fc individually and together significantly reduced tumor growth induced by plasmocytoma cells and mast cells, as compared to controls. Swelam and Tamini [72] demonstrated a significant higher microvascular density and VEGF expression in both endothelial and tumor cells in bone marrow biopsy specimens of MM as compared to solitary plasmocytoma.

5. The Role of Mast Cells in Angiogenesis in Multiple Myeloma

In 1994, we demonstrated for the first time that bone marrow microvascular density is significantly increased in MM compared to monoclonal gammopathies of undetermined significance (MGUS), and moreover in active vs. non-active MM [73]. Angiogenesis is induced by plasma cells via angiogenic factors released by the cells composing the tumor microenvironment and loss of angiostatic activity in MGUS [74].
Within the bone marrow microenvironment, bone marrow stromal cells, hematopoietic stem cells, fibroblasts, osteoblasts/osteoclasts, adipocytes, endothelial precursor cells, T lymphocytes, macrophages, and mast cells, increase the concentration of angiogenic factors and matrix degrading enzymes in the bone marrow microenvironment by direct secretion or following stimulation by myeloma cells or by endothelial cells through paracrine interaction [75].
We have shown that bone marrow angiogenesis and mast cell counts are highly correlated in patients with MM and in those with MGUS. In addition, both parameters increase simultaneously in active MM (Figure 1) [46]. These data suggest that an increasing number of mast cells may be recruited and activated by more malignant plasma cells in active multiple myeloma, and that angiogenesis in this disease phase may be mediated, at least in part, by angiogenic factors contained in their secretory granules (Figure 2) [76]. Interestingly, electron microscopic examination of bone marrow mast cells in MM patients shows ultrastructural features of slow and particulate secretion as it occurs in piecemeal degranulation (Figure 3) [46]. This ultrastructural appearance may reflect slow and progressive release of angiogenic factors by infiltrating mast cells, favoring chronic and progressive stimulation of mast cell degranulation.
Besides stimulating angiogenesis in the bone marrow of MM patients, mast cells have the ability to contribute to vasculogenic mimicry [77]. We have demonstrated at ultrastructural level that vessels from MM bioptic specimens are lined by mast cells whose cytoplasm was filled by numerous and irregular shaped electron dense granules. Indeed, confocal microscopy approaches have demonstrated that in the bone marrow of patients with MM, typical tryptase-positive mast cells interact physically with the endothelial cells lining the vascular lumina, perhaps as a result of dysregulated vasculogenic development (Figure 4).
This evidence highlights the importance of the stromal microenvironment during angiogenesis in the pathophysiology of MM and provides a novel perspective into the complex interplay between stromal and vascular components in the bone marrow microenvironment involved in the induction of hypervascularization. In contrast with this evidence, Mileshkin et al. [78] have found low or absent mast cell bone marrow infiltration in MM and an increase of mast cell number in patients in response to thalidomide, which has anti-angiogenic and immunomodulatory effects in myeloma.
Pappa et al. [79,80,81] showed that bone marrow mast cells density correlated with the clinical stage of MM and decreased after treatment; moreover, they quantified mast cells in bone marrow biopsies of MM patients and correlated with serum concentrations of VEGF, growth-regulated oncogene (GRO)-α, epithelial-derived neutrophil-activating peptide (ENA)-78. Mast cell and serum levels of GRO-α, ENA-78, and VEGF were significantly higher in MM patients compared to controls, and significant correlations were found between mast cell density with VEGF, GRO-α, ENA-78, and with a Ki-67 plasma cell proliferative index. Devetzoglou et al. [82] evaluated the mast cell density in bone marrow of untreated MM patients with markers of disease activity such as serum IL-6, B2M, and C-reactive protein (CRP), the grade of bone marrow infiltration, and the levels of produced paraprotein. The serum concentrations of CRP, B2M, and IL-6, and the mast cell density values were significantly higher in the MM patients’ group in comparison with those found in the control group. Significant differences were found between the grade of infiltration in bone marrow, and the paraprotein values in patients’ serum before and after chemotherapy. Furthermore, there was a significant correlation between the mast cell density values and the prognostic markers CRP, IL-6, bone marrow infiltration, and serum paraprotein.
Vyzoukaki et al. [83,84] demonstrated that bone marrow mast cell density in MM patients is correlated with radiographic skeletal grades and evaluated serum levels of Ang-2 and MMP-9 and found them to be positively correlated with bone marrow mast cell density in patients with active MM.

6. Concluding Remarks and Therapeutic Perspectives

Bone marrow angiogenesis plays an important role in the pathogenesis and progression of hematological malignancies. Growth is halted and a dormancy state is induced in the avascular phase, whereas clonal expansion and epigenetic modifications of the microenvironment cause a switch to an angiogenic phenotype that generates the vascular phase, and involves changes in the local balance between pro- and antiangiogenic factors secreted by inflammatory cells and stromal cells.
The deregulated interactions between MM cells and other cells of the microenvironment are at the basis of the clinical manifestations of the disease, including osteolytic bone lesions, hypercalcemia, and suppressed haematopoietic functions. The vascular niche is comprised of vasculature forming a conduit which enables MM cells both to leave the osteoblastic niche and to enter the vascular system via transendothelial migration, hence to return to the bone marrow via homing mechanisms.
In the treatment of MM, thalidomide has been part of the standard treatment for and is thought to inhibit VEGF-associated angiogenesis, while Bevacizumab, a monoclonal antibody directed against VEGF-A, inhibits VEGF, as well as the proteasome inhibitor bortezomib. Accordingly, the efficacy and safety of these agents alone and in combination in MM patients have been tested [85,86,87].
The new targeted anti-cancer therapies may exert effects on mast cells (Table 2). Many of these drugs have mast cells c-kit as the main target, and inhibition of the SCF/Kit axis in vivo inhibits the migration of bone marrow-derived cultured mast cells to tumors. Chemoprevention with an anti-inflammatory approach has the potential to inhibit neovascularization before the onset of the angiogenic switch, resulting in a significant delay in tumor growth. Moreover, the development of novel therapies to alter mast cell function in the tumor microenvironment could inhibit tissue remodeling and tumor growth and activate the immune system.
In this context, mast cells might act as a new target for the adjuvant treatment of haematological tumors through the selective inhibition of angiogenesis, tissue remodeling and tumor-promoting molecules, permitting the secretion of cytotoxic cytokines and preventing mast cell-mediated immune suppression.

Author Contributions

D.R. wrote the manuscript, A.V. and R.T. revised the manuscript and prepared the figures.

Funding

This work was supported in part by “Associazione Italiana Mastocitosi” to D.R.

Conflicts of Interest

The authors declare no conflict of interest.

References

  1. Corwin, J.; Lindberg, R.D. Solitary plasmacytoma of bone vs. extramedullary plasmacytoma and their relationship to multiple myeloma. Cancer 1979, 43, 1007–1013. [Google Scholar] [CrossRef] [Green Version]
  2. Woodruff, R.K.; Whittle, J.M.; Malpas, J.S. Solitary plasmacytoma. I: Extramedullary soft tissue plasmacytoma. Cancer 1979, 43, 2340–2343. [Google Scholar] [CrossRef] [Green Version]
  3. Bindal, A.K.; Bindal, R.K.; van Loveren, H.; Sawaya, R. Management of intracranial plasmacytoma. J. Neurosurg. 1995, 83, 218–221. [Google Scholar] [CrossRef] [PubMed]
  4. Klein, B.; Zhang, X.G.; Jourdan, M.; Content, J.; Houssiau, F.; Aarden, L.; Piechaczyk, M.; Bataille, R. Paracrine rather than autocrine regulation of myeloma-cell growth and differentiation by interleukin-6. Blood 1989, 73, 517–526. [Google Scholar] [PubMed]
  5. Lemoli, R.M.; Fortuna, A.; Grande, A.; Gamberi, B.; Bonsi, L.; Fogli, M.; Amabile, M.; Cavo, M.; Ferrari, S.; Tura, S. Expression and functional role of c-kit ligand (SCF) in human multiple myeloma cells. Br. J. Haematol. 1994, 88, 760–769. [Google Scholar] [CrossRef]
  6. Ribatti, D.; Crivellato, E. Chapter 4 The Controversial Role of Mast Cells in Tumor Growth. In International Review of Cell and Molecular Biology; Elsevier: Amsterdam, The Netherlands, 2009; pp. 89–131. [Google Scholar]
  7. Fitzsimons, C.; Molinari, B.; Duran, H.; Palmieri, M.; Davio, C.; Cricco, G.; Bergoc, R.; Rivera, E. Atypical association of H 1 and H 2 histamine receptors with signal transduction pathways during multistage mouse skin carcinogenesis. Inflamm. Res. 1997, 46, 292–298. [Google Scholar] [CrossRef]
  8. Jeong, H.J.; Oh, H.A.; Nam, S.Y.; Han, N.R.; Kim, Y.S.; Kim, J.H.; Lee, S.J.; Kim, M.H.; Moon, P.D.; Kim, H.M.; et al. The critical role of mast cell-derived hypoxia-inducible factor-1α in human and mice melanoma growth. Int. J. Cancer 2013, 132, 2492–2501. [Google Scholar] [CrossRef]
  9. Grimbaldeston, M.A.; Nakae, S.; Kalesnikoff, J.; Tsai, M.; Galli, S.J. Mast cell–derived interleukin 10 limits skin pathology in contact dermatitis and chronic irradiation with ultraviolet B. Nat. Immunol. 2007, 8, 1095–1104. [Google Scholar] [CrossRef]
  10. Ullrich, S.E.; Nghiem, D.X.; Khaskina, P. Suppression of an Established Immune Response by UVA? A Critical Role for Mast Cells. Photochem. Photobiol. 2007, 83, 1095–1100. [Google Scholar] [CrossRef]
  11. Ribatti, D.; Crivellato, E. Mast cells, angiogenesis, and tumour growth. Biochim. Biophys. Acta 2012, 1822, 2–8. [Google Scholar] [CrossRef] [Green Version]
  12. Abdel-Majid, R.M.; Marshall, J.S. Prostaglandin E2 Induces Degranulation-Independent Production of Vascular Endothelial Growth Factor by Human Mast Cells. J. Immunol. 2004, 172, 1227–1236. [Google Scholar] [CrossRef] [Green Version]
  13. Boesiger, J.; Tsai, M.; Maurer, M.; Yamaguchi, M.; Brown, L.F.; Claffey, K.P.; Dvorak, H.F.; Galli, S.J. Mast Cells Can Secrete Vascular Permeability Factor/ Vascular Endothelial Cell Growth Factor and Exhibit Enhanced Release after Immunoglobulin E–dependent Upregulation of Fcε Receptor I Expression. J. Exp. Med. 1998, 188, 1135–1145. [Google Scholar] [CrossRef] [PubMed]
  14. Grützkau, A.; Krüger-Krasagakes, S.; Baumeister, H.; Schwarz, C.; Kögel, H.; Welker, P.; Lippert, U.; Henz, B.M.; Möller, A. Synthesis, Storage, and Release of Vascular Endothelial Growth Factor/Vascular Permeability Factor (VEGF/VPF) by Human Mast Cells: Implications for the Biological Significance of VEGF206. Mol. Biol. Cell 1998, 9, 875–884. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  15. Kanbe, N.; Kurosawa, M.; Nagata, H.; Yamashita, T.; Kurimoto, F.; Miyachi, Y. Production of fibrogenic cytokines by cord blood–derived cultured human mast cells. J. Allergy Clin. Immunol. 2000, 106, S85–S90. [Google Scholar] [CrossRef]
  16. Nilsson, G.; Forsberg-Nilsson, K.; Xiang, Z.; Hallböök, F.; Nilsson, K.; Metcalfe, D.D. Human mast cells express functional TrkA and are a source of nerve growth factor. Eur. J. Immunol. 1997, 27, 2295–2301. [Google Scholar] [CrossRef] [PubMed]
  17. Qu, Z.; Huang, X.; Ahmadi, P.; Stenberg, P.; Liebler, J.M.; Le, A.-C.; Planck, S.R.; Rosenbaum, J.T. Synthesis of Basic Fibroblast Growth Factor by Murine Mast CellsRegulation by Transforming Growth Factor β, Tumor Necrosis Factor α, and Stem Cell Factor. Int. Arch. Allergy Immunol. 1997, 115, 47–54. [Google Scholar] [CrossRef]
  18. Qu, Z.; Kayton, R.J.; Ahmadi, P.; Liebler, J.M.; Powers, M.R.; Planck, S.R.; Rosenbaum, J.T. Ultrastructural Immunolocalization of Basic Fibroblast Growth Factor in Mast Cell Secretory Granules: Morphological Evidence for bFGF Release Through Degranulation. J. Histochem. Cytochem. 1998, 46, 1119–1128. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  19. Qu, Z.; Liebler, J.M.; Powers, M.R.; Galey, T.; Ahmadi, P.; Huang, X.N.; Ansel, J.C.; Butterfield, J.H.; Planck, S.R.; Rosenbaum, J.T. Mast cells are a major source of basic fibroblast growth factor in chronic inflammation and cutaneous hemangioma. Am. J. Pathol. 1995, 147, 564–573. [Google Scholar]
  20. Walsh, L.J.; Trinchieri, G.; Waldorf, H.A.; Whitaker, D.; Murphy, G.F. Human dermal mast cells contain and release tumor necrosis factor α, which induces endothelial leukocyte adhesion molecule 1. Proc. Natl. Acad. Sci. USA 1991, 88, 4220–4224. [Google Scholar] [CrossRef]
  21. Moller, A.; Henz, B.M.; Grutzkau, A.; Lippert, U.; Aragane, Y.; Schwarz, T.; Kruger-Krasagakes, S. Comparative cytokine gene expression: Regulation and release by human mast cells. Immunology 1998, 93, 289–295. [Google Scholar] [CrossRef] [PubMed]
  22. Detmar, M.; Brown, L.F.; Schön, M.P.; Elicker, B.M.; Velasco, P.; Richard, L.; Fukumura, D.; Monsky, W.; Claffey, K.P.; Jain, R.K. Increased Microvascular Density and Enhanced Leukocyte Rolling and Adhesion in the Skin of VEGF Transgenic Mice. J. Investig. Dermatol. 1998, 111, 1–6. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  23. Detoraki, A.; Staiano, R.I.; Granata, F.; Giannattasio, G.; Prevete, N.; de Paulis, A.; Ribatti, D.; Genovese, A.; Triggiani, M.; Marone, G. Vascular endothelial growth factors synthesized by human lung mast cells exert angiogenic effects. J. Allergy Clin. Immunol. 2009, 123, 1142–1149. [Google Scholar] [CrossRef]
  24. Gruber, B.L.; Marchese, M.J.; Kiely, J.; Schwartz, L.B.; Schecter, N.M. 520 Human mast cell products degrade connective tissue matrix. J. Allergy Clin. Immunol. 1988, 81, 298. [Google Scholar] [CrossRef]
  25. Ribatti, D.; Crivellato, E.; Candussio, L.; Nico, B.; Vacca, A.; Roncali, L.; Dammacco, F. Mast cells and their secretory granules are angiogenic in the chick embryo chorioallantoic membrane. Clin. Exp. Allergy 2001, 31, 602–608. [Google Scholar] [CrossRef] [PubMed]
  26. Norrby, K.; Jakobsson, A.; Sörbo, J. Mast-cell-mediated angiogenesis: A novel experimental model using the rat mesentery. Virchows Archiv B 1986, 52, 195–206. [Google Scholar] [CrossRef]
  27. Norrby, K.; Jakobsson, A.; Sörbo, J. Mast-cell secretion and angiogenesis, a quantitative study in rats and mice. Virchows Archiv B 1989, 57, 251–256. [Google Scholar] [CrossRef]
  28. Ribatti, D.; Roncali, L.; Nico, B.; Bertossi, M. Effects of Exogenous Heparin on the Vasculogenesis of the Chorioallantoic Membrane. Cells Tissues Organs 1987, 130, 257–263. [Google Scholar] [CrossRef]
  29. Sörbo, J.; Norrby, K. Mast-cell histamine expands the microvasculature spatially. Agents Actions 1992, 36, C387–C389. [Google Scholar] [CrossRef]
  30. Metcalfe, D.D.; Baram, D.; Mekori, Y.A. Mast cells. Physiol. Rev. 1997, 77, 1033–1079. [Google Scholar] [CrossRef]
  31. Blair, R.J.; Meng, H.; Marchese, M.J.; Ren, S.; Schwartz, L.B.; Tonnesen, M.G.; Gruber, B.L. Human mast cells stimulate vascular tube formation. Tryptase is a novel, potent angiogenic factor. J. Clin. Investig. 1997, 99, 2691–2700. [Google Scholar] [CrossRef]
  32. De Souza, D.A.; Toso, V.D.; Campos, M.R.D.C.; Lara, V.S.; Oliver, C.; Jamur, M.C. Expression of Mast Cell Proteases Correlates with Mast Cell Maturation and Angiogenesis during Tumor Progression. PLoS ONE 2012, 7, e40790. [Google Scholar] [CrossRef]
  33. Koskivirta, I.; Rahkonen, O.; Mäyränpää, M.; Pakkanen, S.; Husheem, M.; Sainio, A.; Hakovirta, H.; Laine, J.; Jokinen, E.; Vuorio, E.; et al. Tissue inhibitor of metalloproteinases 4 (TIMP4) is involved in inflammatory processes of human cardiovascular pathology. Histochem. Cell Biol. 2006, 126, 335–342. [Google Scholar] [CrossRef]
  34. Tanaka, A.; Yamane, Y.; Matsuda, H. Mast Cell MMP-9 Production Enhanced by Bacterial Lipopolysaccharide. J. Vet. Med. Sci. 2001, 63, 811–813. [Google Scholar] [CrossRef] [PubMed]
  35. Starkey, J.R.; Crowle, P.K.; Taubenberger, S. Mast-cell-deficient W/Wv mice exhibit A decreased rate of tumor angiogenesis. Int. J. Cancer 1988, 42, 48–52. [Google Scholar] [CrossRef] [PubMed]
  36. Coussens, L.M.; Raymond, W.W.; Bergers, G.; Laig-Webster, M.; Behrendtsen, O.; Werb, Z.; Caughey, G.H.; Hanahan, D. Inflammatory mast cells up-regulate angiogenesis during squamous epithelial carcinogenesis. Genes Dev. 1999, 13, 1382–1397. [Google Scholar] [CrossRef] [Green Version]
  37. Coussens, L.M.; Tinkle, C.L.; Hanahan, D.; Werb, Z. MMP-9 Supplied by Bone Marrow–Derived Cells Contributes to Skin Carcinogenesis. Cell 2000, 103, 481–490. [Google Scholar] [CrossRef] [Green Version]
  38. Ribatti, D.; Ennas, M.G.; Vacca, A.; Ferreli, F.; Nico, B.; Orru, S.; Sirigu, P. Tumor vascularity and tryptase-positive mast cells correlate with a poor prognosis in melanoma. Eur. J. Clin. Investig. 2003, 33, 420–425. [Google Scholar] [CrossRef]
  39. Ribatti, D.; Molica, S.; Vacca, A.; Nico, B.; Crivellato, E.; Roccaro, A.M.; Dammacco, F. Tryptase-positive mast cells correlate positively with bone marrow angiogenesis in B-cell chronic lymphocytic leukemia. Leukemia 2003, 17, 1428–1430. [Google Scholar] [CrossRef] [Green Version]
  40. Tth, T. Cutaneous malignant melanoma: Correlation between neovascularization and peritumor accumulation of mast cells overexpressing vascular endothelial growth factor. Hum. Pathol. 2000, 31, 955–960. [Google Scholar]
  41. Glowacki, J.; Mulliken, J.B. Mast cells in hemangiomas and vascular malformations. Pediatrics 1982, 70, 48–51. [Google Scholar]
  42. Fukushima, N.; Satoh, T.; Sano, M.; Tokunaga, O. Angiogenesis and Mast Cells in Non-Hodgkin’s Lymphoma: A Strong Correlation in Angioimmunoblastic T-Cell Lymphoma. Leuk. Lymphoma 2001, 42, 709–720. [Google Scholar] [CrossRef] [PubMed]
  43. Marinaccio, C.; Ingravallo, G.; Gaudio, F.; Perrone, T.; Nico, B.; Maoirano, E.; Specchia, G.; Ribatti, D. Microvascular density, CD68 and tryptase expression in human Diffuse Large B-Cell Lymphoma. Leuk. Res. 2014, 38, 1374–1377. [Google Scholar] [CrossRef] [PubMed]
  44. Rabenhorst, A.; Schlaak, M.; Heukamp, L.C.; Forster, A.; Theurich, S.; von Bergwelt-Baildon, M.; Buttner, R.; Kurschat, P.; Mauch, C.; Roers, A.; et al. Mast cells play a protumorigenic role in primary cutaneous lymphoma. Blood 2012, 120, 2042–2054. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  45. Ribatti, D.; Nico, B.; Vacca, A.; Marzullo, A.; Calvi, N.; Roncali, L.; Dammacco, F. Do mast cells help to induce angiogenesis in B-cell non-Hodgkin’s lymphomas? Br. J. Cancer 1998, 77, 1900–1906. [Google Scholar] [CrossRef]
  46. Ribatti, D.; Vacca, A.; Nico, B.; Quondamatteo, F.; Ria, R.; Minischetti, M.; Marzullo, A.; Herken, R.; Roncali, L.; Dammacco, F. Bone marrow angiogenesis and mast cell density increase simultaneously with progression of human multiple myeloma. Br. J. Cancer 1999, 79, 451–455. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  47. Ribatti, D.; Polimeno, G.; Vacca, A.; Marzullo, A.; Crivellato, E.; Nico, B.; Lucarelli, G.; Dammacco, F. Correlation of bone marrow angiogenesis and mast cells with tryptase activity in myelodysplastic syndromes. Leukemia 2002, 16, 1680–1684. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  48. Molica, S.; Vacca, A.; Crivellato, E.; Cuneo, A.; Ribatti, D. Tryptase-positive mast cells predict clinical outcome of patients with early B-cell chronic lymphocytic leukemia. Eur. J. Haematol. 2003, 71, 137–139. [Google Scholar] [CrossRef]
  49. Bowrey, P.F.; King, J.; Magarey, C.; Schwartz, P.; Marr, P.; Bolton, E.; Morris, D.L. Histamine, mast cells and tumour cell proliferation in breast cancer: Does preoperative cimetidine administration have an effect? Br. J. Cancer 2000, 82, 167–170. [Google Scholar] [CrossRef] [PubMed]
  50. Hartveit, F. Mast cells and metachromasia in human breast cancer: Their occurrence, significance and consequence: A preliminary report. J. Pathol. 1981, 134, 7–11. [Google Scholar] [CrossRef] [PubMed]
  51. Marech, I.; Ammendola, M.; Leporini, C.; Patruno, R.; Luposella, M.; Zizzo, N.; Passantino, G.; Sacco, R.; Farooqi, A.A.; Zuccalà, V.; et al. C-Kit receptor and tryptase expressing mast cells correlate with angiogenesis in breast cancer patients. Oncotarget 2017, 9, 7918. [Google Scholar] [CrossRef]
  52. Ribatti, D.; Finato, N.; Crivellato, E.; Guidolin, D.; Longo, V.; Mangieri, D.; Nico, B.; Vacca, A.; Beltrami, C.A. Angiogenesis and mast cells in human breast cancer sentinel lymph nodes with and without micrometastases. Histopathology 2007, 51, 837–842. [Google Scholar] [CrossRef]
  53. Ranieri, G.; Ammendola, M.; Patruno, R.; Celano, G.; Zito, F.A.; Montemurro, S.; Rella, A.; Di Lecce, V.; Gadaleta, C.D.; Battista De Sarro, G.; et al. Tryptase-positive mast cells correlate with angiogenesis in early breast cancer patients. Int. J. Oncol. 2009, 35, 115–120. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  54. Ammendola, M.; Sacco, R.; Sammarco, G.; Donato, G.; Zuccalà, V.; Romano, R.; Luposella, M.; Patruno, R.; Vallicelli, C.; Verdecchia, G.M.; et al. Mast Cells Positive to Tryptase and c-Kit Receptor Expressing Cells Correlates with Angiogenesis in Gastric Cancer Patients Surgically Treated. Gastroenterol. Res. Pract. 2013, 2013, 1–5. [Google Scholar] [CrossRef] [PubMed]
  55. Kondo, K.; Muramatsu, M.; Okamoto, Y.; Jin, D.; Takai, S.; Tanigawa, N.; Miyazaki, M. Expression of chymase-positive cells in gastric cancer and its correlation with the angiogenesis. J. Surg. Oncol. 2005, 93, 36–42. [Google Scholar] [CrossRef] [PubMed]
  56. Ribatti, D.; Guidolin, D.; Marzullo, A.; Nico, B.; Annese, T.; Benagiano, V.; Crivellato, E. Mast cells and angiogenesis in gastric carcinoma. Int. J. Exp. Pathol. 2010, 91, 350–356. [Google Scholar] [CrossRef] [PubMed]
  57. Yano, H.; Kinuta, M.; Tateishi, H.; Nakano, Y.; Matsui, S.; Monden, T.; Okamura, J.; Sakai, M.; Okamoto, S. Mast cell infiltration around gastric cancer cells correlates with tumor angiogenesis and metastasis. Gastric Cancer 1999, 2, 26–32. [Google Scholar] [CrossRef] [PubMed]
  58. Ammendola, M.; Sacco, R.; Sammarco, G.; Donato, G.; Montemurro, S.; Ruggieri, E.; Patruno, R.; Marech, I.; Cariello, M.; Vacca, A.; et al. Correlation between Serum Tryptase, Mast Cells Positive to Tryptase and Microvascular Density in Colo-Rectal Cancer Patients: Possible Biological-Clinical Significance. PLoS ONE 2014, 9, e99512. [Google Scholar] [CrossRef] [PubMed]
  59. Lachter, J.; Stein, M.; Lichtig, C.; Eidelman, S.; Munichor, M. Mast cells in colorectal neoplasias and premalignant disorders. Dis. Colon Rectum 1995, 38, 290–293. [Google Scholar] [CrossRef] [PubMed]
  60. Ammendola, M.; Sacco, R.; Sammarco, G.; Donato, G.; Zuccalà, V.; Luposella, M.; Patruno, R.; Marech, I.; Montemurro, S.; Zizzo, N.; et al. Mast Cells Density Positive to Tryptase Correlates with Angiogenesis in Pancreatic Ductal Adenocarcinoma Patients Having Undergone Surgery. Gastroenterol. Res. Pract. 2014, 2014, 1–7. [Google Scholar] [CrossRef] [PubMed]
  61. Longo, V.; Tamma, R.; Brunetti, O.; Pisconti, S.; Argentiero, A.; Silvestris, N.; Ribatti, D. Mast cells and angiogenesis in pancreatic ductal adenocarcinoma. Clin. Exp. Med. 2018, 18, 319–323. [Google Scholar] [CrossRef] [PubMed]
  62. Benítez–Bribiesca, L.; Wong, A.; Utrera, D.; Castellanos, E. The Role of Mast Cell Tryptase in Neoangiogenesis of Premalignant and Malignant Lesions of the Uterine Cervix. J. Histochem. Cytochem. 2001, 49, 1061–1062. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  63. Graham, R.M.; Graham, J.B. Cytological prognosis in cancer of the uterine cervix treated radiologically. Cancer 1955, 8, 59–70. [Google Scholar] [CrossRef] [Green Version]
  64. Ribatti, D.; Finato, N.; Crivellato, E.; Marzullo, A.; Mangieri, D.; Nico, B.; Vacca, A.; Beltrami, C.A. Neovascularization and mast cells with tryptase activity increase simultaneously with pathologic progression in human endometrial cancer. Am. J. Obstet. Gynecol. 2005, 193, 1961–1965. [Google Scholar] [CrossRef] [PubMed]
  65. Dvorak, A.M.; Mihm, M.C.; Osage, J.E.; Dvorak, H.F. Melanoma. An Ultrastructural Study of the Host Inflammatory and Vascular Responses. J. Investig. Dermatol. 1980, 75, 388–393. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  66. Reed, J.A.; McNutt, N.S.; Bogdany, J.K.; Albino, A.P. Expression of the mast cell growth factor interleukin-3 in melanocytic lesions correlates with an increased number of mast cells in the perilesional stroma: Implications for melanoma progression. J. Cutan. Pathol. 2006, 23, 495–505. [Google Scholar] [CrossRef]
  67. Ullah, E.; Nagi, A.H.; Lail, R.A. Angiogenesis and mast cell density in invasive pulmonary adenocarcinoma. J. Cancer Res. Ther. 2012, 8, 537–541. [Google Scholar] [CrossRef] [PubMed]
  68. Melillo, R.M.; Guarino, V.; Avilla, E.; Galdiero, M.R.; Liotti, F.; Prevete, N.; Rossi, F.W.; Basolo, F.; Ugolini, C.; de Paulis, A.; et al. Mast cells have a protumorigenic role in human thyroid cancer. Oncogene 2010, 29, 6203–6215. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  69. Kumar, S. Prognostic value of angiogenesis in solitary bone plasmacytoma. Blood 2002, 101, 1715–1717. [Google Scholar] [CrossRef] [Green Version]
  70. Naganuma, H.; Sakatsume, S.; Sugita, M.; Satoh, E.; Asahara, T.; Nukui, H. Solitary Plasmacytoma of the Skull: Immunohistochemical Study of Angiogenic Factors and Syndecan-1-Two Case Reports. Neurologia Medico-Chirurgica 2004, 44, 195–200. [Google Scholar] [CrossRef]
  71. Nakayama, T.; Yao, L.; Tosato, G. Mast cell–derived angiopoietin-1 plays a critical role in the growth of plasma cell tumors. J. Clin. Investig. 2004, 114, 1317–1325. [Google Scholar] [CrossRef] [Green Version]
  72. Swelam, W.M.; Al Tamimi, D.M. Biological impact of vascular endothelial growth factor on vessel density and survival in multiple myeloma and plasmacytoma. Pathol. Res. Pract. 2010, 206, 753–759. [Google Scholar] [CrossRef]
  73. Vacca, A.; Ribatti, D.; Roncali, L.; Ranieri, G.; Serio, G.; Silvestris, F.; Dammacco, F. Bone marrow angiogenesis and progression in multiple myeloma. Br. J. Haematol. 1994, 87, 503–508. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  74. Vacca, A.; Ribatti, D.; Presta, M.; Minischetti, M.; Iurlaro, M.; Ria, R.; Albini, A.; Bussolino, F.; Dammacco, F. Bone marrow neovascularization, plasma cell angiogenic potential, and matrix metalloproteinase-2 secretion parallel progression of human multiple myeloma. Blood 1999, 93, 3064–3073. [Google Scholar] [PubMed]
  75. Ribatti, D.; Nico, B.; Vacca, A. Importance of the bone marrow microenvironment in inducing the angiogenic response in multiple myeloma. Oncogene 2006, 25, 4257–4266. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  76. Vacca, A.; Ribatti, D. Bone marrow angiogenesis in multiple myeloma. Leukemia 2005, 20, 193–199. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  77. Nico, B.; Mangieri, D.; Crivellato, E.; Vacca, A.; Ribatti, D. Mast Cells Contribute to Vasculogenic Mimicry in Multiple Myeloma. Stem Cells Dev. 2008, 17, 19–22. [Google Scholar] [CrossRef]
  78. Mileshkin, L.; Honemann, D.; Gambell, P.; Trivett, M.; Hayakawa, Y.; Smyth, M.; Beshay, V.; Ritchie, D.; Simmons, P.; Milner, A.D.; et al. Patients with multiple myeloma treated with thalidomide: Evaluation of clinical parameters, cytokines, angiogenic markers, mast cells and marrow CD57+ cytotoxic T cells as predictors of outcome. Haematologica 2007, 92, 1075–1082. [Google Scholar] [CrossRef]
  79. Pappa, C.A.; Tsirakis, G.; Devetzoglou, M.; Zafeiri, M.; Vyzoukaki, R.; Androvitsanea, A.; Xekalou, A.; Sfiridaki, K.; Alexandrakis, M.G. Bone marrow mast cell density correlates with serum levels of VEGF and CXC chemokines ENA-78 and GRO-α in multiple myeloma. Tumor Biol. 2014, 35, 5647–5651. [Google Scholar] [CrossRef]
  80. Pappa, C.A.; Tsirakis, G.; Roussou, P.; Xekalou, A.; Goulidaki, N.; Konsolas, I.; Alexandrakis, M.G.; Stathopoulos, E.N. Positive correlation between bone marrow mast cell density and ISS prognostic index in patients with multiple myeloma. Leuk. Res. 2013, 37, 1628–1631. [Google Scholar] [CrossRef]
  81. Pappa, C.A.; Tsirakis, G.; Stavroulaki, E.; Kokonozaki, M.; Xekalou, A.; Konsolas, I.; Alexandrakis, M.G. Mast Cells Influence the Proliferation Rate of Myeloma Plasma Cells. Cancer Investig. 2015, 33, 137–141. [Google Scholar] [CrossRef]
  82. Devetzoglou, M.; Vyzoukaki, R.; Kokonozaki, M.; Xekalou, A.; Pappa, C.A.; Papadopoulou, A.; Alegakis, A.; Androulakis, N.; Alexandrakis, M.G. High density of tryptase-positive mast cells in patients with multiple myeloma: Correlation with parameters of disease activity. Tumor Biol. 2015, 36, 8491–8497. [Google Scholar] [CrossRef] [PubMed]
  83. Vyzoukaki, R.; Tsirakis, G.; Pappa, C.A.; Androulakis, N.; Kokonozaki, M.; Tzardi, M.; Alexandrakis, M.G. Correlation of Mast Cell Density with Angiogenic Cytokines in Patients with Active Multiple Myeloma. Clin. Ther. 2016, 38, 297–301. [Google Scholar] [CrossRef] [PubMed]
  84. Vyzoukaki, R.; Tsirakis, G.; Pappa, C.A.; Devetzoglou, M.; Tzardi, M.; Alexandrakis, M.G. The Impact of Mast Cell Density on the Progression of Bone Disease in Multiple Myeloma Patients. Int. Arch. Allergy Immunol. 2015, 168, 263–268. [Google Scholar] [CrossRef]
  85. Attar-Schneider, O.; Drucker, L.; Zismanov, V.; Tartakover-Matalon, S.; Rashid, G.; Lishner, M. Bevacizumab attenuates major signaling cascades and eIF4E translation initiation factor in multiple myeloma cells. Lab. Investig. 2012, 92, 178–190. [Google Scholar] [CrossRef] [PubMed]
  86. White, D.; Kassim, A.; Bhaskar, B.; Yi, J.; Wamstad, K.; Paton, V.E. Results from AMBER, a randomized phase 2 study of bevacizumab and bortezomib versus bortezomib in relapsed or refractory multiple myeloma. Cancer 2013, 119, 339–347. [Google Scholar] [CrossRef] [PubMed]
  87. Somlo, G.; Lashkari, A.; Bellamy, W.; Zimmerman, T.M.; Tuscano, J.M.; O’Donnell, M.R.; Mohrbacher, A.F.; Forman, S.J.; Frankel, P.; Chen, H.X.; et al. Phase II randomized trial of bevacizumab versus bevacizumab and thalidomide forelapsed/refractory multiple myeloma: A California Cancer Consortium trial. Br. J. Hematol. 2011, 154, 533–535. [Google Scholar] [CrossRef] [PubMed]
Ijms 20 00481 g001 550
Figure 1. Mast cell counts in comparison with the microvessel area in the bone marrow of patients with active and non-active multiple myeloma (MM) and with monoclonal gammopathy of undetermined significance (MGUS). Significance of the regression analysis was calculated by the Pearson’s (r) test. (Modified from reference [46]).
Figure 1. Mast cell counts in comparison with the microvessel area in the bone marrow of patients with active and non-active multiple myeloma (MM) and with monoclonal gammopathy of undetermined significance (MGUS). Significance of the regression analysis was calculated by the Pearson’s (r) test. (Modified from reference [46]).
Ijms 20 00481 g001
Ijms 20 00481 g002 550
Figure 2. Interplay between plasma cells and mast cells in inducing angiogenic response in multiple myeloma.
Figure 2. Interplay between plasma cells and mast cells in inducing angiogenic response in multiple myeloma.
Ijms 20 00481 g002
Ijms 20 00481 g003 550
Figure 3. Ultrastructural findings of bone marrow biopsies from patients with active multiple myeloma. In (A), a mast cell with typical electron-dense round granules and in (B), at higher magnification, a cytoplasmic granule with a semilunar aspect (arrow), among other typical round granules, is recognizable. Bars, (A) 0.08 μm; (B) 0.02 μm (Reproduced from reference [46]).
Figure 3. Ultrastructural findings of bone marrow biopsies from patients with active multiple myeloma. In (A), a mast cell with typical electron-dense round granules and in (B), at higher magnification, a cytoplasmic granule with a semilunar aspect (arrow), among other typical round granules, is recognizable. Bars, (A) 0.08 μm; (B) 0.02 μm (Reproduced from reference [46]).
Ijms 20 00481 g003
Ijms 20 00481 g004 550
Figure 4. Double FVIII-RA (green) and tryptase (red) confocal laser microscopy from multiple myeloma (MM) (A) and monoclonal gammopathy of undetermined significance (MGUS) (B) bone marrow biopsy specimens. In (A), a MM vessel is lined by both endothelial cells positive for FVIII-RA and by mast cells positive for tryptase (arrowheads). Mast cells containing tryptase-positive granules (arrows) are also recognizable on the abluminal side of the vessel. In (B), a MGUS vessel is lined only by endothelial cells positive for FVIII-RA and is surrounded by tryptase-positive mast cells (arrows). Bars, (A) 15.8 μm; (B) 12.5 μm (Reproduced from reference [77]).
Figure 4. Double FVIII-RA (green) and tryptase (red) confocal laser microscopy from multiple myeloma (MM) (A) and monoclonal gammopathy of undetermined significance (MGUS) (B) bone marrow biopsy specimens. In (A), a MM vessel is lined by both endothelial cells positive for FVIII-RA and by mast cells positive for tryptase (arrowheads). Mast cells containing tryptase-positive granules (arrows) are also recognizable on the abluminal side of the vessel. In (B), a MGUS vessel is lined only by endothelial cells positive for FVIII-RA and is surrounded by tryptase-positive mast cells (arrows). Bars, (A) 15.8 μm; (B) 12.5 μm (Reproduced from reference [77]).
Ijms 20 00481 g004
Table
Table 1. Tumors in which a relationship between angiogenesis and mast cell number has been established.
Table 1. Tumors in which a relationship between angiogenesis and mast cell number has been established.
TumorReferences
Haemangioma, haemangioblastoma [41]
Lymphomas [42,43,44,45]
Multiple myeloma [46]
Bagg AlbinoMyelodysplastic syndrome [47]
B-cell chronic lymphocytic leukemia [38,48]
Breast cancer [49,50,51,52,53]
Gastric cancer [54,55,56,57]
Colorectal cancer [58,59]
Pancreatic cancer [60,61]
Uterine cervix cancer [62,63,64]
Melanoma[39,65,66]
Pulmonary adenocarcinoma [67]
Thyroid cancer [68]
Table
Table 2. Anti-tumor drugs that target regulatory mast cell molecules.
Table 2. Anti-tumor drugs that target regulatory mast cell molecules.
DrugMain Target in Mast Cell
Imatinib mesylate (Gleevec, ST1571)c-kit
Sorafenibc-kit
Sunitinibc-kit
Pazopanib (GW786034)c-kit
Axitinibc-kit
Dasatinibc-kit
EnzastaurinPKC-β
Alemtuzumab (Campath)CD52
CpG activator (Promune)TLR9
MDX 060CD30 (ligand for CD301) *
Tanespimycin (17AAG)Heat shock protein 90 β
* Which can regulate chemokine secretion by mast cells.

Share and Cite

MDPI and ACS Style

Ribatti, D.; Tamma, R.; Vacca, A. Mast Cells and Angiogenesis in Human Plasma Cell Malignancies. Int. J. Mol. Sci. 2019, 20, 481. https://doi.org/10.3390/ijms20030481

AMA Style

Ribatti D, Tamma R, Vacca A. Mast Cells and Angiogenesis in Human Plasma Cell Malignancies. International Journal of Molecular Sciences. 2019; 20(3):481. https://doi.org/10.3390/ijms20030481

Chicago/Turabian Style

Ribatti, Domenico, Roberto Tamma, and Angelo Vacca. 2019. "Mast Cells and Angiogenesis in Human Plasma Cell Malignancies" International Journal of Molecular Sciences 20, no. 3: 481. https://doi.org/10.3390/ijms20030481

APA Style

Ribatti, D., Tamma, R., & Vacca, A. (2019). Mast Cells and Angiogenesis in Human Plasma Cell Malignancies. International Journal of Molecular Sciences, 20(3), 481. https://doi.org/10.3390/ijms20030481

Note that from the first issue of 2016, this journal uses article numbers instead of page numbers. See further details here.

Article Metrics

Back to TopTop