Mast cells promote the growth of Hodgkin's lymphoma cell tumor by modifying the tumor microenvironment that can be perturbed by bortezomib

• Published in: Leukemia Vol. 26; no. 10; pp. 2269 - 2276
• Main Authors: Mizuno, H, Nakayama, T, Miyata, Y, Saito, S, Nishiwaki, S, Nakao, N, Takeshita, K, Naoe, T
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.10.2012; Nature Publishing Group
• Subjects: 631/443/1338/16; 631/67/1059/99; 631/67/327; 692/699/67/1990/291/1556; Animals; Antineoplastic Agents - pharmacology; Biological and medical sciences; Boronic Acids - pharmacology; Bortezomib; Cancer; Cancer cells; Cancer Research; Cell death; Cell Line, Tumor; Cell Proliferation - drug effects; Critical Care Medicine; Cytokines; Degranulation; Disease; Drug therapy; Female; Fibrosis; Genetic aspects; Growth; Growth factors; Health aspects; Hematologic and hematopoietic diseases; Hematology; Hodgkin Disease - drug therapy; Hodgkin Disease - pathology; Hodgkin's disease; Hodgkin's lymphoma; Humans; Intensive; Internal Medicine; Laboratory animals; Leukemia; Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis; Lymphoma; Mast cells; Mast Cells - drug effects; Mast Cells - physiology; Medical sciences; Medicine; Medicine & Public Health; Metastases; Mice; Mice, Inbred C57BL; Mice, SCID; Monocyte chemoattractant protein 1; Oncology; original-article; Prognosis; Prostaglandin E2; Pyrazines - pharmacology; Transplantation; Tumor microenvironment; Tumor Microenvironment - drug effects; Tumors; Vascular endothelial growth factor; Vascularization; United States > US; Japan; fibrosis; mast cells; bortezomib; angiogenesis; Hodgkin's lymphoma; Antineoplastic agent; Cell proliferation; Bortezomib; Hematology; Cell microenvironment; Hodgkin disease; Malignant hemopathy; Lymphoma; Angiogenesis; Analog; Proteasome inhibitor; Lymphoproliferative syndrome; Fibrosis; Dipeptides; Mast cell; Neovascularization; Tumor cell; Cancer
• ISSN: 0887-6924; 1476-5551
• DOI: 10.1038/leu.2012.81

Hodgkin's lymphoma is frequently associated with mast cell infiltration that correlates directly with disease severity, but the mechanisms underlying this relationship remain unclear. Here, we report that mast cells promote the growth of Hodgkin's tumor by modifying the tumor microenvironment. A transplantation assay shows that primary murine mast cells accelerate tumor growth by established Hodgkin's cell lines, and promote marked neovascularization and fibrosis. Both mast cells and Hodgkin's cells were sensitive to bortezomib, but mast cells were more resistant to bortezomib. However, bortezomib inhibited degranulation, PGE 2 -induced rapid release of CCL2, and continuous release of vascular endothelial growth factor-A from mast cells even at the concentration that did not induce cell death. Bortezomib-treated mast cells lost the ability to induce neovasculization and fibrosis, and did not promote the growth of Hodgkin tumor in vivo . These results provide further evidence supporting causal relationships between inflammation and tumor growth, and demonstrate that bortezomib can target the tumor microenvironment.