Ryuta Nakao

Autocrine and paracrine loops between cancer cells and macrophages promote lymph node metastasis via CCR4/CCL22 in head and neck squamous cell carcinoma

Lymph node metastasis is a poor prognostic factor for patients with head and neck squamous cell carcinoma (HNSCC). However, its molecular mechanism has not yet been fully understood. In our study, we investigated the expression of CCR4 and its ligand CCL22 in the HNSCC tumor microenvironment and found that the CCR4/CCL22 axis was involved in lymph node metastasis of HNSCC. CCR4 was expressed in 20 of 31 (64.5%) human tongue cancer tissues, and its expression was significantly correlated with lymph node metastasis (p < 0.01) and lymphatic invasion (p < 0.05). CCR4 was expressed in three of five human HNSCC cell lines tested. CCR4+ HNSCC cells, but not CCR4− cells, showed enhanced migration toward CCL22, indicating that functional CCR4 was expressed in HNSCC cell lines. CCL22 was also expressed in cancer cells (48.4% of tongue cancer tissues) or CD206+ M2‐like macrophages infiltrated in tumors and draining lymph nodes. CCL22 produced by cancer cells or CD206high M2‐like macrophages increased the cell motility of CCR4+ HNSCC cells in vitro in an autocrine or paracrine manner. In the mouse SCCVII in vivo model, CCR4+ cancer cells, but not CCR4− cells, metastasized to lymph nodes which contained CCL22 producing M2‐like macrophages. These results demonstrate that lymph node metastasis of CCR4+ HNSCC is promoted by CCL22 in an autocrine or M2‐like macrophage‐dependent paracrine manner. Therefore, the CCR4/CCL22 axis may be an attractive target for the development of diagnostic and therapeutic strategies for patients with HNSCC.

Immunohistochemical analysis for Sox9 reveals the cartilaginous character of chondroblastoma and chondromyxoid fibroma of the bone.

Chondroblastoma, which is histologically composed of mononuclear cell proliferation and lobules of immature cartilage, and chondromyxoid fibroma, which is composed of myxoid lobules with spindle or stellate cells and a cellular fibrous rim with spindle cells, are both rare tumors. Based on histogenetic investigation including immunohistochemistry, matrix biochemistry, and electron microscopy, chondroblastoma is thought to contain chondrogenic cells, whereas chondromyxoid fibroma is considered to contain myofibroblastic cells, as well as chondrogenic cells, and chondroid matrix. In this study, we performed immunohistochemical analysis for Sox9, which is an essential transcriptional factor for chondrogenesis, to examine the possible chondrogenic nature of chondroblastoma and chondromyxoid fibroma. Formalin-fixed, paraffin-embedded tissues obtained from 10 cases of chondroblastoma and 11 cases of chondromyxoid fibroma were immunostained with antibody to Sox9. In addition, immunohistochemical study for collagen type II, which is a major component of cartilaginous matrix, was performed. Sox9 was positive in 8 chondroblastomas and 10 chondromyxoid fibromas. Positive staining was observed in the nuclei of the tumor cells. The matrices of 7 chondroblastomas and of 8 chondromyxoid fibromas were immunopositive for collagen type II. The findings suggest the cartilaginous differentiation of chondroblastoma and chondromyxoid fibroma.

Close pathogenetic relationship between ocular immunoglobulin G4-related disease (IgG4-RD) and ocular adnexal mucosa-associated lymphoid tissue (MALT) lymphoma

Immmunoglobulin G4 (IgG4)-related disease (IgG4-RD) is a chronic sclerosing inflammatory disease characterized by mass-forming lesions such as swelling, nodules or hypertrophy in one or more organs...

The reciprocal change of neurotrophin-4 and glial cell line-derived neurotrophic factor protein in the muscles, spinal cord and cerebellum of the dy mouse.

Abstract. Laminin α2 (merosin)-deficient congenital muscular dystrophy (CMD) patients show progressive muscle fiber necrosis and ineffective muscle regeneration, probably due to a lower formation of multinucleated myotubes due to an adhesion defect of myoblasts to each other. Some recent studies found that CMD patients have a white matter disorder and cerebellum atrophy. In the spinal cord of dy mice, a model of CMD, inducible nitric oxide synthase (iNOS) was markedly expressed. Using Western blotting and immunohistochemical analyses, we investigated the levels of neurotrophin-4 (NT-4), brain-derived neurotrophic factor, glial cell line-derived neurotrophic factor (GDNF) and ciliary neurotrophic factor (CNTF) in the central nervous system and skeletal muscles of dy mice. In the dy mice, the microtubule-associated protein-2 (MAP-2) protein level was markedly decreased in the Purkinje and granule cells of the cerebellum, and in lumbar motoneurons of the spinal cord. The motoneurons and axons of dy mice possessed lower expressions of phosphorylated tau. The amount of NT-4 was markedly lower in the cerebellum, spinal cord and hindlimb muscles of dy mice. In dy mice, GDNF was markedly enhanced in the Purkinje and granule cells of the cerebellum, in many lumbar motoneurons, and in the regenerating atrophied fibers. The CNTF protein level did not differ in the hindlimb muscles between the normal and dy mice. Therefore, GDNF could act to inhibit the death of Purkinje and granular neurons, and motoneurons, and to promote the remodeling of the neuromuscular junction of atrophied muscle fibers of dy mice. Furthermore, dy mice include neurogenic abnormalities in the cerebellum and spinal cord along with myogenic disorder of muscle fibers.

Primary Intra-aortic Epstein-Barr Virus–Positive Large B-Cell Lymphoma Presenting as Aortic Mural Thrombosis: An Entity Distinct From Intravascular Large B-Cell Lymphoma

Intravascular selective growth of neoplastic B lymphocytes is a characteristic finding of intravascular large B-cell lymphoma (IVLBCL). However, because neoplastic B cells of IVLBCL grow merely in the lumina of capillaries or small vessels, primary IVLBCL of the great vessels is considered exceptional. To our knowledge, only 2 primary B-cell lymphomas in the lumina of the vena cava have been reported. However, there has been no report of primary B-cell lymphoma with intra-aortic growth. We describe a novel manifestation of primary Epstein-Barr virus–positive large B-cell lymphoma mainly affecting the lumina of the aorta and its major branches in a 76-year-old man. He had a long-term fever that was refractory to antibiotics and aortic mural thrombosis with visceral embolization. Because he had no detectable mass suggesting a malignancy, it was difficult to diagnose while he was alive. He died without anticancer treatment, and the confirmed diagnosis was made at autopsy.