No abstract

Although obesity is known as a risk factor for several human cancers, the association of obesity with cancer recurrence and metastasis remains to be characterized. Here, B16-BL6 melanoma and Lewis lung carcinoma cells were intravenously injected into diabetic (db/db) and obese (ob/ob) mice. The number of experimental lung colonies was markedly promoted in these mice when compared with C57BL/6 mice. In contrast, tumor growth at the implanted site was comparable when cells were inoculated orthotopically. The use of B16-BL6 cells stably transfected with the luciferase gene revealed that the increased metastasis reflected a difference mainly within 6 hr after the intravenous inoculation of tumor cells. Administration of recombinant leptin in ob/ob mice abolished the increase in metastasis early on as well as the decrease in the splenic NK cell number. In addition, depletion of NK cells by an anti-asialo-GM1 antibody abrogated the enhanced metastasis in db/db mice. These results demonstrate that metastasis is markedly promoted in diabetic and obese mice mainly because of decreased NK cell function during the early phase of metastasis. ' 2006 Wiley-Liss, Inc.Key words: obesity; metastasis; NK cell; leptin Obesity has become one of the most critical problems in human health, because it can lead to more serious disorders such as cardiovascular disease, pulmonary disorders and metabolic syndrome. 1 Attention has recently been focused on the influence of obesity on carcinogenesis and the progression of cancer. A cohort study in the United States revealed that an increased body-mass index is significantly associated with higher rates of death because of cancer. 2 In addition, obesity increases the risk of cancer developing in the prostate, colorectum, breast, endometrium and elsewhere. [3][4][5][6][7] Similarly, the risk of renal cell cancer is increased in patients with diabetes mellitus, a disease closely associated with obesity. 8 These observations are well correlated with the finding that the carcinogen-induced multiplicity of premalignant colonic lesions is increased in db/db obese and diabetic mice. 9 Metastasis is the major cause of mortality in cancer patients. Maehle et al. reported that breast cancer patients with obesity had a higher risk of lymph node metastases. 10 Although evidence has accumulated of an association of cancer with obesity, the influence of obesity and diabetes on cancer metastasis remains to be investigated. In addition, the mechanisms by which obesity promotes the development and progression of cancer are still unknown. Material and methods MiceMale C57BL/6, C57BL/KsJ-db/db (db/db) and C57BL/6J-ob/ob (ob/ob) mice, 5-6 weeks old, were maintained in a specific pathogen-free barrier facility under laminar airflow conditions with a 12-hr light/dark cycle, a controlled humidity of 55% 6 5% and a temperature of 22°C 6 1°C. This study was conducted in accordance with the standards outlined in the Guidelines for the Care and Use of Laboratory Animals of the University of Toyama. Cell cultureB16-BL6 ...

HTLV-1 Tax oncoprotein induces persistent activation of the transcription factor NF-B and CREB (cAMP-response element-binding protein)/ATF.Transforming growth factor-␤-activated kinase 1 (TAK1) has been shown to play a critical role in these transcription factors. Here, we found that TAK1 was constitutively activated in Tax-positive HTLV-1-transformed T cells. Tax induced persistent overexpression of TAK1-binding protein 2 (TAB2), but not TAB3, which is essential for TAK1 activation. Surprisingly, TAK1 was not involved in the activation of NF-B. On the other hand, JNK and p38 mitogen-activated protein kinases were activated by TAK1. In addition, ATF2, but not CREB, was a target for the TAK1-JNK pathway, and p38 negatively regulated TAK1 activity through TAB1 phosphorylation. These results indicate that Tax-mediated TAK1 activation is important for the activation of ATF2 rather than NF-B.Human T-cell lymphotropic virus type 1 (HTLV-1) 2 is known as the cause of adult T-cell leukemia/lymphoma (ATLL). Infection with this virus results in the activation of several transcriptional factors including NF-B and CREB in host CD4ϩ T cells. In particular, the activation of NF-B correlates with the expression of HTLV-1-derived oncoprotein Tax (1). It has been reported that Tax associates with IKK␥ to activate IB kinase (IKK) complex (2).Transforming growth factor-␤-activated kinase 1 (TAK1) is one of the most characterized MAPK kinase kinase family members and is activated by various cellular stresses, including tumor necrosis factor-␣ (TNF-␣) and interleukin-1 (3-13). It has recently been shown that TAK1 participates in diverse cellular functions, including activation and differentiation of T lymphocytes (14 -17). TAK1 functions as an upstream stimulatory molecule of the JNK, p38, and IKK signaling pathways. We have reported that phosphorylation at Thr-187 is essential for TAK1 activation, and TAK1-binding protein 1 (TAB1) and TAB2 are important for inducing phosphorylation (18). Cheung et al. (12) report that the association of TAB1 with p38␣ negatively regulates TAK1 kinase activity by phosphorylating TAB1 at Ser-423, Thr-431, and Ser-438. On the other hand, TAB2 functions as an adaptor protein to recruit TAK1 to TRAF2 (TNF-␣ receptor-associated factor) and TRAF6 in the TNF-␣ and interleukin-1 signaling pathways, respectively (8,11,13). Recently, TAB3 has been reported as a new TAK1-binding protein (13). This molecule has a structure similar to TAB2 and functions as a supportive protein of TAB2.Various alternations of intracellular functions by infecting HTLV-1 and Tax expression result in the onset of ATLL; however, the molecular mechanisms of these alternations are still unclear. The present study investigated whether TAK1 is involved in Tax-dependent NF-B activation and other signaling pathways in HTLV-1-transformed cells. , and CREB were purchased from Cell Signaling Technology. Phospho-specific anti-TAK1 (Thr-187) and anti-TAB1 (Ser-438) antibodies are described previously (12, 18). Antibody against TAB3 was generat...

No abstract

No abstract

No abstract

No abstract

A case is reported of lymphoplasmacytoid lymphoma (LPL) associated with a monoclonal immunoglobulin (Ig) M and cold agglutinin disease (CAD) that was successfully treated with rituximab. A 52-yr-old male was admitted with a direct antiglobulin test positive haemolytic anaemia and thrombocytopenia associated with monoclonal IgM. Bone marrow examinations disclosed the marked infiltration of medium-sized lymphoma cells with plasmacytoid differentiation that indicated non-Hodgkin's lymphoma of B-cell origin (LPL). Prednisolone and combination chemotherapy were temporarily effective for both anaemia and thrombocytopenia, although these strategies became refractory and bone marrow lymphoplasmacytosis persisted. CAD ameliorated, and the serum level of IgM decreased in association with the disappearance of lymphoma cells and clonal rearrangement of the Ig heavy chains in the bone marrow after treatment with rituximab. Rituximab played a significant role in the treatment of refractory CAD associated with LPL.