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Query: UMLS:C0027651 (tumor)
 685,946 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The mitogen-activated protein kinase-extracellular signal-regulated kinase signaling element (MAPK-ERK) plays a critical role in natural killer (NK) cell lysis of tumor cells, but its upstream effectors were previously unknown. We show that inhibition of phosphoinositide-3 kinase (PI3K) in NK cells blocks p21-activated kinase 1 (PAK1), MAPK kinase (MEK) and ERK activation by target cell ligation, interferes with perforin and granzyme B movement toward target cells and suppresses NK cytotoxicity. Dominant-negative N17Rac1 and PAK1 mimic the suppressive effects of PI3K inhibitors, whereas constitutively active V12Rac1 has the opposite effect. V12Rac1 restores the activity of downstream effectors and lytic function in LY294002- or wortmannin-treated, but not PD98059-treated, NK cells. These results document a specific PI3K-->Rac1-->PAK1-->MEK-->ERK pathway in NK cells that effects lysis.
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PMID:Pivotal role of phosphoinositide-3 kinase in regulation of cytotoxicity in natural killer cells. 1106 2

Sinonasal natural killer (NK)/T-cell lymphomas are common in Asia and areas of South and Central America but are rarely seen in the United States, where they have not been as well characterized. Fifteen cases diagnosed in Southern California were studied with respect to histologic features, immunophenotype, Epstein-Barr virus EBER in-situ hybridization (EBV EBER-ISH), and T-cell receptor gamma chain (TCR-gamma) gene rearrangement. Although ethnic background was available for only seven patients, six were of Asian or Hispanic descent with only one non-Hispanic white known. Twelve presented as sinonasal lesions, but three were limited to the oropharynx. Most cases (11 of 15) demonstrated both necrosis and an angiodestructive pattern. All cases demonstrated cytoplasmic CD3 positivity (15 of 15), and were positive for both TIA-1 and granzyme B (14 of 14). Perforin was positive in 5 of 14. CD56 was expressed in 10 of 15 and CD8 in 3 of 15. EBV EBER-ISH was positive in 14 of 14 and TCR-gamma gene rearrangement was detected in 1 of 14 cases. None (0 of 14) were positive for CD16 or CD57. Although CD16-positive histiocytes were abundant, double-label EBER-ISH/IHC failed to identify CD16 expression on EBV-positive tumor cells. Three cases with pleomorphic large cell morphology showed focal CD30 positivity, raising the differential diagnosis of anaplastic large cell lymphoma, but all were ALK-1-negative and otherwise similar to the other cases of NK/T-cell lymphoma. Sinonasal NK/T-cell lymphomas in the United States most often occur in ethnic groups from areas of reported high frequency (Asia, Central and South America), although less commonly than in endemic populations, and are otherwise similar phenotypically. A combined approach, including immunohistochemistry, EBV EBER-ISH, and TCR gene rearrangement studies, is most helpful to arrive at the correct diagnosis.
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PMID:Sinonasal NK/T-cell lymphomas in the United States. 1107 52

A case of primary gastric T-cell lymphoma, which was positive for granzyme B, is reported. The patient was a 47-year-old Japanese female who complained of a dull upper abdominal pain. Radiographic and endoscopic examinations revealed an ulcerative infiltrative lesion in her stomach. Following the confirmation of a high-grade malignant lymphoma, a distal gastrectomy with regional lymph nodal dissection was performed. The histology of the gastric lesion revealed a malignant lymphoma of the diffuse pleomorphic type without lymph nodal involvement. Immunohistochemistry revealed that the tumor cells were positive for LCA, CD3, TIA-1 and granzyme B, but were negative for CD4, CD8, CD56, CD30, L-26, EMA, TCR alpha/beta and TCR gamma/delta. Because the tumor cells showed T cell nature with cytotoxic activity proved by TIA-1 and granzyme B, and without evidence of further maturation of T cell, a malignant lymphoma originating from extrathymic-derived T cells was suggested.
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PMID:Granzyme B-positive primary gastric T-cell lymphoma: gastric T-cell lymphoma with the possibility of extrathymic T cell origin. 1110 59

We studied 10 cases of Lennert's lymphoma (lymphoepithelioid lymphoma) to evaluate the cellular origin of the neoplastic cells. There were six men and four women, aged 38 to 75 years (median, 56 yrs; mean, 59 yrs). The lymphoma cells tended to remain confined to lymph nodes, and extranodal involvement was rare. The mean overall survival was 42.2 months, which is relatively good compared with other peripheral T-cell lymphomas. Morphologically, the lymph node was occupied by small to large clusters of epithelioid cells interspersed with medium to large atypical lymphoid cells. In seven cases, large atypical lymphoid cells resembling Hodgkin's or Reed-Sternberg cells were observed. The phenotypes of these neoplastic cells were CD3+ CD4- CD8+ in five cases, CD3+ CD4+ CD8- in four cases, and CD3+ CD4- CD8- in one case. TIA-1 was positive by immunohistochemical staining in seven cases, whereas four cases were positive for granzyme B. Clonal rearrangement of the T-cell receptor gene was confirmed in all cases by either Southern blot hybridization or a polymerase chain reaction-based denature gradient gel electrophoresis method. Epstein-Barr virus was negative by in situ hybridization in all but one case. Lennert's lymphoma was formerly known as a CD4+ helper T-cell neoplasm. Our results suggest that, at least in some cases, the neoplastic cells are of cytotoxic T-cell origin.
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PMID:Lennert's lymphoma: a variant of cytotoxic T-cell lymphoma? 1111 83

Recently, we demonstrated that the presence of high percentages of activated cytotoxic T-lymphocytes (CTLs) in biopsy specimens of both Hodgkin's disease (HD) and ALK negative anaplastic large cell lymphoma (ALCL) is associated with a poor prognosis. To test whether this biological prognostic factor is more important in predicting clinical outcome than histological diagnosis or clinical factors, we compared the prognostic value of these parameters in an expanded group of classical HD and ALK negative ALCL. Tumor biopsies of classical HD (n = 83) and ALK negative systemic nodal ALCL (n = 43) were investigated for the presence of activated CTLs by immunohistochemistry, using a monoclonal antibody directed against granzyme B. Percentages of activated CTLs were quantified using Q-PRODIT, and their prognostic value was compared to that of histological diagnosis and clinical parameters, including age and stage. Both in classical HD and ALK negative ALCL, a high percentage of activated CTLs (ie > or = 15%) identified a group of patients with poor overall and progression-free survival time, even when adjusted for stage. In multivariate analysis, percentage of activated CTLs remained a strong independent prognostic marker, and was more sensitive than histological diagnosis or clinical factors in predicting overall survival time. We conclude that a high percentage of activated CTLs in the reactive infiltrate of ALK negative ALCL and classical HD is a strong indicator for an unfavorable clinical outcome, regardless of histological diagnosis or clinical parameters. As such, this biological parameter may be an especially helpful tool to determine therapeutic strategies in cases in which the differentiation between ALK negative ALCL and HD remains difficult.
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PMID:Percentage of activated cytotoxic T-lymphocytes in anaplastic large cell lymphoma and Hodgkin's disease: an independent biological prognostic marker. 1123 71

Epstein-Barr virus (EBV) gene expression in tumor cells of posttransplant lymphoproliferative disorder (PTLD) patients resembles that of EBV transformed B-cell lines (LCL). EBV-specific cytotoxic T-lymphocytes can be generated by stimulating peripheral blood lymphocytes with autologous LCL. We describe a standardized method for the growth inactivation and cryopreservation of LCL for optimal T-cell stimulation and analyzed the function and phenotype of responding T-cells. LCL growth was completely blocked by mitomycin C treatment (McLCL) and McLCL could be cryopreserved while retaining excellent APC function. McLCL stimulated both CD4(+) and CD8(+) T-cells as measured by HLA-DR and CD25 expression using FACS analysis. EBV-specific CTL activity and T-cell proliferation were induced and immunocytochemical staining showed CD4(+) and (granzyme B positive) CD8(+) T-cells rosetting with McLCL. Granzymes A and B, IFN-gamma, and IL-6 were detected at significant levels in the supernatant. Thus, ex vivo T-cell activation with cryopreserved McLCL results in activation of both CD4(+) and CD8(+) T-cells producing a Th1-like cytokine profile, making this a suitable protocol for adoptive therapy of PTLD.
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PMID:Functional CD4(+) and CD8(+) T-cell responses induced by autologous mitomycin C treated Epstein-Barr virus transformed lymphoblastoid cell lines. 1127 16

Cytotoxic T lymphocytes kill virus-infected and tumor cell targets through the concerted action of proteins contained in cytolytic granules, primarily granzyme B and perforin. Granzyme B, a serine proteinase with substrate specificity similar to the caspase family of apoptotic cysteine proteinases, is capable of cleaving and activating a number of death proteins in target cells. Despite the ability to engage the death pathway at multiple entry points, the preferred mechanism for rapid induction of apoptosis by granzyme B has yet to be clearly established. Here we use time lapse confocal microscopy to demonstrate that mitochondrial cytochrome c release is the primary mode of granzyme B-induced apoptosis and that Bcl-2 is a potent inhibitor of this pivotal event. Caspase activation is not required for cytochrome c release, an activity that correlates with cleavage and activation of Bid, which we have found to be cleaved more readily by granzyme B than either caspase-3 or caspase-8. Bcl-2 blocks the rapid destruction of targets by granzyme B by blocking mitochondrial involvement in the process.
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PMID:Granzyme B-mediated apoptosis proceeds predominantly through a Bcl-2-inhibitable mitochondrial pathway. 1127 59

This work aims to demonstrate that CD4(+)CD56(+) malignancies arise from transformed cells of the lymphoid-related plasmacytoid dendritic cell (pDC) subset. The analysis of malignant cells from 7 patients shows that in all cases, like pDCs, leukemic cells are negative for lineage markers CD3, CD19, CD13, CD33, and CD11c but express high levels of interleukin-3 receptor alpha chain (IL-3Ralpha), HLA-DR, and CD45RA. Tumor cells produce interferon-alpha in response to influenza virus, while upon maturation with IL-3 they become a powerful inducer of naive CD4(+) T-cell proliferation and promote their T-helper 2 polarization. As pDCs, leukemic cells also express pre-Talpha and lambda-like 14.1 transcripts, arguing in favor of a lymphoid origin. In addition, malignant cells express significant levels of CD56 and granzyme B. Overall, those observations suggest that CD4(+)CD56(+) leukemic cells could represent the malignant counterpart of pDCs, both of which are closely related to B, T, and NK cells.
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PMID:Identification of a leukemic counterpart of the plasmacytoid dendritic cells. 1134 51

Caspase-associated recruitment domains (CARDs) are protein interaction domains that participate in activation or suppression of CARD-carrying members of the caspase family of apoptosis-inducing proteases. A novel CARD-containing protein was identified that is overexpressed in some types of cancer and that binds and suppresses activation of procaspase-9, which we term TUCAN (tumor-up-regulated CARD-containing antagonist of caspase nine). The CARD domain of TUCAN selectively binds itself and procaspase-9. TUCAN interferes with binding of Apaf1 to procaspase-9 and suppresses caspase activation induced by the Apaf1 activator, cytochrome c. Overexpression of TUCAN in cells by stable or transient transfection inhibits apoptosis and caspase activation induced by Apaf1/caspase-9-dependent stimuli, including Bax, VP16, and staurosporine, but not by Apaf1/caspase-9-independent stimuli, Fas and granzyme B. High levels of endogenous TUCAN protein were detected in several tumor cell lines and in colon cancer specimens, correlating with shorter patient survival. Thus, TUCAN represents a new member of the CARD family that selectively suppresses apoptosis induced via the mitochondrial pathway for caspase activation.
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PMID:TUCAN, an antiapoptotic caspase-associated recruitment domain family protein overexpressed in cancer. 1140 76

A 65-year-old man was admitted with swelling of the right neck and bilateral inguinal lymph nodes. Endoscopic examination revealed no nasal infiltration. Pathological examination of a neck lymph node biopsy specimen revealed peripheral T-cell lymphoma according to the Revised European-American Classification of Lymphoid Neoplasms (REAL). The phenotype of the lymphoma cells was CD56+, CD16-, CD2+, surface CD3-, cytoplasmic CD3+, CD4+, CD8-, CD5+, CD7- and CD45RO+. May-Giemsa staining demonstrated no azurophilic granules in the lymphoma cells. Immunohistopathologic examination showed negativity for TIA-1 and granzyme B, and rearrangement of the TCR C beta 1 gene was also noted. These findings strongly suggested that this was a T-cell lymphoma. The patient received 8 courses of CHOP chemotherapy plus sobuzoxane. This led to a marked decrease of lymph node swelling, and currently the patient is still in remission. According to the REAL classification, T/NK-cell lymphomas are included among the peripheral T cell tumours, and seem to constitute a heterogeneous group of neoplasms. Although some cases of CD4+ CD56+ lymphoma have been reported, the present case appears to be the first example to show TCR gene rearrangement and negativity for TIA-1 and granzyme B. Since the classification of T/NK-cell lymphoma is still controversial, accumulation of such cases may help to better define T/NK-cell neoplasms.
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PMID:[CD56- and CD4-positive non-Hodgkin's lymphoma of probable T-cell origin]. 1145 63


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