FasL is more frequently expressed in liver metastases of colorectal cancer than in matched primary carcinomas

Colorectal carcinoma cells have recently been shown to express Fas ligand (FasL). This ligand could allow the tumour cells to evade activated tumour-infiltrating lymphocytes (TILs) by inducing their apoptosis and would thus promote tumour survival and possibly metastasis formation. To test this hypothesis in vivo we analysed the expression of FasL mRNA and protein in paired tissue samples of normal colonic mucosa (N), primary colorectal carcinomas (T) and their metastases (M) from a total of 21 patients by four different methods. Additionally, the presence and activation status of infiltrating lymphocytes, which might contribute to the total amount of FasL in the tissue, was determined by semiquantitative reverse transcription–polymerase chain reaction (RT–PCR) in the same samples. The frequency of FasL detection was 30–40% in T and was 60–100% in M, depending on the sensitivity of the method. Simultaneously, the amount of CD25 mRNA, used as a measure of the number of activated TILs, was in 90% of patients lower in M than in T. The increased frequency of FasL detection in liver metastases was therefore not due to the presence of activated TILs. We conclude that metastasizing subpopulations of colorectal tumour cells express FasL more frequently than the primary carcinomas and may be able to eliminate activated TILs in vivo via Fas/FasL-induced apoptosis or other hitherto unknown mechanisms. © 1999 Cancer Research Campaig

Revelations About Carotid Body Function Through its Pathological Role in Resistant Hypertension

Much recent attention has been given to the carotid body because of its potential role in cardiovascular disease states. One disease, neurogenic hypertension, characterised by excessive sympathetic activity, appears dependent on carotid body activity that may or may not be accompanied by sleep-disordered breathing. Herein, we review recent literature suggesting that the carotid body acquires tonicity in hypertension. We predict that carotid glomectomy will be a powerful way to temper excessive sympathetic discharge in diseases such as hypertension. We propose a model to explain that signalling from the ‘hypertensive’ carotid body is tonic, and hypothesise that there will be a sub-population of glomus cells that channel separately into reflex pathways controlling sympathetic motor outflows

Patterns of cytokine gene expression in peripheral T-cell lymphoma of angioimmunoblastic lymphadenopathy type

Peripheral T-cell lymphoma of angioimmunoblastic lymph-adenopathy type (AILD-TCL) is histologically characterized by a mixed infiltrate of atypical T-cells, B-cells including B immunoblasts, and plasma cells, as well as eosinophilic granulocytes accompanied by proliferated high endothelial venules, while, clinically, fever and weight loss are often observed. These morphologic and clinical pecularities are widely believed to reflect abnormal patterns of cytokine expression. To evaluate this hypothesis, 11 lymph nodes with AILD-TCL were studied for the presence of tumor necrosis factor-alpha (TNF), lymphotoxin (LT), interleukin-6 (IL-6), and IL-1 beta transcripts by in situ hybridization (ISH) using [35S]-labeled cytokine-specific RNA probes in seven cases subsequent to immunohistology for cell type characteristic antigens. Expression of all four cytokines was strongly enhanced in AILD-TCL when compared with the control groups of lymphoblastic lymphomas and peripheral T-cell lymphomas, other than AILD-TCL. TNF and LT transcripts were present in atypical T cells and in a variable proportion of B immunoblasts in all AILD-TCL cases, whereas IL-6 and IL-1 beta specific transcripts were mainly found in nonlymphoid cells. To verify a possible cytokine expression by Epstein-Barr virus (EBV)-infected cells, which are frequently present in AILD-TCL, the detection of EBV-encoded nuclear RNAs (EBER) was combined with ISH for cytokine transcripts. It became evident that expression of LT and TNF by EBV-infected cells was largely restricted to B immunoblasts, which were only infrequently present in most AILD-TCL cases, whereas the expression of IL-6 was very rare, and IL-1 beta was not found in EBV-infected cells. These data suggest that expression of TNF and LT genes may contribute to the characteristic histologic and clinical features of AILD-TCL and that cytokine expression by EBV-infected cells does not, in most cases, contribute significantly to the overall cytokine expression. Because it has been shown that LT is an autocrine growth factor for EBV-infected B cells, expression of this cytokine could contribute to the proliferation of EBV-infected B cells in AILD-TCL and, in the setting of immunosuppression, may ultimately play a role in the development of B-immunoblastic lymphomas.</jats:p

Anaplastic large-cell lymphomas of T-cell and null-cell phenotype express cytotoxic molecules

To further specify the cellular origin and nature of anaplastic large- cell lymphoma (ALCL) and its relationship to other lymphoid neoplasms, particularly Hodgkin's disease (HD), we investigated the presence of cytotoxic molecules in a large well-characterized series of these tumors. For expression of the cytotoxic molecules perforin and granzyme B, in situ hybridization (ISH) and immunohistology were used, respectively. Overall, 23 of 25 ALCLs of T/null phenotype and five (three mixed cellularity and two nodular sclerosis) of 57 HD cases showed the presence of perforin transcripts and/or granzyme B molecules in neoplastic cells. Polymerase chain reaction (PCR) analysis of ALCLs showed that most (10 of 11) cases of null-cell ALCL (null-ALCL) contained a clonal rearrangement of T-cell receptor beta-chain genes, as did T-cell ALCL (T-ALCL; 9 of 10 cases). However, both cytotoxic molecules and clonally rearranged T-cell receptor beta-chain genes were absent in seven of seven and eight of nine cases of B-cell ALCL (B-ALCL), respectively. These data show that all or nearly all T-ALCLs, irrespective of the clinical subform or the lack of T-cell-associated molecules, are derived from activated cytotoxic T cells. The same appears to be true for the neoplastic cells of rare HD cases. These findings indicate that T-ALCLs are different from B-ALCLs and the majority of HD cases, and suggest that some HD cases, especially those with T-cell antigen-positive tumor cells, may be closely related to T- ALCL, at least in terms of cellular origin.</jats:p

Expression of Epstein-Barr virus-gene products in Burkitt's lymphoma in Northeast Brazil

The Epstein-Barr Virus (EBV) is consistently found in tumor cells of Burkitt's lymphoma (BL) endemic in central Africa and malaria is considered a pathogenic cofactor. In contrast, fewer than 20% of BL cases occurring in Western countries are EBV-associated. We have investigated 54 BL cases from Bahia, a tropical region of Northeast Brazil, for expression of EBV gene products by in situ hybridization and immunohistology and performed typing of the EBV by polymerase chain reaction. Ten pediatric BL cases from Germany served as controls. New cases of malaria were not observed in the period and area of our study. Small nuclear EBV encoded transcripts, EBER, were found in tumor cells of 47 of 54 Brazilian cases (87%) but in only 2 of 10 German cases (20%). Type I latency of the EBV infection with absence of EBV-encoded proteins LMP1 and EBNA2 was found in 45 of 47 of the EBER-positive Brazilian cases. In two cases, occasional LMP1-containing tumor cells were found in the neighborhood of small Schistosoma mansoni granulomas and scars. BHLF1 transcripts associated with lytic EBV infection could be detected in few cells in 3 of the 40 EBER-positive Brazilian cases investigated. EBV type A was found in the majority of Brazilian BL cases (20 of 30 A-type, 7 of 30 B-type, and 3 of 30 not amplifiable). Our results indicate that the association of Bahian BL with EBV, but not the regional prevalence of malaria, is similar to endemic African BL. In two cases, type II latency was found in association with schistosomiasis, suggesting a role of this parasitosis in the induction of an EBV expression pattern that is unusual for BL. Because chronic schistosomiasis is associated with elevated Th2 cytokine expression resulting in reduced cell-mediated cytotoxicity, it seems possible that altered local immunity is responsible for this peculiar phenotype.</jats:p

Patterns of cytokine gene expression in infectious mononucleosis

Abstract Primary infection with Epstein-Barr virus (EBV) may arise as infectious mononucleosis (IM) in adolescents and young adults. Morphologically, IM- affected lymphoid tissue is characterized by expanded interfollicular areas with formation of atypical lymphoid blasts. It is assumed that morphology and clinical presentation of IM are related to characteristic patterns of cytokine production by EBV-infected and reactive cells. We studied IM tonsils of eight patients and six normal tonsils with a double in situ hybridization procedure using [35S]- labeled RNA probes specific for various cytokines and digoxigenin- labeled probes for the detection of the nuclear EBV encoded RNA transcripts, EBER 1 and 2. All of the IM cases displayed the same distinct cytokine gene expression pattern. When compared with interfollicular areas of normal tonsils, expression of lymphotoxin (LT), tumor necrosis factor-alpha (TNF-alpha), interleukin-6 (IL-6), and IL-1 beta, but not IL-8 or IL-1 alpha was strongly enhanced in interfollicular areas in IM tonsils. LT was expressed predominantly by EBV-infected cells. TNF-alpha transcripts were also present in EBV- infected cells, although in smaller proportions. IL-6 specific signals were only found in few EBV-infected cells. IL-1 alpha-, IL-1 beta-, and IL-8-specific signals were not observed in EBV-infected cells, but were present at high signal intensity in many cells within and around foci of EBV-infected cells (IL-1 beta), next to areas of necrosis (IL-8, IL- 1 beta), or in epithelial cells (IL-1 alpha). These data suggest that EBV infection in form of IM results in induction of specific sets of cytokine genes in EBV-infected and in neighboring EBV-negative cells contributing to the characteristic morphology and cellular arrangement of the lesion as well as the clinical presentation.</jats:p