Redefined nomenclature for members of the carcinoembryonic antigen family.
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Alternative Splicing↗
Biomedical subjects
S von Kleist
Publications and source records attributed to S von Kleist.
Caring About Women and Cancer (CAWAC): a European survey of the perspectives and experiences of women with female cancers.
This paper reports on the findings of the largest ever European survey of female patients' perceptions of their cancer treatment. It has provided clarification of what women consider important in relation to their management and has identified several areas where more research is needed. It has shown that women's knowledge about cancer before diagnosis is poor and the number undergoing regular screening could be improved. Women are not being adequately prepared and educated about what to expect from treatment and steps should be taken as a matter of urgency to redress this shortcoming. It was revealed that whilst families were the primary source of support to female cancer patients, women also derive considerable support from healthcare professionals, particularly senior doctors; more attention should be paid by specialists and nurses to developing psychological skills to cope with this. In this context, further research is needed into how support groups may best meet patient needs.
Attitude to Health↗
[Secretion of interleukin-2 (IL-2) and interferon (IFN gamma)in whole blood cell culture stimulated with mitogens in patients with lung neoplasms].
UNLABELLED: The aim of this study was to compare the ability of blood lymphocytes from lung cancer patients to secrete interleukin-2 (IL-2) and interferon gamma (IFNg) upon stimulation with mitogens with that of healthy donors. 42 patients with small cell lung cancer (SCLC), 30 patients with non small cell lung cancer (NSCLC) and 30 healthy donors were studied. The test was done in lung cancer patients before treatment. IL-2 and IFNg levels were measured with Elisa ready kits (Genzyme) in the supernatants of whole blood culture after stimulation with Pokeweed (PWM) and Phytohemagglutinin (PHA) mitogens. The results of the cytokine levels after stimulation were not normally distributed and thus were transformed to logarthms for statistical evaluation. The t-test for transformed results were used to asses the difference between groups. The median level of IFNg in the supernatant of whole blood cultures was significantly lower in lung cancer patients than in healthy blood donors both after PWM as well as after PHA stimulation. When patients with NSCLC and SCLC were regarded separately the lower level of IFNg in comparison with healthy donors was found in the supernatant of the blood cultures only after stimulation with PWM. The median level of IL-2 in the supernatant of whole blood culture in lung cancer patients was lower than in healthy blood donors only after PWM stimulation. The same was true for SCLC patients. In NSCLC IL-2 levels were significantly lower after stimulation with PWM as well after PHA stimulation. IN CONCLUSION: secretion of IL-2 and IFNg in whole blood culture after mitogen stimulation in lung cancer patients is significantly lower than in healthy donors. No significant differences between SCLC and NSCLC were found.
Adult↗
A distinct distribution of natural killer cell subgroups in human tissues and blood.
Natural killer (NK) cells have been subdivided according to their CD16/CD56 expression into at least 2 subgroups. We examined the distribution of these NK subgroups in humans. In the blood of normal individuals, CD16++/CD56+/CD3- NK cells predominate, constituting more than 90% of all NK cells. In contrast, decidua is infiltrated almost exclusively by CD16(+/-)/CD56+/CD3- NK cells (>90%), a fact so far seen in context with decidua being an immunoprivileged tissue. However, this NK subgroup can also be detected in the blood, where it comprises about 10% of NK cells. We have found that normal (colon) as well as neoplastic (ovarian and urothelial carcinoma) tissues are also predominantly infiltrated by this CD16+/- NK subgroup. Lymphatic fluid draining solid tissues contains CD16+/- NK cells exclusively, with absolute numbers of NK cells being very low. No predominating NK subgroup was seen in ascites. CD16+/- NK cells, when tested against the target cell lines K562 and JAR, revealed a cytotoxic spectrum different from CD16++ NK cells and from T cells. A change in the CD16/CD56/CD3 phenotype was not seen in either subgroup in long-term cultures containing IL-2 (1,000 U/ml). Our data indicate that the decidua is not the only solid tissue infiltrated by CD16+/- NK cells. Other normal and malignant tissues were also infiltrated predominantly by this NK cell subgroup. We suggest that CD16+/- NK cells represent a functionally distinct NK subgroup involved in the surveillance of solid tissues.
Body Fluids↗
Biliary glycoprotein (CD66a), a cell adhesion molecule of the immunoglobulin superfamily, on human lymphocytes: structure, expression and involvement in T cell activation.
The biliary glycoproteins (BGP or CD66a), a group of different splice variants of a single gene, are members of the carcinoembryonic antigen family and the immunoglobulin superfamily. Recently, we detected CD66a on IL-2 activated lymphocytes. In this study we characterized the structure and the expression pattern of BGP on human lymphocytes and investigated its role in T cell activation. Lymphocytes express 2 of the 13 known splice variants, i.e. BGPa and BGPb, which are glycosylated in a lymphocyte-specific manner. Both BGPa and BGPb have the long cytoplasmic tail, which contains two immunoreceptor tyrosine-based inhibitory motif (ITIM)-like motifs, but differ in their extracellular region containing 4 and 3 immunoglobulin-like domains, respectively. On PBL BGP is expressed in small amounts only on B cells and Th cells. Stimulation with IL-2 leads to a strong up-regulation of BGP by these cells, and induces de novo BGP expression on gammabeta T cells, CD8+ and CD56+ cells, but not on CD16+ lymphocytes. This up-regulation of BGP seems to be part of the physiological process of T cell activation, since stimulation with anti-CD3 mAb is sufficient to induce BGP up-regulation. Based on the presence of the two ITIM-like motifs, one may expect that BGP inhibits T cell activation, but surprisingly, engagement of BGP enhances the proliferation of anti-CD3-stimulated T cells.
Antigens, CD↗
Isolated extracellular matrix-based three-dimensional in vitro models to study orthotopically cancer cell infiltration and invasion.
An initial event in colon cancer progression is the migration of epithelial cells through the basement membrane (BM) and the invasion of the colon submucosa, where tumour cells enter blood and lymph vessels to spread throughout the body. To interrupt this process would mean the prevention of metastasis. In order to investigate tumour cell invasion orthotopically in the human system, we established novel in vitro models which mimic normal human colon tissue (colon reproductions, CoRes) and primary colon carcinomas (artificial tumours, ArTs). These models are based on the isolated extracellular matrix (iECM) of the respective human tissues. Two isolation methods were established, the Digestion Method and the Lysis Method neither of which destroyed the characteristic architecture of the ECM found in the original tissues. BM components, i.e. laminin, fibronectin and collagen IV, were detectable in the iECM isolated with the Lysis Method but not those isolated with the Digestion Method. Scanning electron microscopic analysis of the normal colon iECM demonstrated that even if the BM was missing, the luminal surface consisted of densely packed ECM filaments which do not allow cell infiltration without degradation of the iECM. Furthermore, we demonstrated that iECM can be separately supplemented with different cell types, i.e. colorectal carcinoma cells, normal fibroblasts and immune cells at any desired concentration, combination and localisation. Therefore, these models could be used to determine the role of the BM and of the tumour cell/normal cell crosstalk in the infiltration process of human colorectal carcinoma cells.
Basement Membrane↗
Analysis of the T cell receptor variability of tumor-infiltrating lymphocytes in colorectal carcinomas.
While there is good clinical and experimental evidence for immunological tumor control in some tumors--malignant melanomas, for instance--the immunogenicity of colorectal carcinoma (CRC) still remains unsettled. We examined surgical specimens from 4 CRC patients for T cell clones among tumor-infiltrating lymphocytes (TIL). The growth of specific lymphocyte clones in a tumor indicates an immunological response in vivo. We used a T cell receptor V beta family-specific semiquantitative PCR with additional sequencing to examine TIL for clonal expansion. In CRC, specific T cell clones could not be demonstrated. However, we observed a predominance of V beta 9 in 3 of 4 tumors.
Adenocarcinoma↗
Th1 and Th2 cytokine response patterns in leukocyte cultures of patients with urinary bladder, renal cell and prostate carcinomas.
As a decreased production of Th1 cytokines by stimulated peripheral blood leukocytes has recently been shown in patients with various carcinomas, the present study was performed to determine whether these patients also exhibit a Th1/Th2 imbalance compared to healthy controls. We measured the production of the Th1 cytokines IL-2 and IFN-gamma as well as the Th2 cytokines IL-4, IL-6 and IL-10 in mitogen-stimulated peripheral blood mononuclear cell (PBMC) cultures of patients with urinary bladder carcinomas (n = 47), prostate carcinomas (n = 111) and renal cell carcinomas (n = 67) as compared to 40 age-matched healthy controls. In the PBMC cultures of the tumor patients, the levels of the Th1 cytokines IL-2 and IFN-gamma were lower as compared to the controls. For IFN-gamma, the differences were highly significant and in the patients with renal cell carcinomas it could be shown that the values decreased with increasing tumor mass. In contrast, the levels of the Th2 cytokines IL-4, IL-6 and IL-10 were comparable in the PBMC cultures of tumor patients and controls. From these results, it is concluded that there is only a malfunction in Th1 cells but no switch from a Th1 type to a Th2 type cytokine profile in the PBMCs of cancer patients.
Aged↗
Adhesion and migration are differentially regulated in hematopoietic progenitor cells by cytokines and extracellular matrix.
The conditions that control the migratory status of hematopoietic progenitor cells on extracellular matrix (ECM) and that decide whether a cell migrates or adheres are incompletely understood. We analyzed the migratory behavior of murine hematopoietic progenitor cells factor-dependent-cell-paterson (FDCP)-mix and purified lin-Sca1+ bone marrow cells on ECM. We found that migration on fibronectin (Fn) or laminin (Lam) becomes dependent on beta1-integrins if a surface restraint force is introduced by tilting the ECM-coated culture vessels. Under these conditions, migration specifically occured on Fn and Lam, and was not detected on collagen IV-, hyaluronate-, or bovine serum albumin- coated surfaces. Migration depended on the continuous presence of hematopoietic cytokines interleukin-3 (IL-3), granulocyte colony-stimulating factor (G-CSF), macrophage-CSF (M-CSF), granulocyte-macrophage-CSF (GM-CSF), or stem cell factor (SCF), whereas other cytokines, such as IL-8, macrophage inflammatory protein-1alpha, macrophage-chemotactic and activating factor, and erythropoietin resulted in very little or no migratory response. IL-3 induced migration was synergistically enhanced by other CSFs, but was completely inhibited by addition of transforming growth factor-beta1. In contrast to firm local adhesion of previously cytokine depleted progenitors that was rapidly inducible within 1 hour after exposure to cytokines, preincubation on Fn matrix for 4 to 6 hours was required before cytokines could induce migration. A sudden increase of cytokine concentration reversibly inhibited migration and induced a fully adhesive state; this effect could be prolonged by consecutive stimulation with heterologous cytokines. Whereas cytokines activated resting progenitor cells to migrate on ECM, cell migration speed was regulated by Fn concentration. These results indicate that beta1-integrin-mediated progenitor cell adhesion and migration are differentially regulated by external stimuli and suggest that this regulation corresponds to different activation states of beta1-integrins in hematopoietic progenitor cells.
Animals↗
Modulations of the effector function and cytokine production of human lymphocytes by secreted factors derived from colorectal-carcinoma cells.
We investigated the in vitro effects of factors secreted by 3 freshly explanted human colorectal-carcinoma (CRC) cell lines on lymphocyte proliferation, IL-2-receptor expression, LAK-cell generation and cytokine secretion. We found that the supernatants of all 3 CRC cell lines inhibited T-cell proliferation in a dose-dependent manner, due to the secretion of immunosuppressive factors (ISFs). In addition, the supernatants of 2 cell lines were able to inhibit LAK-cell generation and to depress IL-2R, but not HLA-DR expression, on PHA-activated T cells. Furthermore, the secretion of cytokines, i.e., IFN-gamma, IL-1beta, IL-2 and TNF-alpha, by peripheral-blood mononuclear cells (PBMC) was differently modulated by the tumor-cell supernatants, e.g., the production of IFN-gamma was reduced in normal PBMC stimulated with PHA. However, the effects induced by the supernatants were not identical: for example, factors from one CRC cell line (w25) influenced early and late events of T-cell activation and division, while 2 others (w19 and te6) contributed only to the inhibition of early events. Some biochemical properties of the ISFs were characterized. Our results suggest that colon-tumor cells can secrete ISFs, which may lead to the in vivo immunosuppression often observed in patients with these tumors.
Colorectal Neoplasms↗
The carcinoembryonic antigen (CEA) modulates effector-target cell interaction by binding to activated lymphocytes.
We and others have shown that the carcinoembryonic antigen (CEA) modulates the susceptibility of human colorectal carcinoma cells to cytotoxic lymphocytes. We now demonstrate that the density of the CEA molecules on the tumor cell surface has a determining influence on its protective function. In contrast, CEA released by tumor cells has no protective effect for CEA-negative cells. To elucidate the responsible mechanism, we analyzed the binding properties of CEA to lymphokine activated killer (LAK) cells. In agreement with our observation that only membrane-bound CEA provides protection, we found that intercellular contact between LAK cells and CEA-expressing tumor cells is required for binding of CEA to LAK cells. Using FACScan analysis, we demonstrate the presence of CEA on lymphocytes co-cultured with CEA-transfected cells but not after co-culture with their parental cells and after incubation with soluble CEA. Interestingly, following overnight co-culture the amount of bound CEA on LAK cells was identical regardless of adherence on tumor cells or loss of contact with tumor cells. This indicates that CEA is released from the tumor cells after binding to LAK cells. Our results suggest that tumor cells can modulate effector cell adhesion by regulating the turnover rate of CEA on the tumor cell membrane.
Carcinoembryonic Antigen↗
Biliary glycoprotein (BGP) expression on T cells and on a natural-killer-cell sub-population.
Human T and natural-killer (NK) cells, that are thought to be the major cytotoxic effector-cell populations in the defence against neoplastic cells, were isolated from blood and decidua in order to analyze their expression of carcinoembronic-antigen-(CEA)-family-member proteins. Biliary glycoprotein (BGP,CD66a) was the only member of the carcinoembryonic antigen family detected. While freshly isolated T-cells expressed low amounts of BGP, freshly isolated NK cells were negative. After in vitro stimulation for 3 days, T cells up-regulated their BGP expression and a sub-group of NK cells (CD16- CD56+), known to predominate in decidua revealed de novo expression of BGP. In contrast, stimulated CD16+ CD56+ NK cells, which occur exclusively in the blood, remained negative. The expression of BGP could be shown on the protein level by using a panel of 12 well-defined MAbs and on the transcription level in rt-PCR and subsequent oligonucleotide hybridization. Interestingly, rIL-2-stimulated T cells expressed 3-fold higher levels of BGP compared with those seen after stimulation with phytohemagglutinin (PHA). PHA, on the other hand, induced a higher expression of HLA-DR, an activation marker of T cells. The differential regulation implies a distinct function of BGP and HLA-DR.
Antigens, CD↗
Assessment of urinary gonadotropin in solid carcinomas other than gynecological tumors.
To the already long list of existing tumor markers, a new marker has been recently added, the urinary gonadotropin peptide (UGP). This marker is determined in the urine of cancer patients and is considered to be particularly specific for ovarian carcinomas. The purpose of our study was to assess the specificity of UGP in a variety of malignancies other than ovarian carcinomas, e.g., breast, colonic, lung, and urogenital tumors (n = 50 each). The tumors were compared with benign lesions of the same organs. Urine samples of 50 healthy donors served as controls. The 450 urine samples were tested in duplicate using the UGP EIA-kit from Ciba Corning Diagnostics. All tumors were staged and histologically classified. For normalization in all samples, creatinine levels were determined. UGP was found in all tested tumors, however, with very low sensitivity of 20% in urogenital tumors, 46% in lung, and 30% or 27% in colon and breast carcinomas, respectively. The specificity of UGP was comprised between 100% (breast) and 88%. Clearly elevated UGP-concentrations were seen in postmenopausal women. A comparison of UGP with the optimal markers for each tumor system showed that UGP is not superior to these markers. However, we can confirm UGP as being an optimal marker for gynecological carcinomas.
Adolescent↗
Cytokine production in leukocyte cultures during therapy with Echinacea extract.
We measured the levels of the cytokines IL-1-alpha, IL-1-beta, IL-2, IL-6, TNF-alpha, and IFN-gamma in culture supernatants of stimulated whole blood cells derived from 23 tumor patients undergoing a 4-week oral treatment with a spagyric extract from Echinacea angustifolia, Eupatorium perfoliatum, and Thuja occidentalis (Echinacea complex). All patients had had curative surgery for a localized solid malignant tumor. Blood was taken before treatment and after 2 and 4 weeks of therapy. Twelve untreated tumor patients at the same clinical stage, also after curative surgery, served as a control group. In the blood cell cultures of all patients, a rather wide range of cytokine levels was found. After therapy with Echinacea complex, no significant alteration in the production of the cytokines could be seen in comparison to the controls, and also the leukocyte populations remained constant. We conclude that at this application and dosage, the therapy with Echinacea complex has no detectable effect on tumor patients' lymphocytes activity as measured by their cytokine production.
Administration, Oral↗
Analysis of the immune reactivity of infiltrating and peripheral lymphocytes from patients with renal cell carcinoma by measuring cytokine secretion.
The immunological properties of tumour-infiltrating (TIL) and peripheral blood lymphocytes (PBL) from 29 patients with renal cell carcinomas were characterized with respect to their phenotypic expression and cytokine production. TIL were isolated from mechanically disaggregated tumor material and PBL from peripheral blood by gradient centrifugation. To eliminate all non-lymphoid cells, CD3-positive cells were specifically separated from these cell fractions with anti-CD3 magnetic beads. These pure CD3-positive PBL (CD3+PBL) and TIL (CD3+TIL) were cultured with pokeweed mitogen and the levels of the cytokines interleukin-1alpha (IL-1 alpha), IL-1 beta, IL-2, interferon gamma (IFNgamma), and tumor necrosis factor alpha (TNFalpha) measured in the 4-day post-inductional cell culture supernatants. In all cell cultures a wide range of cytokine values was found, indicating a large variation in the immunological activity of the lymphocytes of each individual. When the cell cultures of the CD3+TIL and CD3+PBL were compared in each patient similar values for IL-1 alpha, IL-1 beta, IFNgamma and TNFalpha were found. However CD3+TIL produced significantly lower levels of IL-2 than CD3+PBL upon mitogenic stimulation. This may be due to a lower CD4/CD8 ratio in the CD3+TIL as compared to the CD3+PBL. These results suggest that there are no fundamental qualitative and quantitative differences in the lymphokine-producing capacity of CD3+TIL and CD3+PBL derived from patients with renal cell carcinomas.
CD3 Complex↗
Immunosuppressive activity of sera from patients with colorectal and gynecological carcinomas as evaluated by impaired IFN-gamma, IL-1 alpha and TNF-alpha production of human peripheral mononuclear cells.
The sera from patients with preoperative colorectal and gynecological carcinomas (ovarian and breast cancer) were investigated for their putative immunosuppressive activity (ISA). ISA was measured by determining the changes in the production of IFN-gamma, IL-1 alpha and TNF-alpha by human peripheral mononuclear cells (PBMC) from six normal donors. Phytohemagglutinin-stimulated PBMC were incubated with sera from patients with colorectal and gynecological carcinomas and healthy controls and in the 4-day post-inductional supernatants the cytokines were measured by an enzymoimmunological assay (ELISA). Sera from patients with carcinomas significantly decreased the IFN-gamma production as compared to the controls. In the cultures containing sera from patients with colorectal and ovarian but not breast carcinoma, significantly lower levels of IL-1 alpha and TNF-alpha were measured compared to the cultures with sera from healthy controls.
Adult↗
CD66b, CD66c and carcinoembryonic antigen (CEA) are independently regulated markers in sera of tumor patients.
Non-specific cross-reacting antigens (NCA-95 = CD66b and NCA-50/90 = CD66c) are members of the CEA (carcinoembryonic antigen = CD66e) family. Analysis of mRNA levels of CD66c in colon tumors suggests that this antigen is strongly up-regulated compared to its normal counterpart and could, therefore, be of clinical interest. CD66c is also expressed in normal lung and spleen tissues and, above all, on granulocytes. The appearance of CD66b in serum, the only strictly granulocyte-specific antigen, could point to the involvement of granulocytes in disease. Specific sandwich ELISAs have been established to determine CEA, CD66b and CD66c levels in serum. Controls have been carried out by testing sera from patients with benign tumors or inflammatory diseases and from healthy individuals. In sera of most patients suffering from solid tumors, sensitivities for CD66c are comparable to or lower than those for CEA. CD66c showed a much higher sensitivity in early colon tumor stages. Sensitivities over 40% have been determined for CD66b in sera of patients with uterine and kidney carcinomas. CML patients revealed sensitivities of 84% for CD66c and 47% for CD66b. Investigations of sera from patients with inflammatory colon diseases which are negative for CEA showed high sensitivity for CD66c but not for the granulocyte-specific CD66b. Patients with mastopathy revealed sensitivities of over 40% for both CD66c and CD66b. CD66b, CD66c and CEA are independently regulated proteins in a high percentage of patients. The simultaneous determination of CEA and CD66b/c can increase the sensitivities for malignant tumors but high sensitivities of CD66b/c for benign diseases limit their usefulness as tumor markers. CD66b may be interesting as a marker for kidney and corpus carcinomas, for which good markers are not yet available.
Adult↗
The influence of the local environment on tissue architecture of colorectal carcinoma (CRC) cell aggregates and its consequence for tumour attack by lymphocytes in vitro and in vivo.
We analysed colorectal carcinoma (CRC) specimens, tumour cell spheroids and artificial tumours (ArTs) for tissue architecture, carcinoembryonic antigen (CEA) expression and lymphocyte infiltration. Two distinct organisation forms of well-differentiated CRC cells were found in vivo and in vitro. Tumour cells having contact with the tumour stroma in primary tumours, and tumour cells growing within a stroma-like structure in vitro (ArTs) were arranged as pseudoglands. In contrast, tumour cells grown as spheroids or tumour cells having lost contact with the tumour stroma in primary tumours, and most probably in the circulation, showed an inversion of the architecture of these pseudoglands, presenting their apical cell membrane to the environment. These different tumour cell formations affect lymphocytes attacking the tumour, which need contact with specific cellular membranes of polarised tumour cells, depending on the tumour architecture. Recently, we demonstrated that the CEA expression of CRC cells correlated with their resistance against LAK-cell lysis. Since CEA is mainly expressed on the apical membrane of the tumour cells, independent of the tissue architecture, the change from the pseudoglandular to the spheroid-like formation may represent an escape mechanism for malignant cells.
Carcinoembryonic Antigen↗