Biomedical subjects

Peter Altevogt

Publications and source records attributed to Peter Altevogt.

27 records · Page 2Linked to original sources

PubMed2004

Brain development in mice lacking L1-L1 homophilic adhesion.

A new mouse line has been produced in which the sixth Ig domain of the L1 cell adhesion molecule has been deleted. Despite the rather large deletion, L1 expression is preserved at normal levels. In vitro experiments showed that L1-L1 homophilic binding was lost, along with L1-alpha5beta1 integrin binding. However, L1-neurocan and L1-neuropilin binding were preserved and sema3a responses were intact. Surprisingly, many of the axon guidance defects present in the L1 knockout mice, such as abnormal corticospinal tract and corpus callosum, were not observed. Nonetheless, when backcrossed on the C57BL/6 strain, a severe hydrocephalus was observed and after several generations, became an embryonic lethal. These results imply that L1 binding to L1, TAG-1, or F3, and L1-alpha5beta1 integrin binding are not essential for normal development of a variety of axon pathways, and suggest that L1-L1 homophilic binding is important in the production of X-linked hydrocephalus.

Animals↗

PubMed2004

Specifically activated memory T cell subsets from cancer patients recognize and reject xenotransplanted autologous tumors.

Bone marrow of breast cancer patients was found to contain CD8(+) T cells specific for peptides derived from breast cancer-associated proteins MUC1 and Her-2/neu. Most of these cells had a central or effector memory phenotype (CD45RA(-)CD62L(+) or CD45RA(-)CD62L(-), respectively). To test their in vivo function, we separated bone marrow-derived CD45RA(+) naive or CD45RA(-)CD45RO(+) memory T cells, stimulated them with autologous dendritic cells pulsed with tumor lysate, and transferred them into NOD/SCID mice bearing autologous breast tumors and normal skin transplants. CD45RA(-) memory but not CD45RA(+) naive T cells infiltrated autologous tumor but not skin tissues after the transfer. These tumor-infiltrating cells had a central or effector memory phenotype and produced perforin. Many of them expressed the P-selectin glycoprotein ligand 1 and were found around P-selectin(+) tumor endothelium. Tumor infiltration included cluster formation in tumor tissue by memory T cells with cotransferred dendritic cells. It was associated with the induction of tumor cell apoptosis and significant tumor reduction. We thus demonstrate selective homing of memory T cells to human tumors and suggest that tumor rejection is based on the recognition of tumor-associated antigens on tumor cells and dendritic cells by autologous specifically activated central and effector memory T cells.

Adoptive Transfer↗

PubMed2004

L1 (CD171) as a novel biomarker for ovarian and endometrial carcinomas.

The L1 molecule has emerged as a promising new biomarker for the diagnosis and prognosis of human ovarian and endometrial tumors. It was initially described as an adhesion molecule for neural cells but its function on tumor cells is less well known. In this article, the role of L1 in promoting tumor cell adhesion and migration is discussed. The question of how L1 determination in tumor tissue samples, serum and ascites could potentially improve the diagnosis and monitoring of gynecologic tumor patients is also addressed. The presence of L1 in tissue and serum was found to be associated with recurrent disease and short survival, independently of the tumor's histological type. This provides an alternative classification of gynecologic tumors according to their aggressiveness rather than their histology. L1 expression was correlated with disease progression even in patients with Stage I endometrioid-type endometrial tumors, identifying them as high-risk patients on preoperative curettage specimens. Monitoring of soluble L1 during the follow-up period was found to signal disease progression and recurrence before clinical symptoms occur. L1-based diagnosis and prognosis has the potential to contribute to an improved disease management and could represent the basic rationale for novel tailored therapy.

Biomarkers, Tumor↗

PubMed2003

CD24 expression is a new prognostic marker in breast cancer.

PURPOSE: CD24 is expressed in hematological malignancies as well as in a large variety of solid tumors including breast cancer. We aimed to evaluate CD24 protein expression in breast cancer and to correlate to clinicopathological data including patient survival. EXPERIMENTAL DESIGN: Primary breast carcinomas (201) with a mean clinical follow-up time of 53 months were immunostained using a monoclonal CD24 antibody (Ab-2, clone 24C02). The staining was evaluated as negative versus positive for statistical analysis. RESULTS: In invasive breast carcinomas, CD24 expression was observed in 84.6% of cases. In univariate survival analyses, a significant association of CD24 expression with shortened patient overall survival (5-year survival rate 91.9% versus 83.8%; P = 0.031; log rank test) and disease-free survival (5-year progression rate 88.3% versus 57.0%; P = 0.0008) was demonstrated. In multivariate analyses CD24, tumor grading and nodal status were significant prognostic parameters for shortened disease-free survival. CONCLUSIONS: Our data suggest that CD24 expression in primary breast cancer as detected by immunohistochemistry might be a new marker for a more aggressive breast cancer biology.

Aged↗

PubMed2003

L1 expression as a predictor of progression and survival in patients with uterine and ovarian carcinomas.

BACKGROUND: Ovarian and uterine carcinomas are the most common cause of cancer-related deaths in gynecological malignant diseases. We aimed to assess whether the L1 adhesion molecule, an important mediator for cell migration for neural and tumour cells, is expressed in these carcinomas. METHODS: We investigated L1 expression by immunohistochemistry, RT-PCR, and Western blot analysis of tumour samples. Soluble L1 in the serum was detected by ELISA and immunoprecipitation. FINDINGS: We detected the L1 adhesion molecule in ovarian and uterine tumours in a stage-dependent manner. In a retrospective study L1 was found in 46 of 58 ovarian carcinomas and 20 of 72 uterine adenocarcinomas. L1 expression was an excellent predictor of poor outlook (p<0.00001). Patients with L1 positive uterine tumours were at high risk for progression even in the endometrioid-type tumours, which usually have a favourable prognosis. In uterine tumours, expression of L1 in curettage samples enabled us to identify aggressive tumours before the operation. Soluble L1 was specifically detected in serum samples from patients with ovarian and uterine tumours. ADAM10, which was implicated in previous studies as L1 sheddase, was expressed in tumours in which soluble L1 was present in the serum. INTERPRETATION: L1 is overexpressed in ovarian and uterine carcinomas and is associated with short survival. L1 can serve as a new marker for prediction of clinical outcome and could be helpful to identify patients with uterine tumours who are at high risk for recurrent disease. L1 expression and cleavage could promote dissemination of tumours by facilitating cell migration.

Antigens, Neoplasm↗

PubMed2003

L1 adhesion molecule (CD 171) in development and progression of human malignant melanoma.

The L1 adhesion molecule (CD171) plays an important role in axon guidance and cell migration in the nervous system. In the human, L1 is expressed on tumors derived from neurocrest and on certain carcinomas. We have analyzed immunohistochemically L1 expression on paraffin embedded specimens of acquired melanocytic nevi, primary cutaneous melanomas, and cutaneous and lymph node metastases of malignant melanomas. We found an increase in L1 immunoreactivity in malignant melanomas and metastases of malignant melanomas as compared to acquired melanocytic nevi that was statistically significant (P<0.05). Additionally, a correlation of L1 immunoreactivity with histological data of prognostic value such as Clark level and the expression of alphav-integrins was found. We detected soluble L1 in the conditioned medium of cultivated melanoma cells but only in 1/40 serum samples from a panel of melanoma patients representing various stages of disease. Our findings suggest that the presence of L1 might contribute to tumor progression by promoting cell adhesion and migration.

Antibodies, Monoclonal↗

PubMed2003

Molecular mechanisms of L-selectin-induced co-localization in rafts and shedding [corrected].

Leukocyte recruitment to lymph nodes or inflammatory sites is regulated by adhesion and activation. L-selectin (CD62L) is expressed on leukocytes and mediates tethering and rolling of leukocytes on endothelial cells. Upon stimulation L-selectin is down-regulated by proteolytic cleavage but the molecular mechanisms regulating this shedding step are poorly defined. To study intracellular mechanisms, we induced shedding of L-selectin by cross-linking with an immobilized L-selectin antibody (Dreg56) in Jurkat cells. The loss of surface expression was quantitated by flow cytometry and the increase of soluble L-selectin was determined by Western blot analysis. We find that Jurkat and p56(lck)-deficient JCaM1.6 cells released L-selectin to similar extent (18+/-4% and 17+/-3%, respectively) and revealed comparable inhibition with the src-tyrosine kinase inhibitor PP2. Glutathione (GSH), an inhibitor of the neutral sphingomyelinase, PD98059, a MAP-kinase (MAP-K) inhibitor and metalloprotease inhibitors (MPI) (TAPI, Ro 31-9790, and BB-3103) reduced significantly L-selectin-induced shedding by 60-80%. In Jurkat cells, L-selectin was present in Triton X-100 insoluble membrane rafts and was constitutively tyr-phosphorylated. Dreg56 cross-linking enhanced phosphorylation and recruitment of L-selectin into rafts which was significantly decreased by pretreatment of cells with PD98059. We conclude, that the metalloproteinase-mediated cleavage of L-selectin from cell surface is triggered by intracellular signaling pathways that are independent of p56(lck) tyrosine kinase activity, but require other tyrosine kinases and the neutral sphingomyelinase. The cleavage of L-selectin might involve membrane rafts as signaling platform.

Antibodies↗

PubMed2003

Adhesion molecules CD171 (L1CAM) and CD24 are expressed by primary neuroendocrine carcinomas of the skin (Merkel cell carcinomas).

BACKGROUND: The neuroendocrine carcinoma of the skin is a rare malignant neuroendocrine tumor, which frequently metastasizes in regional lymph nodes or visceral organs. As adhesive interactions with endothelia, leukocytes, or thrombocytes enable malignant cells to penetrate the endothelium and to circulate in blood or lymphatic vessels, we here addressed the adhesion molecules CD171 (L1CAM) and CD24, which are known to be expressed by neurons, neuroblastomas, and other malignant tumors. METHODS: Thirty-one neuroendocrine carcinomas of the skin (22 primary tumors, four recurrent tumors, and five metastases) were included in the study. Immunohistochemical staining of CD171 and CD24 was performed by the streptavidin-biotin-peroxidase-complex technique and a nickel-enhanced diaminobenzidine (DAB) reaction using the monoclonal antibodies UJ 127.11 and ML-5, respectively. RESULTS: CD171 expression was detected in most neuroendocrine carcinomas of the skin, and staining was less frequent in metastases and recurrences in comparison with primary tumors which was statistically significant. The majority of neuroendocrine carcinomas of the skin was also positive for the mucin-like adhesion protein CD24. In contrast to tumor cells, cytokeratin 20-positive Merkel cells in 12 trichoblastomas and one fibroepithelioma of Pinkus were all negative for CD171 and CD24 staining. CONCLUSIONS: Expression of CD171 and CD24 is found in most neuroendocrine carcinomas of the skin, which may be used diagnostically. Further studies will assess whether this feature may contribute to metastasis of neuroendocrine carcinomas of the skin by facilitating transendothelial migration or tumor cell dissemination as has been suggested for other malignancies.

Antigens, CD↗

PubMedDate not supplied

Mesothelial cells in suspension expose an enriched integrin repertoire capable of capturing soluble fibronectin and laminin.

Pleural cavities are lined by a polarized monolayer of mesothelial cells (MC). During pleuritis, MC are shed into effusions, and pleural obstruction may occur. Integrins are cell surface receptors mediating interactions with extracellular matrix (ECM) proteins. The distribution of beta 1-, beta 3-, beta 4-integrins and fibronectin and laminin in normal and chronically inflamed pleura and in/on MC from pleural effusions was examined by immunomorphology and flow cytometry. Adhesion assays of MC to fibronectin and laminin were performed. In situ, resting MC expressed beta 1-, beta 3-, and beta 4-, and alpha v-subunits. Activated MC were beta 1- and alpha v-positive and also expressed alpha 3 and alpha 6; beta 4 was confined to the basal surface of MC; beta 3 was absent. Floating MC from effusions neoexpressed alpha 5 and reexpressed beta 3. In vitro, MC surface expressed beta 1, beta 3, alpha 3, alpha 5, alpha 6, alpha v, and also alpha 1 and alpha 2. In normal pleura, fibronectin and laminin were components of the basement membrane. In pleuritis, the basement membrane was desintegrated. Instead, newly formed fibronectin/laminin containing fibrils extended into the submesothelial connective tissue. Floating MC freshly isolated from effusions carried fibronectin and laminin on their surface and showed specific binding to these ECM proteins. Binding was blocked by anti-beta 1 or anti-alpha 5 and anti-alpha 6 antibodies, respectively. MC incubated with fibronectin showed a clear shift to the S phase, while laminin had no effect. In conclusion, activated and detached MC progressively enrich their integrin repertoire. By capturing soluble fibronectin and laminin and by matrix-mediated bridging, readhering MC may contribute to pleural obstruction. Further, soluble fibronectin bound to alpha 5 beta 1 might be life-sustaining for floating MC by driving cells into cell cycle.

Antigens, CD↗