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Publications (16) View all
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Article: SV40 large T antigen-transformed human primary normal and cancerous mammary epithelial cells are phenotypically similar but can be distinguished in 3D culture with selection medium.
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ABSTRACT: Human normal mammary epithelial cells (NMECs) have 2 major in vitro growth restrictions, senescence and crisis. Cellular immortalization is considered a hallmark of malignancy. However, cancerous mammary epithelial cells (CMECs) that are thought to have passed growth barriers in vivo usually cannot be established long-term in vitro. Here we show that CMECs deprived of their natural environment and grown in conventional complete medium behave similar to NMECs, e.g., they stop producing telomerase and become senescent. Like NMECs, CMECs are rescued by SV40 large T (LT) from senescence but not from crisis. The telomere length of both LT-transformed NMEC (N-LT) and CMEC (C-LT) cells first shortens but later partially recovers after telomerase activation. Both cell types upregulate ErbB2 expression, acquire genetic changes, remain long-term dependent on LT and ErbB2 and are nontumorigenic. Despite these similarities, N-LT and C-LT cells cultured in selection medium show different growth characteristics in 3D culture and in vivo tumorigenesis. Thus, CMECs are under a comparable in vitro selective pressure in conventional monolayer culture as NMECs despite their in vivo malignancy. This data demonstrate that most primary breast cancer cells are still unable to overcome the in vitro growth restrictions and suggest that the relationship of in vitro immortalization and in vivo carcinogenesis should be re-evaluated.International Journal of Cancer 10/2008; 123(7):1516-25. · 5.44 Impact Factor -
Article: Prognostic value of cytokeratin-positive bone marrow cells of gastric cancer patients.
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ABSTRACT: Epithelial cells in the bone marrow of patients with gastric cancer suggest tumor dissemination; however, their prognostic implications are controversial. We prospectively evaluated the correlation of bone marrow findings, recurrence rate, and disease-free survival after long-term follow-up. Bone marrow were aspirated from both iliac crests and stained with monoclonal cytokeratin (CK)-18 antibody in 209 patients before their initial operation. Patients were followed up for a median of 56 months. Overall, 39 (19%) of 209 patients and 15 (14%) of 109 R0-resected patients had CK-positive cells. CK-positive patients had more local, regional, and distant recurrence than CK-negative patients (P < .05). We found a significantly shorter disease-free survival (P < .05) in the patients with >2 CK-positive cells per 2 x 10(6) bone marrow cells (mean, 35 months) than in patients with <or=2 CK-positive cells per 2 x 10(6 )bone marrow cells (mean, 70 months) or in patients with no CK-positive cells (mean, 86 months). Multivariate analysis confirmed that >2 CK-positive cells per 2 x 10(6) bone marrow cells was an independent prognostic factor for tumor-related death (P < .05). Not only the mere presence of CK-positive epithelial cells in bone marrow, but also the cell number, correlates with prognosis. Our findings suggest that classifying CK-positive bone marrow cells in these patients will facilitate future studies.Annals of Surgical Oncology 02/2007; 14(2):373-80. · 4.17 Impact Factor -
Article: Gastric cancer surgery in elderly patients.
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ABSTRACT: To investigate the value of individual risk-adapted therapy in geriatric patients, we performed a consecutive analysis of 363 patients undergoing potentially curative surgery for gastric cancer. All patients underwent extensive preoperative workup to assess surgical risk. The following criteria were evaluated in 3 age groups (<60 years, 60-75 years, and >75 years): comorbidity, tumor characteristics, type of resection, postoperative morbidity and mortality, recurrence rate, overall survival, and disease-free survival. There was an increased rate of comorbidity in the higher age groups (51% vs 76% vs 83%; P<0.05). Cardiovascular and pulmonary diseases were most common. There was a decrease in the rate of both total gastrectomy (74%, 54%, 46%; P<0.05) and D2 lymphadenectomy (78%, 53%, 31%; P<0.05). The 30-day mortality in the 3 age groups was 0%, 1%, and 8%, respectively (P<0.05). There was only a slight difference in tumor recurrence rate (35%, 37%, and 27%; P=0.437), with no significant difference in 5-year cancer-related survival (61%, 53%, 61%; P=0.199). Patient selection and risk-adapted surgery in elderly patients can result in acceptable therapeutic results comparable to younger patients. Limited surgery in elderly gastric cancer patients with high comorbidity does not necessarily compromise oncological outcome.World Journal of Surgery 08/2006; 30(8):1468-74. · 2.36 Impact Factor -
Article: Mutation and expression of PDGFRA and KIT in malignant peripheral nerve sheath tumors, and its implications for imatinib sensitivity.
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ABSTRACT: Platelet-derived growth factor receptor alpha (PDGFRalpha) and c-Kit are receptor tyrosine kinases. Both are targets of the tyrosine kinase inhibitor imatinib mesylate which is approved for treatment of some cancers. In order to assess the role of PDGFRalpha and c-Kit in malignant peripheral nerve sheath tumours (MPNST) we examined human tumours for structural alterations, protein and ligand expression. We investigated 34 MPNST, 6 corresponding plexiform neurofibromas (pNF) and 1 MPNST cell culture from 31 patients for mutations and polymorphisms in PDGFRA (exon 2-21) and KIT (exon 9, 11, 13, 17). PDGFRA was amplified in seven tumours from six patients and MPNST cell culture S462. KIT was amplified in five tumours from four patients and in the cell culture. Two MPNST carried somatic PDGFRA mutations in exons coding for the extracellular domain. In addition we detected several polymorphisms in PDGFRA. No point mutations or polymorphisms were detected in the four KIT exons analysed. PDGFRalpha expression was present in 21 of 28 MPNST patients (75%) and the MPNST cell culture. Expression analysis of PDGFRalpha ligands in MPNST and neurofibromas revealed that PDGF-A was more widely expressed than PDGF-B. Focal c-Kit expression was detected in 2 of 29 (7%) MPNST patients. Imatinib treatment of MPNST cell culture S462 exerted a growth inhibitory effect and prevented PDGF-AA induced PDGFRalpha phosphorylation. In summary, PDGFRA, PDGF and KIT dysregulation as well as growth inhibition of cell culture S462 by imatinib may suggest that MPNST patients benefit from treatment with imatinib.Carcinogenesis 04/2006; 27(3):664-71. · 5.70 Impact Factor -
Article: Subclassification of nerve sheath tumors by gene expression profiling.
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ABSTRACT: Nerve sheath tumors are the most common tumors of Neurofibromatosis type 1 (NF1) patients. Dermal neurofibromas develop in nearly all NF1-patients, whereas plexiform neurofibromas are only observed in one-third of the patients. NF1-patients have about a 10% lifetime risk for developing malignant pheripheral nerve sheath tumors (MPNST). The origin of these tumors is thought to be the Schwann cell lacking functional neurofibromin. However, additional genetic alterations are likely to modulate tumor biology and to contribute to individual nerve sheath tumor entities. To gain insight into the molecular events and to determine whether these tumors can be classified according to gene expression profiles, we performed expression analysis applying cDNA array technology. Nine dermal neurofibromas, 7 plexiform neurofibromas, ten MPNST and two MPNST cell cultures were examined. All tumors but 6 sporadic MPNST were obtained from NF1-patients. We detected significant differences in gene expression patterns between neurofibromas and MPNST and between dermal neurofibromas and plexiform neurofibromas. Tumor class prediction agreed in all but one case with histological and clinical classification. NF1-associated and sporadic MPNST could not be distinguished by their gene expression patterns. We present a panel of discriminating genes that may assist subclassification of nerve sheath tumors.Brain Pathology 08/2004; 14(3):258-64. · 3.99 Impact Factor
