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K Lamszus

Publications and source records attributed to K Lamszus.

30 records · Page 2Linked to original sources
PubMed1998

Regulation of BRCA1 and BRCA2 expression in human breast cancer cells by DNA-damaging agents.

Germline mutations in the breast cancer susceptibility genes BRCA1 and BRCA2 have been linked to the development of breast cancer, ovarian cancer, and other malignancies. Recent studies suggest that the BRCA1 and BRCA2 gene products may function in the sensing and/or repair of DNA damage. To investigate this possibility, we determined the effects of various DNA-damaging agents and other cytotoxic agents on the mRNA levels of BRCA1 and BRCA2 in the MCF-7 and other human breast cancer cell lines. We found that several agents, including adriamycin (a DNA intercalator and inhibitor of topoisomerase II), camptothecin (a topoisomerase I inhibitor), and ultraviolet radiation induced significant decreases in BRCA1 and BRCA2 mRNA levels. Decreased levels of BRCA1 and BRCA2 mRNAs were observed within 6-12 h after treatment with adriamycin and persisted for at least 72 h. Adriamycin also induced decreases in BRCA1 protein levels; but these decreases required several days. U.V. radiation induced dose-dependent down-regulation of BRCA1 and BRCA2 mRNAs, with significant decreases in both mRNAs at doses as low as 2.5 J/m2, a dose that yielded very little cytotoxicity. Adriamycin-induced down-regulation of BRCA1 and BRCA2 mRNAs was first observed at doses that yielded relatively little cytotoxicity and little or no apoptotic DNA fragmentation. Adriamycin and U.V. radiation induced distinct dose- and time-dependent alterations in the cell cycle distribution; but these alterations did not correlate well with corresponding changes in BRCA1 and BRCA2 mRNA levels. However, the adriamycin-induced reduction in BRCA1 and BRCA2 mRNA levels was correlated with p53 functional status. MCF-7 cells transfected with a dominant negative mutant p53 (143 val-->ala) required at least tenfold higher doses of adriamycin to down-regulate BRCA1 and BRCA2 mRNAs than did parental MCF-7 cells or control-transfected MCF-7 clones. These results suggest that BRCA1 and BRCA2 may play roles in the cellular response to DNA-damaging agents and that there may be a p53-sensitive component to the regulation of BRCA1 and BRCA2 mRNA expression.

Antineoplastic Agents↗
PubMed1998

Scatter factor promotes motility of human glioma and neuromicrovascular endothelial cells.

Malignant gliomas are characterized by rapid growth, infiltration of normal brain tissue, and high levels of tumor-associated angiogenesis. The genetic and local environmental tissue factors responsible for the malignant progression from low to high grade gliomas and the highly malignant behavior of glioblastomas are not well understood. In a study of 77 human brain tissue extracts, high grade (III-IV) tumors had significantly greater scatter factor (SF) content than did low grade tumors or non-neoplastic tissue. To investigate the potential significance of SF accumulation in gliomas, we measured the effects of SF on DNA synthesis and motility of cultured human glioma cell lines. SF stimulated DNA synthesis in 7/10 glioma cell lines and in 3/3 neuromicrovascular endothelial cell (NMVEC) lines, consistent with our previous report that SF stimulated cell proliferation of a few human glioma cell lines. SF markedly stimulated the chemotactic migration of 10/10 glioma cell lines as well as 3/3 NMVEC lines. In addition, SF stimulated the 2-dimensional migration of glioma cells on culture surfaces coated with specific extracellular matrix molecules (collagen i.v., laminin, and fibronection). As expected based on these biologic responses to SF, 10/10 glioma lines and 4/4 NMVEC lines expressed mRNA for c-met, the SF receptor. To assess the possible in vivo significance of these migration assays, we compared the chemotactic response of a glioma cell line to human brain cyst fluids and tumor extracts that contained high or low SF concentrations. Fluids and extracts with high SF content tended to induce higher levels of chemotactic migration than did fluids and extracts with low SF content. Addition of anti-SF monoclonal antibody (MAb) inhibited migration induced by fluids and extracts with high SF content by about 30-50%.

Brain Neoplasms↗
PubMed1997

Expression of scatter factor and c-met receptor in benign and malignant breast tissue.

BACKGROUND: Scatter factor (SF), also known as hepatocyte growth factor, is an angiogenic cytokine that stimulates epithelial cell motility and invasion. Its receptor is a transmembrane tyrosine kinase encoded by the c-met protooncogene. Several prior experimental and clinical studies have suggested that SF might play a role in the development and progression of breast carcinoma. To investigate the possible involvement of SF and c-met in the evolution of breast carcinoma, the authors studied their expression in sections of human breast tissue. METHODS: A variety of paraffin embedded tissue specimens (of normal breast tissue tissue, benign hyperplasia, ductal carcinoma-in-situ [DCIS], and invasive ductal carcinoma) from 125 patients were immunoperoxidase-stained using specific antisera against SF and c-met. The staining intensities of epithelial mammary cells were scored semiquantitatively, and the staining scores were analyzed as a function of tissue type. In addition, in situ hybridization to detect SF mRNA was performed for a small number of cancer sections. RESULTS: Specific SF staining was observed in tumor cells, normal cell types (epithelium and vascular smooth muscle), and acellular stroma, whereas c- met staining was observed in tumor cells and normal cell types but not in stroma. Analysis of the staining scores of epithelial mammary cells revealed several patterns: (1) SF and c-met staining scores each increased in the following order: normal breast/benign hyperplasias (lowest) --> DCIS (higher) --> invasive carcinoma (highest); (2) normal-appearing mammary ducts and lobules in invasive cancer sections showed less SF and c-met staining than tumor cells in the same specimens but more staining than normal ducts and lobules in sections of normal breast tissue and benign hyperplasia; (3) within the DCIS and invasive cancer groups, SF and c-met staining scores were correlated; and (4) among 40 consecutive cases of DCIS, higher levels of SF and c-met staining showed a trend toward association with other features suggestive of aggressive tumor biology (comedo histology, high nuclear grade, p53 positivity, and bcl-2 negativity). In situ hybridization analysis revealed that the same cell types that expressed SF protein (including tumor cells) also expressed SF mRNA transcripts. CONCLUSIONS: SF and c-met are overexpressed in breast carcinoma as compared with benign breast tissue, and they tend to be coexpressed in cancerous tissue. These findings are consistent with the idea that the SF:c-met ligand:receptor pair may have a role in breast carcinoma progression.

Breast↗
PubMed1997

HGF/SF in angiogenesis.

Hepatocyte growth factor/scatter factor (HGF/SF) is a mesenchyme-derived cytokine that stimulates motility and invasiveness of epithelial and cancer cells. These responses are transduced through the c-met proto-oncogene product, a transmembrane tyrosine kinase that functions as the HGF/SF receptor. We have shown that HGF/SF is a potent angiogenic molecule and that its angiogenic activity is mediated primarily through direct actions on vascular endothelial cells. These include stimulation of cell migration, proliferation, protease production, invasion, and organization into capillary-like tubes. We further showed that HGF/SF is overexpressed in invasive human cancers, including breast cancer, relative to non-invasive cancers and benign conditions. In invasive breast cancers, the content of HGF/SF is strongly correlated with that of von Willebrand's factor, a marker of vascular endothelial cells. Furthermore, transfection of breast cancer and glioma cell lines with HGF/SF cDNA greatly enhanced the ability of these cells to grow as tumours in orthotopic sites in syngeneic or immunocompromized host animals. The increased growth rate of the HGF/SF-transfected cells was attributable, in part, to increased tumour angiogenesis. These findings suggest that HGF/SF may function as a tumour progression factor, in part by stimulating tumour cell invasiveness and in part by stimulating angiogenesis.

Animals↗
PubMed1997

Somatostatin and somatostatin receptors in the diagnosis and treatment of gliomas.

Somatostatin analogues are in clinical use for the diagnosis and treatment of several oncological indications, namely pituitary adenomas and endocrine gastrointestinal tumors. In addition for a variety of malignancies their potential value is being studied. It has been speculated that somatostatin plays a role in the homeostasis of gliomas, and that gliomas could be susceptible to antiproliferative effects of somatostatin analogues. These assumptions were tested in 20 human cell lines derived from malignant gliomas and 4 glioblastoma tissue specimens, which were analyzed for their expression of the five known somatostatin receptor genes (SSTR1-5) and for the receptor function. Using semiquantitative PCR techniques, SSTR2 transcripts were found in all 20 cell lines and 4 glioblastomas, SSTR1 transcripts were detected in 9 cell lines and 4 glioblastomas, and SSTR3 transcripts were noted in 7 cell lines and 1 glioblastoma. SSTR4 and SSTR5 transcripts were only rarely detected. Gene expression profiles in glioblastoma tissue specimens resembled those of the cell lines in quality as well as quantity, with average transcript levels being highest for the SSTR2, followed by SSTR1 and SSTR3. However, when compared to GH3 anterior pituitary tumor cells, the relative amounts of PCR amplified DNA fragments were found to be at least 120 fold lower in glioblastoma cell lines and tumor specimens. Binding studies indicated that glioblastoma derived cells contained only minute amounts of SSTRs. No inhibition of proliferation was observed when 10 selected cell lines were incubated with somatostatin-14 (SST-14) or octreotide (SMS 201-995) at concentrations ranging from 10(-9) M to 10(-6) M, however, the proliferation of two cell lines was weakly stimulated after 6 days of incubation with 10(-6) M octreotide. The activity of adenylate cyclase, stimulated by forskolin, was inhibited by maximally 25% at 10(-6) M SST-14 or octreotide in one of 5 selected glioblastoma cell lines. Somatostatin peptides do not seem to exert anti-proliferative effects on glioblastoma cells and therefore appear to be of no obvious value for glioblastoma therapy. Most likely the amount of cell surface SSTRs is not sufficient to mediate antiproliferative effects. Since it has been described that SSTRs are detectable on most differentiated gliomas as well as astrocytes, it may be speculated that SSTRs may be relevant only in the context of well differentiated cellular programs but lose their significance with progressive dedifferentiation.

Animals↗
PubMed1997

Scatter factor/hepatocyte growth factor gene transfer enhances glioma growth and angiogenesis in vivo.

Scatter factor (SF), also known as hepatocyte growth factor, is angiogenic in systemic tissue, and SF titers correlate with the malignancy and metastatic phenotype of certain systemic cancers. Human gliomas express SF and its receptor c-met, but their role in the malignant progression of these tumors has not been defined. To examine this, 9L glioma cells that express c-met but not SF were transfected with human SF cDNA, and their behavior in vitro and in vivo was examined. SF gene expression was detected in conditioned medium of 9L-SF but not in control 9L-neo-transfected cell lines, by reverse transcriptase-PCR, immunoblot, ELISA, and scatter activity assays. Gliomas derived from 9L-SF and control 9L-neo cell lines implanted in the caudate/putamen of Fisher 344 rats (intracranially) and in the flanks of SCID/Beige mice (subcutaneously) were examined. Extracts from intracranial (i.c.) gliomas contained elevated levels of SF protein as determined by ELISA (1 to 5.5 ng SF/mg protein), whereas no SF was detected in control tumors. Reverse transcriptase-PCR of RNA from i.c. gliomas revealed that only 9L-SF gliomas expressed SF and both 9L-neo and 9L-SF gliomas expressed the c-met SF receptor. By postimplantation Day 14, 9L-SF i.c. gliomas were approximately 5-fold larger than 9L-neo control tumors (p < 0.001). Subcutaneous 9L-SF glioma growth was also greater than that in controls, although the differences were more variable. SF-producing i.c. gliomas contained elevated levels of 48-kd urokinase (3.5-fold) and 92-kd type IV collagenase (2.8-fold), both enzymes that correlate with the malignant progression of human gliomas (p < 0.001). SF-producing and control 9L cell lines did not differ in rates of proliferation, thymidine incorporation, or adhesion-independent growth in vitro. Conditioned medium from 9L-SF cells stimulated thymidine incorporation into microvessel brain endothelial cells 3- to 4-fold higher than did CM from 9L-neo controls (p < 0.001). Intracranial 9L-SF gliomas were more angiogenic than controls based on elevated peak (2.25-fold; p < 0.005) and mean (1.7-fold; p < 0.008) blood vessel densities. These results suggest that SF production by glioma cells enhances glioma malignancy in vivo, in part, by paracrine mechanisms involving glioma-associated angiogenesis.

Animals↗
PubMed1997

Scatter factor stimulates tumor growth and tumor angiogenesis in human breast cancers in the mammary fat pads of nude mice.

Scatter factor (SF) (also known as hepatocyte growth factor) is a plasminogen-related growth factor that induces tumor cell motility, invasion, and angiogenesis. Its receptor is a tyrosine kinase encoded by c-met, a protooncogene. Human breast cancer cells express SF and c-met in vivo; but human breast cancer cell lines do not produce SF in vitro. To determine whether SF can modulate the in vivo growth of human breast cancers within a natural mammary environment, we studied the orthotopic growth of SF-transfected (SF+) versus control (SF-) clones of MDAMB231 human mammary carcinoma cells in the mammary fat pads of athymic nude mice. SF+ clones expressed SF mRNA and produced very high titers of SF protein, whereas SF- clones did not express SF mRNA or produce detectable SF protein. Two SF+ clones (21 and 29) showed significantly increased tumor growth rates, reaching 3- to 4-fold larger primary tumor volumes and weights by time of killing (p < 0.001), as well as higher rates of axillary lymph node metastasis (p < 0.02), as compared with two SF- clones (32 and 34). In contrast, in vitro proliferation rates, two-dimensional colony formation, and soft agar colony formation were no greater in SF+ than in SF- clones. We performed further studies to investigate the discrepancy between the in vivo and in vitro growth results. Tumor extracts from SF+ clone (21 + 29) tumors had 50-fold higher SF content than did SF- clone (32 + 34) tumors, confirming high-level SF expression in vivo in SF+ tumors. Immunostaining of tumor sections for proliferating cell nuclear antigen revealed only a modest increase in the proportion of cycling cells in SF+ versus SF- tumors (70% versus 60%, respectively). The terminal deoxytransferase-labeling index was equally low (approximately 1%) in SF+ and SF- tumors, suggesting that apoptosis was not responsible for the slower growth of SF- tumors. However, SF+ tumors had significantly higher tumor microvessel densities than SF- tumors (p < 0.001). Moreover, there were much higher titers of chemotactic activity for microvascular endothelial cells in cell-conditioned media and primary tumor extracts from SF+ clones as compared with SF- clones. As demonstrated using the rat cornea assay, there was more angiogenic activity in SF+ tumor extracts than in SF- extracts. The increased chemotactic and angiogenic activities in SF+ tumor extracts were not explained by secondary alterations in the content of the angiogenic mediator, vascular endothelial growth factor, or the antiangiogenic glycoprotein, thrombospondin-1; and those activities were neutralized using an anti-SF monoclonal antibody. These findings suggest that SF promotes the orthotopic growth of human breast cancers, at least in part, by stimulating tumor angiogenesis.

Adipose Tissue↗
PubMed1996

Scatter factor binds to thrombospondin and other extracellular matrix components.

Scatter factor (SF) is an angiogenic growth factor that stimulates motility and invasion of carcinoma cells. SF is present in the extracellular matrix (ECM) of breast cancers, where it might act to promote tumor cell invasion and angiogenesis. To investigate how SF is incorporated into the ECM, we studied the binding of SF to various ECM components using a solid-phase binding assay based on the SF enzyme-linked immunosorbent assay. We found that SF binds to a variety of ECM molecules, with different binding capacities. The highest SF binding capacities were observed for thrombospondin-1 (TSP-1), fibronectin (Fn), and heparan sulfate proteoglycan, although SF did not bind to albumin. Mature two-chain SF and precursor single-chain SF bound approximately equally well to TSP-1 and Fn. Moreover, two SF alpha-chain peptides (NK1 and NK2) both bound to TSP-1 and Fn, suggesting that the whole SF molecule is not required for binding. Based on binding competition assays, TSP-1 exhibited higher affinity for SF than did nine other ECM molecules, including Fn and heparan sulfate proteoglycan. Although heparin in solution potently inhibited the binding of SF to TSP-1-coated surfaces, even very high concentrations of heparin could not elute SF already bound to TSP-1. SF binding was modulated by binding interactions among ECM molecules (TSP-1-Fn, TSP-1-collagen I, and Fn-collagen I), suggesting that the matrix capacity to bind SF depends upon its exact composition. SF bound in a dose-dependent fashion to ECMs secreted by three human breast carcinoma cell lines. Binding of SF to matrices from all three cell lines was significantly inhibited by preincubation of the matrices with antibodies against TSP-1, whereas antibodies against several other ECM components were less effective or ineffective in inhibiting SF binding. In addition, TSP-1 markedly inhibited chemotaxis of microvascular endothelial cells toward SF and SF-induced angiogenesis in the rat cornea neovascularization assay. Our findings suggest that 1) SF interacts with a variety of ECM components, 2) high affinity SF-TSP-1 interactions may mediate the binding of SF to the breast cancer matrix, and 3) the SF-TSP-1 interaction may contribute to modulation of angiogenesis. Possible implications of these findings for tumor angiogenesis are discussed.

Animals↗
PubMed1995

[Social support of radiotherapy patients in emotional stress and crisis situations].

PURPOSE: This study assesses the psychosocial strains imposed upon radio-oncological patients throughout their treatment. We investigated patients' resources of social support and their relationship towards doctors, nursing staff and technical staff. PATIENTS AND METHODS: One hundred and fifty radio-oncological follow-up patients were asked retrospectively to complete a standardised written questionnaire. This was preceded by 30 in-depth interviews led with radio-oncological in-patients who currently received treatment. RESULTS: Radiotherapy patients reported a spectrum of major stresses, which showed a considerable individual variability. Many patients had experienced emotional crises during hospitalization for their radiation treatment. Most frequently the main social support was provided by relatives. Still, medical staff also played an important supportive role in alleviating emotional distress. Almost half of all patients appeared to have a generally positive attitude towards psychological counseling. CONCLUSION: This study is part of a psychosocial intervention project established in a radiotherapy department. Support is provided for patients directly, e.g. through crisis intervention, supportive therapy, creative therapy, etc. In addition, indirect intervention is aimed at enhancing psychosocial competences of the clinical staff, through lectures, case conferences and seminars.

Crisis Intervention↗
PubMed1994

[How do patients experience radiotherapy?].

PURPOSE: In the course of a radiotherapy treatment oncological patients--in addition to some physical symptoms--often experience severe psychological distress. This study assesses and analyses the psychological strains emerging throughout a radio-oncological treatment. Specific intervention measures are being suggested to alleviate patient's psychosocial distress. This study is part of a psychosocial intervention project performed in a radio-oncological department. PATIENTS AND METHODS: Using a semi-standardised interviewing technique 30 radio-oncological in-patients were questioned in depth about their psychosocial situation. Subsequently a fully standardised written questionnaire was designed, enabling a further 150 patients to be investigated retrospectively, when presenting themselves for routine radio-oncological follow-up examinations. RESULTS: In particular, the irradiation session itself, the waiting time beforehand, and the relationship to fellow patients were found to be potentially stressful. More than half of all patients reported anxiety during their first irradiation, which usually decreased during subsequent sessions, and in no case increased. One third of the 30 inpatients wished to have more contact and conversations with fellow-patients, e.g. while waiting for their treatment. The 150 retrospectively assessed patients stated a substantially lower wish for further contact. Almost one third of the in-patients apparently gained comfort from a downward comparison to patients who they perceived as being worse off than themselves. CONCLUSION: Psychosocial intervention can help radiotherapy patients to cope with fears and distress, and thus enhance their quality of life. Support should be provided by psychological specialists, as well as by clinical staff in various ways. Anxiety concerning radiotherapy can often be alleviated through a sensitive and empathetic manner while explaining the radiotherapy process. Patient groups and seminars offer patients the opportunity to exchange experiences and to gain further information about their disease and treatment. In situations of extreme distress psychologists can accompany patients, and if necessary perform crisis intervention. Psychological specialists can also provide further education and support for the clinical staff.

Anxiety↗
PubMedDate not supplied

Scatter factor/hepatocyte growth factor (SF/HGF) content and function in human gliomas.

Scatter factor/hepatocyte growth factor (SF/HGF) is a pleiotrophic cytokine that stimulates motility and invasion of several cancer cell types and induces angiogenesis. Its receptor MET is a transmembrane tyrosine kinase encoded by the C-MET proto-oncogene. To assess the potential relevance of SF/HGF in gliomas we performed functional studies in vivo and in vitro, expression analyses and correlative studies. We showed that both SF/HGF and MET are expressed in gliomas in vivo and are upregulated during transition from low grade to malignant glioma. When SF/HGF cDNA was transfected into glioma cells that expressed the MET receptor the cells formed considerably larger and more vascularized intracranial tumors in vivo than SF/HGF negative control clones. In other glioma cells, which constitutively expressed both SF/HGF and MET, we abolished SF/HGF expression by antisense ribozyme-targeting, which led to a significant decrease in tumorigenicity and tumor growth. In vitro SF/HGF strongly stimulated glioma cell motility and to a lesser degree proliferation. SF/HGF also strongly increased endothelial cell motility in vitro and extracts of tumors derived from SF/HGF-transfected glioma cells were more mitogenic for endothelial cells and more angiogenic in the rat cornea angiogenesis assay than extracts from control tumors. In a three-dimensional in vitro angiogenesis assay basic fibroblast growth factor (bFGF) was found to synergize with either SF/HGF or vascular endothelial growth factor (VEGF) in inducing endothelial capillary-like tubes, whereas neither SF/HGF nor VEGF alone or in combination were effective. Interestingly, while both VEGF and SF/HGF levels appeared to be increased in malignant gliomas compared with low grade ones, this was not the case for bFGF of which biologically relevant levels were already present in low grade gliomas. It thus seems that bFGF alone is insufficient to induce angiogenesis in gliomas but may act synergistically with either VEGF and/or SF/HGF when these become upregulated during malignant progression. In conclusion, we showed that SF/HGF may contribute to glioma progression by stimulating tumor invasiveness, proliferation and neovascularization.

Animals↗