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Matthias Christgen

Publications and source records attributed to Matthias Christgen.

5 recordsLinked to original sources
PubMed2006

Stable expression of temperature-sensitive p53: a suitable model to study wild-type p53 function in pancreatic carcinoma cells.

Pancreatic adenocarcinoma is an extremely aggressive malignancy with a dismal prognosis. Inactivation of the p53 tumor-suppressor gene occurs in approximately 50% of primary tumors and is thought to account for a failure of the tumor cells to undergo growth arrest and apoptosis in response to chemotherapy. Hence, it is of interest to study the consequences of the restoration of wild-type (wt) p53 function in pancreatic carcinoma cells. Therefore, we retrovirally transduced temperature-sensitive (ts) human p53 into the p53-null pancreatic carcinoma cell line AsPC-1. ts p53 has a mutant phenotype at 37.5 degrees C, and a wt conformation at 32.5 degrees C. Stable expression of p53 in wt conformation caused upregulation of the p53 responsive gene p21Waf1/Cip1, and G1 growth arrest, but failed to induce Bax expression or apoptosis. In addition, we examined the effect of wt p53 expression on DNA damaging treatment. Interestingly, the doxorubicin- and radiation-induced S-/G2-phase arrests were suppressed by p53 in wt conformation. These results demonstrate that the ts p53/AsPC-1 model is suitable to investigate the effect of wt p53 restoration in pancreatic carcinoma cells.

Adenocarcinoma↗
PubMed2005

Gemcitabine-mediated apoptosis is associated with increased CD95 surface expression but is not inhibited by DN-FADD in Colo357 pancreatic cancer cells.

This study investigates the role of caspase-8 and DN-FADD, an inhibitor of CD95-dependent caspase-8 activation, in gemcitabine-induced apoptosis of Colo357 pancreatic cancer cells. Gemcitabine-mediated apoptosis was monitored by the kinetics of caspase-8 activation and cytochrome c release. Gemcitabine treatment of Colo357 cells increased CD95 surface expression, raising the possibility of the involvement of CD95 in gemcitabine-mediated caspase-8 activation. However, ectopic expression of DN-FADD and treatment of cells with the antagonistic anti-CD95 antibody ZB4 both failed to suppress gemcitabine-induced apoptosis but substantially inhibited CD95-mediated apoptosis. DN-FADD, which surprisingly accumulated in nuclei of Colo357 cells, was unable to block caspase-8 activation mediated by either gemcitabine or CD95. These observations argue against a role of CD95 in gemcitabine-induced caspase-8 activation and reveal that the anti-apoptotic function of DN-FADD differs from caspase-8 inhibition in Colo357 cells.

Adaptor Proteins, Signal Transducing↗
PubMed2005

Paraneoplastic leukemoid reaction and rapid progression in a patient with malignant melanoma: establishment of KT293, a novel G-CSF-secreting melanoma cell line.

Paraneoplastic leukemoid reaction (PLR) is a rare condition of leucocytosis in cancer patients. Here we report the rapid progression of a patient suffering from a metastasized malignant melanoma and PLR. The patient's white blood cell count exceeded 200,000 cells per mul and the serum level of Granulocyte Colony-Stimulating Factor (G-CSF) was elevated up to 780 pg/mul. A Tc-m99-labeled anti-NCA90/95 based granulocyte scan demonstrated reactive bone marrow expansion, splenomegaly and granulocyte infiltration into the tumor. KT293, a S100, gp100 and CD68 positive melanoma cell line derived from an axillary metastasis, produced large amounts of G-CSF in vitro and induced rapidly growing tumors and PLR after subcutaneous inoculation in SCID mice. In contrast to G-CSF-secreting cancer cells of other tissue origin, G-CSF-neutralizing antibodies failed to inhibit the growth of KT293 cells. In addition, KT293 cells did not express G-CSF-receptor. These observations suggest that paracrine effects of G-CSF-secretion and PLR might promote an aggressive melanoma phenotype, as seen in this patient.

Animals↗
PubMed2004

Resistance of pancreatic cancer to gemcitabine treatment is dependent on mitochondria-mediated apoptosis.

Palliative chemotherapy with gemcitabine, a common mode of treatment of pancreatic cancer, has little influence on patients' survival. We investigated the impact of anti-apoptotic Bcl-xL protein and its antagonist Bax on gemcitabine-induced apoptosis in human pancreatic carcinoma cells in vitro and in vivo. The level of Bcl-xL and Bax expression was determined in 3 established pancreatic cancer cell lines that differ in their sensitivity to gemcitabine-mediated apoptosis. Bcl-xL and Bax genes were transduced into Colo357 cells by retroviral infection. In addition, cells were transfected with c-FLIP to assess involvement of CD95 and caspase-8. The impact of Bax/Bcl-xL expression on gemcitabine-sensitivity in vivo was evaluated in orthotopic Colo357 tumors in SCID mice. The apoptotic index revealed a strong inverse correlation between Bcl-xL expression and gemcitabine-induced apoptosis in the pancreatic carcinoma cell lines tested. Caspase-8 and Bid were cleaved in Colo357 cells exposed to gemcitabine, and there was no correlation with either Bcl-xL or with Bax expression. In contrast, the lack of mitochondrial transmembrane potential transition, release of cytochrome-c and absence of caspase-9- and PARP-cleavage showed a strong correlation with Bcl-xL expression. Expression of c-FLIP significantly increased the resistance towards gemcitabine. Orthotopically growing Colo357-bcl-xl tumors in SCID mice were refractory to gemcitabine treatment, and in contrast to the in vitro data, Colo357-bax tumors exhibited a 12-fold greater tumor regression than Colo357-wild-type tumors in the control group. Gemcitabine-induced apoptosis involves the mitochondria-mediated signaling pathway. A functional restoration of this pathway appears to be essential to overcome the resistance mechanisms of pancreatic tumor cells and to improve the response to therapy as demonstrated by Bax overexpression in a clinically relevant tumor model.

Animals↗