Publications (3)19.76 Total impact
- [Show abstract] [Hide abstract] ABSTRACT: To establish xenograft mouse models of metastatic and nonmetastatic human prostate cancer and to apply these models to the search for aberrant glycosylation patterns associated with tumor progression in vivo and in patients. Prostate cancer cells (LNCaP, PC-3, LuCaP 23.1, and DU-145) were xenografted subcutaneously into immunodeficient pfp(-/-)/rag2(-/-) mice. Tumor growth and metastasis formation were quantified and as altered glycosylation patterns have been associated with metastasis formation in several other malignancies, prostate cancer cells were profiled by a quantitative real-time PCR (qRT-PCR) glycosylation array and compared with normal human prostate cells. The activity of upregulated glycosyltransferases was analyzed by their sugar residues end products using lectin histochemistry on primary tumors and metastases in the animal experiments and on 2,085 clinical samples. PC-3 cells produced the largest number of spontaneous lung metastases, followed by LNCaP and LuCaP 23.1, whereas DU-145 was nonmetastatic. qRT-PCR revealed an upregulation of β1,6-N-acetylglucosaminyltransferase-5b (Mgat5b) in all prostate cancer cell lines. Mgat5b products [β(1,6)-branched oligosaccharides] were predominantly detectable in metastatic xenografts as shown by increased binding of Phaseolus vulgaris leukoagglutinin (PHA-L). The percentage of prostate cancer patients who were PHA-L positive was 86.5. PHA-L intensity correlated with serum prostate-specific antigen and a cytoplasmic staining negatively affected disease-free survival. We show a novel xenograft mouse model for human prostate cancer respecting the complete metastatic cascade. Specific glycosylation patterns reveal Mgat5b products as relevant markers of both metastatic competence in mice and disease-free survival in patients. This is the first description of Mgat5b in prostate cancer indicating a significant biologic importance of β(1,6)-branched oligosaccharides for prostate cancer progression.
- [Show abstract] [Hide abstract] ABSTRACT: Although survival rates of colon cancer patients diagnosed at an early stage (T1-2N0M0; Dukes A) vary considerably according to the studies cited, several studies indicate development of distant metastases already occurring in a considerable percentage of these patients leading to the death of the patients. This particular high risk group cannot be identified properly as no marker exists to identify these patients. As the Wnt/Win pathway plays a crucial role in metastasis formation in colorectal carcinoma, we analysed whether the transcription factor brachyury critically involved in this pathway may predict metastasis formation in these patients. The expression of brachyury-homologous (T) was immunohistochemically analysed in 748 patients and the data were correlated with classical and newer prognostic markers in colorectal cancer. Early stages colorectal cancer patients (T1-2N0M0, Dukes A) showed a significantly decreased survival when brachyury was expressed in the tumour tissue while no correlation was observed in later tumour stages. Hence a subset of colorectal cancers exists in which the ability to metastasise is already present at early stages of tumour growth and this high risk group can now be detected by immunohistochemistry.
- [Show abstract] [Hide abstract] ABSTRACT: The peroxisome proliferator-activated receptor (PPARgamma) is a nuclear receptor that plays a regulatory role in cell differentiation and proliferation. PPARgamma was first detected in adipocytes, however, it has been shown that this receptor is also expressed in normal as well as tumor cells including malignant colonic epithelial cells. In this study, the effect of the PPARgamma agonist RO205-2349, a recently developed thiazolidinedione, on tumor growth was evaluated. For this purpose, human colon cancer cells (HT29) were grown in severe combined immunodeficient mice. Under daily RO205-2349 treatment (50 mg/kg/day) a significantly reduced tumor weight became evident after 3 weeks. In the control (n = 10) and treatment (n = 10) groups the mean tumor weights were 0.45 and 0.16 g, respectively. The mean percentages of apoptotic cells were 0.8 and 2.7% in the control and treatment groups, respectively, and the cell diameter measured on average 11.4 and 9.4 microm. In contrast, cell proliferation and differentiation, which are considered to be influenced by the PPARgamma, remained unaffected as could be seen by Ki-67 and carcinoembryonic antigen immunoreactivity indicating that increased rate of apoptosis and cell shrinkage are responsible for the differences in tumor growth. Hence, in this human/mouse xenograft model, mechanisms other than the classical activation of PPARgamma are likely reasons causing limited tumor growth.
University Medical Center Hamburg - Eppendorf
Hamburg, Hamburg, Germany
- Department Anatomy and Experimental Morphology