Rensing, Ludger

Thyroid tumors belong to the most frequent epithelial tumors. On the basis of their histologically and clinically definable forms and stages they represent an outstanding model system for tumorgenesis. Cytogenetic analyses can serve here as an excellent and efficient tool for cloning tumor-relevant genes. Known important cytogenetic changes in adenomas are trisomy 7 as well as breaks in chromosomal bands 19q13.4 and 2p21. Starting from these data, in the present work the breakpoint cluster 19q13.4 was cloned. The newly found upstream lying zinc finger gene ZNF331 was described as a candidate-gene. The second relevant breakpoint cluster in band 2p21 was cloned as well. Here the newly found candidate gene THADA was described which fuses through translocations to different other chromosomes, creating a truncated fusion protein. It could clearly be shown that the HMGA2 gene has an influence on the tumor progression of epithelial thyroid gland cells. Since in animal tissues HMGA2, as shown in mice, is only active during the embryonal stages, the issue arises whether an observed overexpression evokes a tumorigenic status and therefore might be a suitable central point of application for a therapy.

The high mobility group (HMG) proteins HMGA1, HMGA2, and HMGB1 have been discussed as potential tumour markers for years. They belong to the group of HMG proteins acting as architectural transcription factors regulating chromatin structure and gene expression. Over- or re-expression of these embryonic proteins have been detected in various malignancies.Since at the outset of this work in the year 2002 no quantitative analyses of HMGA expression in malignant tumours existed, it was the aim of this study to examineHMGA2 expression in solid tumours and in the peripheral blood of patients mainly with malignant neoplasias using quantitative real-time RT-PCR (qRT-PCR). Absolute quantification of HMGA2 expression in matching tumourous and non-tumourous lung tissue of 34 non-small cell lung cancer patients revealed a highly significant overexpression in the adenocarcinoma as well as in the squamous cell carcinoma samples. In some of the non-neoplastic tissues elevated levels of HMGA2 transcripts were detected which could be due to premalignant changes frequently observed in bronchoalveolar epithelium of smokers and/or lung cancer patients. In 16 canine prostatic tissues with diverse histologic findings a correlation of HMGA2 level and malignant potential was apparent using an accordingly modified qRT-PCR protocol.These results underline the relevance of HMGA2 expression as diagnostic and prognostic marker in cancer therapy.By relative quantification using qRT-PCR HMGA2 expression could be detected in the peripheral blood of all 22 mamma carcinoma patients tested, which is in contrast to previous studies with conventional RT-PCR. Furthermore, no significant differences of HMGA2 expression were detected between patients with or without metastatic disease, indicating that HMGA2 expression in the peripheral blood is not applicable as prognostic marker for breast cancer. qRT-PCR analyses of 36 blood samples from patients with solid tumours, malign diseases of the haematopoietic andlymphatic system, and various autoimmune diseases compared to seven samples of healthy donors showed a strong HMGA2 over-expression solely for one CML patient. Based on this result a study on 56 patients with diseases of the haematopoietic and lymphatic system was conducted. For the leukaemia patients in general as well as for the AML patients in particular a significant over-expression of HMGA2 could be shown. In addition, for the twelve CML patients examined a positive correlation of HMGA2 mRNA transcript levels and white blood cell count at the time of blood drawl was found.Since it was shown that HMGB1 can sensitise cancer cells to cisplatin and this cytostatic drug is commonly used for the treatment of osteosarcomas of the dog, HMGB1 expression was examined in seven canine sarcomas. Preceding sequence analyses revealed a strong similarity of the canine HMGB1 gene and the deduced protein to the human orthologs. Northern Blot analysis and semi-quantitative RT-PCR consistently showed a clear variation of HMGB1 expression, which could be of importance for further therapeutic protocols using cisplatin. Apart from the nuclear function of the HMGB1 protein as architectural transcription factor, extra cellular HMGB1 plays an important role as mediator of inflammation and in tumour metastasis. Herein the angiogenic potential of recombinant HMGB1 protein was shown in vitro for the first time. Application of HMGB1 induced cell migration and sprouting in an endothelial sprouting assay in a dose dependent manner.

Rensing, Ludger

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