Deregulation von Zellzyklus und Apoptose beim Plattenepithelkarzinom des Ösophagus
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Medizinische Fakultät - Universitätsklinikum Charité
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Abstract
Störung des G1-Restriktionspunkts des Zellzyklus und Verlust der Wachstumskontrolle in Folge der Inaktivierung des Rb-Signalwegs ist ein häufiges Ereignis in malignen Tumoren. Gemeinsam mit der Hemmung von Apoptose-Signalwegen sind solche genetischen Ereignisse zentrale pathogenetische Faktoren der Tumorentstehung. Diese Veränderungen prägen aber auch entscheidend die Tumorbiologie und bestimmen somit intrinische und erworbene Therapieresistenz und konsequenterweise auch die klinische Prognose der Tumorerkrankung. In der vorliegenden Arbeit wurden Veränderungen im Rb- und im p53-Signalweg in Plattenepithelkarzinomen des Ösophagus untersucht. Diese retrospektive Studie wurde an Tumorproben von 53 mit kurativer Intention R0-resezierten Patienten durchgeführt. Proteinexpression wurde mittels Immunhistochemie und Mutationen mittels SSCP-PCR analysiert. Aktivierende Punktmutationen des K-ras Onkogens wurden mittels mutationsselektiver genomischer PCR und eines sequenzspezifischen Festphasen-Hybridisierungstests nachgewiesen. Die Analyse der individuellen Gene zeigte, dass Expressionsverlust der Rb-Signalwegskomponenten p16INK4a, p21CIP/WAF-1, p27KIP1 und von Rb selbst, sowie die Überexpression von Cyclin D1 bzw. Verlust des pro-apoptotischen Bcl-2 Homologs Bax mit schlechter Prognose, d.h. kürzerem Überleben korrelierte. Überexpression von Cyclin E, p53 oder Bcl-2, sowie Mutation von p53 bzw. K-ras zeigten hingegen keinen Einfluss auf die Prognose. Das längste Überleben wurde in einer Subgruppe von Patienten beobachtet deren Tumore eine Kombination günstiger Genotypen zeigte, und zwar niedrige Cyclin D1 Expression, sowie hohe Expression von Rb, p21CIP/WAF-1, p16INK4a und Bax. Diese Ergebnisse zeigen, dass eine Multigen- oder "Multimarker"-Analyse von Genen, die konsekutiv oder synergistisch in Zellzyklus- und Apoptose-Signalwegen agieren, zur Prognoseabschätzung der Analyse individueller Gene deutlich überlegen ist. Die Identifikation solcher genetischer Markerprofile sollte sich auch zukünftig als nützlich für die klinische Entscheidungsfindung in der Therapie maligner Tumore erweisen und wird konventionelle klinische und pathologische Faktoren komplementieren, die bisher keine ausreichende Prognoseabschätzung erlauben.
Malignant tumors frequently show inactivation of the Rb pathway and, as a result, deregulation of the G1 restriction point of the cell cycle and loss of growth control. Together with the inhibition of apoptosis signaling pathways, such events are key pathogenetic factors in tumor development. Moreover, these aberrations are decisive in determining tumor biology and characteristics such as intrinisic or acquired resistance to therapy and, consequently, the clinical prognosis of the malignant disease. In the present work, aberrations in the Rb and the p53 pathway were analysed. This retrospective study was undertaken in a cohort of 53 patients with esophageal squamous cell carcinoma who underwent R0 resection with a curative intent. Protein expression in tumor samples was analysed by means of immunohistochemistry and mutations were investigated by the use of genomic SSCP-PCR. Activating point mutations of the K-ras oncogene were detected by the use of mutation-selective genomic PCR and a sequence specific solid phase hybridization assay. The analysis of individual genes showed a correlation between poor prognosis, i.e. short overall survival, and loss of the Rb pathway components p16INK4a, p21CIP/WAF-1, p27KIP1, and Rb itself, or overexpression of cyclin D1 or loss of the pro-apoptotic Bcl-2 homolog Bax. In contrast, overexpression of cyclin E, p53 or Bcl-2 and mutation of p53 or K-ras had no influence on disease prognosis. The longest survival was found in a subgroup of patients whose tumors exhibited a combination of favorable genotypes, i.e. low expression of cyclin D1, and high expression of Rb, p21CIP/WAF-1, p16INK4a and Bax. These results demonstrate that a multigene or "multimarker"-analysis of genes that act consecutively or synergistically in cell cycle and apoptosis signaling pathways is far superior to determine disease prognosis when compared to the analysis of individual genes. The identification of such genetic marker profiles should proove beneficial in clinical decision making in the therapy of malignant tumors. In the future, such diagnostic tools may be useful to complement conventional clinical and pathologic factors which in most instances do not allow prediction of disease prognosis.
Malignant tumors frequently show inactivation of the Rb pathway and, as a result, deregulation of the G1 restriction point of the cell cycle and loss of growth control. Together with the inhibition of apoptosis signaling pathways, such events are key pathogenetic factors in tumor development. Moreover, these aberrations are decisive in determining tumor biology and characteristics such as intrinisic or acquired resistance to therapy and, consequently, the clinical prognosis of the malignant disease. In the present work, aberrations in the Rb and the p53 pathway were analysed. This retrospective study was undertaken in a cohort of 53 patients with esophageal squamous cell carcinoma who underwent R0 resection with a curative intent. Protein expression in tumor samples was analysed by means of immunohistochemistry and mutations were investigated by the use of genomic SSCP-PCR. Activating point mutations of the K-ras oncogene were detected by the use of mutation-selective genomic PCR and a sequence specific solid phase hybridization assay. The analysis of individual genes showed a correlation between poor prognosis, i.e. short overall survival, and loss of the Rb pathway components p16INK4a, p21CIP/WAF-1, p27KIP1, and Rb itself, or overexpression of cyclin D1 or loss of the pro-apoptotic Bcl-2 homolog Bax. In contrast, overexpression of cyclin E, p53 or Bcl-2 and mutation of p53 or K-ras had no influence on disease prognosis. The longest survival was found in a subgroup of patients whose tumors exhibited a combination of favorable genotypes, i.e. low expression of cyclin D1, and high expression of Rb, p21CIP/WAF-1, p16INK4a and Bax. These results demonstrate that a multigene or "multimarker"-analysis of genes that act consecutively or synergistically in cell cycle and apoptosis signaling pathways is far superior to determine disease prognosis when compared to the analysis of individual genes. The identification of such genetic marker profiles should proove beneficial in clinical decision making in the therapy of malignant tumors. In the future, such diagnostic tools may be useful to complement conventional clinical and pathologic factors which in most instances do not allow prediction of disease prognosis.
Description
Keywords
Bax, p53, Ösophaguskarzinom, K-ras, Rb-Signalweg, p16/Ink4a, Bax, p53, Esophageal carcinoma, K-ras, Rb pathway, p16/Ink4a
Dewey Decimal Classification
610 Medizin und Gesundheit
Citation
Güner, Dilek.(2003). Deregulation von Zellzyklus und Apoptose beim Plattenepithelkarzinom des Ösophagus. 10.18452/14953