Analyses of Rat Tumor Models for DMBA-induced Fibrosarcoma and Spontaneous Endometrial Carcinoma

Sammanfattning: Cancer is a disease of genes. Uncontrolled cell growth is the outcome from genetic as well as epigenetic alterations, resulting in a tumor cell mass that harbors a cancer genome. During progression, the tumor acquires self-dependence and the ability to invade other tissues and metastasize. Genetic predisposition and environmental factors such as life style, diet and exposure to carcinogenetic compounds promote initiation of tumors. The laboratory rat (Rattus norvegicus) has been used as an animal model in medical research for over 150 years. By using a genetically well-defined rat model in a controlled environment, we have studied two cancer models for DMBA-induced fibrosarcoma and spontaneous endometrial cancer. In the fibrosarcoma model an F1 progeny from two inbred rat strains, BN and LE, was used and tumors were induced by a single injection of the carcinogenic agent DMBA. The tumors were used for Allelic Imbalance analysis as well as identifying putative candidate genes on chromosome1 displaying a region with gene amplification. We could successfully identify Jak2 as a candidate gene for the amplification at the distal part of chromosome1 in one of the fibrosarcoma cell lines. Adjacent to this region on chromosome1, the Allelic Imbalance analysis displayed signs for loss of heterozygosity in the Pten locus. No mutation was found in the remaining allele, suggesting that Pten is contributing to the fibrosarcoma development in these DMBA-induced tumors by a haploinsufficient mechanism. The endometrial tumor model is composed of the BDII rat strain, predisposed to spontaneously develop endometrial cancer. Tumors obtained from progeny from intercrosses and backcrosses between the BDII strain and two strains not prone to develop endometrial cancer, were used to classify and characterize the BDII tumors according to the human classification system. We could conclude that the BDII tumors resemble the human hormone dependent type I tumors, best. This conclusion was confirmed when we tested some of our result from the BDII model on human type I tumors in a FISH study for amplification of specific genes located on HSA2p and HSA7q. In summary, we found similar patterns of amplification in the human type I tumors as was previously found in the BDII rat tumors. In addition, we were able to improve the rat ideogram and anchor DNA sequences (i.e. genes) to the physical rat gene map. The molecular profiling of tumors at different levels, i.e. DNA, RNA and epigenetic, has provided an efficient tool for identifying and characterizing cancer related genes. Furthermore, the use of animal tumor models provides an important route to identify molecular biomarkers for prognosis as well as new targets for drug discovery in cancer treatment.

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