Modelling cancer: recapitulation of tumor growth in experimental systems in vivo and in vitro
1University of Oulu, Faculty of Medicine, Department of Pathology
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|Persistent link:|| http://urn.fi/urn:isbn:9514256433
|Publish Date:|| 2000-05-04
|Thesis type:||Doctoral Dissertation
|Defence Note:||Academic Dissertation to be presented with the assent of the Faculty Medicine, University of Oulu, for public discussion in the Auditorium of the Department of Pharmacology and Toxicology, on May 31st, 2000, at 12 noon.
Docent Hannu Haapasalo
Docent Lauri Kangas
The purpose of the study was to evaluate model systems of cancer development and compare some of their critical features with cancer development in vivo. Ovarian and endometrial cancers in man were used as correlates. Tumor development in experimental animals, exposed to carcinogens and UV irradiation, showed the entire spectrum of tumor development as compared to spontaneous carcinomas: hyperplasia, dysplasia, benign papillomas and malignant squamous cell carcinomas. For short-term analysis of differentiated homogenous cell populations, the transplant model proved most useful. For long term analysis of effects of extraneous agents, the skin carcinogenesis model is probably the most rewarding.
Analysis of proliferation markers in human tumor samples as studied by immunohistochemistry, showed that an increased expression of PCNA and Ki-67 was associated with poor prognosis in ovarian neoplasms. Analysis of cell proliferation in model tumors showed that the transplant model has a better sensitivity when compared to the animal skin model and the subcutaneous injection model, in that effect of changes in cell-host interaction on the location and extent of the proliferating cell population can be studied therein.
The expression of some growth factors, their receptors, oncogenes and suppressor genes were studied in ovarian and endometrial carcinomas and in skin cancer model system in mouse exposed to carcinogens and UV irradiation. Variability in expression and methodological problems precluded detailed analysis of these markers in different models.
The expression of TGFβ1, TGFβ2 and TGFβ3 was determined in normal human keratinocytes, and in 7 immortalized and ras-transfected benign and malignant keratinocyte cell lines, maintained as transplants and as subcutaneous tumors in nude mice. By differential immunohistochemical localization of TGFβ isoforms, we demonstrated that each isoform may serve specific roles in tumor development and progression. The complex nature of TGFβ expression prevented detailed analysis of isozymes in different models, the results in this study, however, indicated a similar pattern in the models analyzed.
Morphological methods were used to determine relationship between epithelial growth and formation and deposition of collagens in the extracellular matrix in experimental models and human tumors. The composition of the mesenchyme differed in tumors originating from different cell lines reflecting functional interaction between epithelial cells and the mesenchyme in neoplastic development. Tumor-stroma interaction was distinct in human, comparable alterations were observed in experimental models, more so in transplants, less in subcutaneous tumors, affecting tumor growth and differentiation in the different models.
Acta Universitatis Ouluensis. D, Medica
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