Transforming growth factor beta-1 in experimental carcinogenesis

In vitro analysis of the effect of TGFβ1 on tumour cell behaviour showed that TGF1 significantly inhibits the adhesion of B16 and D122 tumour cells to endothelial cell monolayers, potentially via an inhibition of adhesion factor expression. In vivo analysis of the effect of TGFβ1 on vascular gene expression in tgfb1+/- mice which have significantly reduced levels of TGFβ1, showed that TGFβ1 regulates the expression of several genes in a sex-specific manner. The mRNA expression of several adhesion factors was upregulated in tgfb1+/- mice, suggesting that TGFβ1 may inhibit adhesion factor expression in vivo as well as in vitro. Investigation of the role of host TGFβ1 during experimental carcinogenesis in tgfb1+/- mice showed that host TGFβ1 regulates subcutaneous tumour growth in a sex-specific manner, promoting the growth of subcutaneous B16 tumours in male mice but having little effect in female mice. Strikingly, different patterns of metastatic seeding from subcutaneous tumours in tgfb1+/- and tgfb1+/+ mice were observed, suggesting that host TGFβ1 may also regulate metastatic seeding to different vascular beds, promoting lymph node metastasis and inhibiting metastasis to the lung. More detailed analysis of intravenous B16 cell dissemination in tgfb1+/- mice shoed that the inhibition of lung metastasis by host TGFβ1 could partly be due to stimulatory effects of host TGFβ1 on anti-cancer immune responses, resulting in increased micrometastatic establishment in tgfb1+/- mice compared to tgfb1+/+ counterparts. Finally, a number of transgenic mice designed to express mutant forms of TGFβ1 type I and type II receptors under temporal control were generated. However only one strain of transgenic mice (in which a CMV promoter regulates a ‘GFP-floxed’ constitutively active ALK1 transgene) exhibits high levels of transgene expression in adult tissues.EThOS - Electronic Theses Online ServiceGBUnited Kingdo