In vivo analysis of the role of tenascin-C in tumorigenesis

The extracellular matrix molecule tenascin-C (TNC) is an important factor in tumor progression. In the multistage carcinogenesis Rip1Tag2 (RT2) model, in which the SV40 T antigen induces stochastically non-metastatic insulinomas we determined how ectopically expressed human TNC affects tumor progression. Transgenic RipTNC mice with rat insulin promoter driven ectopic expression of TNC in the pancreatic β-cells were generated. RipTNC mice did not exhibit detectable alterations in pancreas morphology and function, but displayed enhanced angiogenesis. A direct angiogenesis-promoting effect was demonstrated by purified TNC in the chicken chorioallantoic membrane assay. Upon crossing into the RT2 background enhanced tumor cell proliferation and increased angiogenesis with strong hemorrhages was detected in tumors of double transgenic RT2/TNC mice. Ectopically expressed TNC accelerated carcinoma progression with nuclear translocation of β-catenin. Nuclear translocation of β-catenin occurred also in MCF7 breast cancer cells in which TNC induced EMT. RT2/TNC tumor cells accumulated in tubes made of TNC and laminin that were not lined by endothelial cells. In contrast to RT2 mice, RT2/TNC littermates developed local lymph node and distant liver metastasis. In conclusion, in this first tumorigenesis model mimicking ectopic expression of TNC in cancer, TNC induced nuclear translocation of β-catenin that can explain TNC-driven angiogenesis, tumor cell proliferation, invasion and metastasis which may involve tumor cell dissemination by the TNC-containing tubes.