Caveolin-1 plays a crucial role in the development of cancer and its progression. We previously reported that glioblastoma cells expressing low levels of caveolin-1 exerted a more aggressive phenotype than cells expressing high levels. Such phenotype was due to the induction of α5β1 integrin subsequent to the depletion of caveolin-1. Caveolin-1 was identified as a transcriptional repressor of α5β1 integrin. The current study was designed to identify in vitro, the molecular mechanisms by which caveolin-1 controls α5β1 integrin expression and to determine if a negative correlation between caveolin-1 and α5β1 integrins also exists in biopsies and xenografted human brain tumors. We showed that depletion of caveolin-1 lead to the activation of the TGFβ/TGFβRI/Smad2 pathway which in turn induced the expression of α5β1 integrins. We showed that cells expressing the lowest levels of caveolin-1 but the highest levels of α5β1 integrins and TGFβRI were the most sensitive to a α5β1 integrin antagonist and a TGFβRI inhibitor. Screening human glioma biopsies and human glioblastoma xenografts, we isolated subgroups with either low levels of caveolin-1 but high levels of α5β1 integrin and TGFβRI or high levels of caveolin-1 but low levels of α5β1 integrin and TGFβRI. In conclusion, caveolin-1 controls α5β1 integrin expression through the TGFβ/TGFβRI/Smad2 pathway. The status of caveolin-1/α5β1 integrins/TGFβRI might be a useful marker of the tumor evolution/prognosis as well as a predictor of anti-TGFβ or anti-α5β1 integrin therapies.