A Canonical Transforming Growth Factor Beta-Dependent Signaling Pathway is Present in Peripheral Blood Cells of Cancer Patients with Skeletal Metastasis

Background: Patients with advanced metastatic cancer often have elevated levels of circulating transforming growth factor beta (TGF-β) that is thought to stimulate receptor mediated signaling through phosphorylated SMAD transcription factors in peripheral blood mononuclear cells. Methods: To identify this TGF-β-dependent gene expression profile in cancer patients, we first evaluated a multi-gene expression profile from ex-vivo treated PBMCs with TGF-β1 stimulation. Change in expression, when challenged with a specific TGF-β receptor type kinase inhibitor was then derived to be ligand and inhibitor specific. Once this profile was established, we examined its role in identifying the activation of a canonical TGF-β1 signaling pathway in patient samples. Results: We discovered a 37 gene sub-set where the expression profile from ex-vivo treated PBMCs was significantly associated with SMAD phosphorylation in cancer patients. We found significant correlation between the ex-vivo derived expression signature and circulating levels of TGF-β1 in patient samples. Additionally, we report association between the expression profile and the presence of several plasma proteins in disease samples that are known to be concomitantly present with TGF-β- dependent pathway activation. Conclusion: An expression profile for TGF-β1 cytokine mediated-signaling in cancer patients is identified, which may serve as a biomarker to measure the pharmacodynamic effect of TGF-β inhibitors during clinical drug development and as marker of disease diagnosis.