Abstract
Uterine carcinosarcomas (UCS) are rare (3-4%) but highly aggressive, accounting for a disproportionately high (16.4%) mortality among uterine malignancies. Transforming growth factor beta (TGFβ) is a multifunctional cytokine that regulates important cellular processes including epithelial-mesenchymal transition (EMT). Existence of biphasic elements and a report demonstrating amplification of TGFβ at 19q13.1 prompted us to investigate the role of TGFβ signaling in UCS.Here we demonstrated the components of TGFβ pathway are expressed and functional in UCS. TGFβ-I induced significant Smad2/3 phosphorylation, migration and EMT responses in UCS cell lines which could be attenuated by the TGFβ receptor I (TGFβR-I) or TGFβ receptor I/II (TGFβR-I/II) inhibitor developed by Eli Lilly and company. Importantly, TGFβ-I induced proliferation was c-Myc dependent, likely through activation of cell cycle. c-Myc was induced by nuclear translocation of nuclear factor of activated T cells (NFAT-1) in response to TGFβ-I. Inhibition of NFAT-1 or TGFβR-I blocked c-Myc induction, cell cycle progression and proliferation in UCS. In corroboration, mRNA levels of c-Myc were elevated in recurrent versus the non-recurrent UCS patient samples. Interestingly, in the absence of exogenous TGFβ the TGFβR-I/II inhibitor enhanced proliferation likely through non-Smad pathways. Thus, inhibition of TGFβR-I could be efficacious in treatment of UCS.
Highlights
Uterine carcinosarcomas (UCS) are biphasic tumors that are highly aggressive and rare accounting for ~3-4% of all uterine cancers
Components of TGFβ pathway are expressed in UCS patient tissues and cell lines The biphasic nature and a report demonstrating amplification of the TGFβ locus at 19q13.1 in UCS [20] prompted us to determine whether the TGF pathway is active in UCS patient samples
The role of TGFβ signaling was evaluated in UCS patient samples and cell lines and efficacy of TGFβR inhibitors was determined
Summary
UCS are biphasic tumors that are highly aggressive and rare accounting for ~3-4% of all uterine cancers. By definition these tumors are composed of a malignant epithelial component, typically with high grade endometrioid or serous features [1, 2]. Even patients with early stage disease have recurrence rates of 30-50%. Despite the improvements noted with chemotherapy, less than 30% of patients with optimally resected, stage III-IV disease, remain progression free at 3 years. For patients with bulky advanced/recurrent disease, ~15% of patients remain progression free at 2 years, and only 20% remain alive at 2 years [4, 5]. There is a compelling need for improvement of existing treatments
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