Invasion of uterine cervical squamous cell carcinoma cells is facilitated by locoregional interaction with cancer-associated fibroblasts via activating transforming growth factor-beta

• Published in: Gynecologic oncology 2015-01, Vol.136 (1), p.104-111
• Main Authors: Nagura, Michikazu, Matsumura, Noriomi, Baba, Tsukasa, Murakami, Ryusuke, Kharma, Budiman, Hamanishi, Junzo, Yamaguchi, Ken, Abiko, Kaoru, Koshiyama, Masafumi, Mandai, Masaki, Murata, Takuya, Murphy, Susan K, Konishi, Ikuo
• Format: Article
• Language: English
• Subjects: Cancer associated fibroblasts; Carcinoma, Squamous Cell - metabolism; Carcinoma, Squamous Cell - pathology; Cell Communication - physiology; Cervical cancer; Female; Fibroblasts - metabolism; Fibroblasts - pathology; Hematology, Oncology and Palliative Medicine; Humans; Invasion; Middle Aged; Neoplasm Invasiveness; Neoplasm Staging; Obstetrics and Gynecology; Signal Transduction; TGF-beta; Transforming Growth Factor beta - metabolism; Uterine Cervical Neoplasms - metabolism; Uterine Cervical Neoplasms - pathology
• ISSN: 0090-8258; 1095-6859
• DOI: 10.1016/j.ygyno.2014.11.075

Abstract Objective Local invasion is a common pattern of spread in uterine cervical squamous cell carcinoma (CSCC). Although transforming growth factor-beta (TGF-β) facilitates invasion of various types of cancer cells, the role of the TGF-β pathway in CSCC is unclear. In this study, we analyzed the role of TGF-β signaling in the progression of CSCC. Methods Immunohistochemistry was used to examine the expression of TGF-β pathway molecules in 67 CSCC samples with clinicopathological data. Activation of the TGF-β pathway was investigated following co-culture of CSCC cells and cervical cancer-associated fibroblasts (CCAFs). Results Clinicopathological analysis of CSCC samples revealed that prominent expression of TGF-β receptor-2 was more frequent in CSCC with lymphovascular space invasion (LVSI) than without LVSI ( p < 0.01). Lymph node metastasis was more frequent in cases in which phosphorylated SMAD3 (pSMAD3) was localized exclusively at the boundary of tumor clusters (n = 9, p < 0.05). Recombinant TGF-β1 increased pSMAD3 expression and enhanced cellular invasion ( p < 0.005) in CSCC cells, which was attenuated by an inhibitor of the TGF-β receptor ( p < 0.005). Enhanced pSMAD3 expression and invasion was also observed when conditioned media from CSCC cells co-cultured with CCAFs were administered. Luciferase assays showed that this medium contained a large amount of active TGF-β. Along with TGF-β activation, thrombospondin-1 was upregulated in both CSCC cells and CCAFs, while thrombospondin-1 silencing in either CSCC cells or CCAFs repressed the activity of TGF-β. Thrombospondin-1 was prominently expressed in cases with pSMAD3 boundary staining ( p < 0.05). Conclusions These results suggest that interaction between CSCC cells and surrounding CCAFs activates TGF-β via thrombospondin-1 secretion to facilitate CSCC invasion.