Invasion of uterine cervical squamous cell carcinoma cells is facilitated by locoregional interaction with cancer-associated fibroblasts via activating transforming growth factor-beta
Introduction
Despite widespread vaccination against human papilloma virus and periodic cancer screening, cervical cancer remains one of the highest ranking diseases causing mortality in women, and new strategies to treat this disease are urgently needed. Squamous cell carcinoma, the most common histological subtype of cervical cancer, spreads principally by migrating into the lymphatics or by invading adjacent soft tissues. Eradication of locoregional lesions is critical but is not attainable in cases with tumor extension into the urinary tract and/or rectum for fear of impairing urinary or bowel function. Even if the extension is more limited, it is also difficult to obtain cancer-free-margins, leading to pelvic recurrence from residual cancer cells. Obstruction of the ureter(s) is not trivial and is observed in 55.8% of advanced cases [1]. It is, therefore, important to develop effective treatments for invasive extension of this disease, and to this end, it is essential to further elucidate the mechanisms of cervical cancer invasion.
Transforming growth factor-beta (TGF-β) is currently known to promote cancer invasion [2]. TGF-β serves as a potent growth inhibitor for normal epithelial cells [3], but malignant transformed cells acquire resistance to the growth inhibitory effect of TGF-β [4]. Moreover, as breast cancer advances, TGF-β acts as a promoter by inducing epithelial to mesenchymal transition (EMT), invasion, and metastasis [5], [6]. In gynecologic cancers, activated TGF-β signaling promotes peritoneal dissemination of ovarian cancer [7]. Thus, TGF-β is widely recognized as a key molecule that drives cancer cell progression, but little is known about the role of TGF-β in uterine cervical cancer.
Growing evidence has shown that the stroma around cancer cells plays an important role in cancer progression. Cancer-associated fibroblasts (CAFs) exhibit morphological phenotypes of myofibroblasts and are known to promote cancer progression through interactions with adjacent cancer cells. TGF-β is a key cytokine mediating such interactions [8], [9]. However, we presently lack clarification regarding the role of TGF-β in these interactions in cervical squamous cell carcinoma (CSCC).
In this study, we analyze the role of TGF-β signaling in the progression of CSCC. We show that activation of TGF-β induced by the interaction between CSCC cells and CAFs plays a key role in the initiation of tumor metastasis.
Section snippets
Tissue samples and immunohistochemistry
Tissue samples and clinicopathological information were collected from sixty-seven patients (median age, 54 +/− 23 years) with stage IB–IIB CSCC who underwent radical hysterectomy or trachelectomy in Kyoto University Hospital from January 2003 to July 2010 with written consent under the approval of the ethics committee. Patient characteristics are described in Table 1.
Immunohistochemical staining was performed for six molecules: TGF-β, TGF-β receptor type 1 (TGFBR1), TGF-β receptor type 2
Clinicopathological analysis of CSCC in association with the TGF-β pathway
A total of 67 patients were treated for locally advanced CSCC (IB1; n = 38, IB2; n = 6, IIA1; n = 5, IIA2; n = 2, and IIB; n = 16). The 67 cases included 22 with lymph node metastasis and two with distant metastasis. Patients with lymphovascular space invasion (LVSI) or lymph node metastasis (LNM) exhibited worse clinical outcomes than those without these characteristics (p < 0.05 for each, Table 1). Immunohistochemical staining was conducted for TGF-β, TGFBR1, TGFBR2, pSMAD3, α-SMA, and TSP1. TGF-β was
Discussion
TGF-β is known to play various roles in malignant progression. It inhibits growth of normal epithelial cells, and conversely, it promotes EMT, invasion and metastasis in cancer cells, thus eluding tumor-suppressive effects [2], [3], [4]. With regard to CSCC, the role of TGF-β signaling is more complicated and not well understood. TGF-β pathway functions in an inhibitory manner for pelvic lymph node metastasis [13], while TGF-β1 expression increases through progression from cervical
Conflict of interest statement
All authors declare that they have no conflicts of interest to disclose.
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