Role of estrogen receptor alpha in human cervical cancer-associated fibroblasts: a transcriptomic study

Abstract

Cancer-Associated Fibroblasts (CAFs) are crucial in genesis and progression of tumors; however, cervical CAFs (C-CAFs) are not well characterized. Estradiol (E2) has been implicated as a cofactor in human papillomavirus (HPV)-mediated cervical cancer (CxCa), both in animal models and in women using oral contraceptives; however, the exact role of the hormone is unclear. Human C-CAFs have recently been shown to express estrogen receptor alpha (ER-α). We investigated gene expression patterns in ex vivo cultured early and late stage C-CAFs in the context of E2. CAFs were isolated from four patients with early and two patients with late stage CxCa. ER-α expression in CxCa tissues was localized to stromal fibroblast-like cells and confirmed in ex vivo cultured C-CAFs. Two ER antagonists (ICI 182,780 and Methyl Piperidino Pyrazole) were used to unravel ER signaling in CAFs. Microarray technology was used for expression profiling and validated by quantitative reverse transcription PCR. The transcriptomes of C-CAFs across stages indicated their activated state. C-CAFs had gene expression patterns associated with both pro-tumorigenic and pro-inflammatory signaling. Late-stage C-CAFs compared to those of early stage appeared to be more actively metabolizing and cycling but expressed fewer genes related to immune function. We report differential expression profiles between C-CAFs: early vs. late stage and in the presence of ER antagonists. Both ER antagonists seemed to modulate C-CAF function by down regulating genes associated with cell cycle and metabolism, affecting angiogenesis and cancer progression. This study characterized C-CAFs from early and late stage disease, and experiments with ER inhibitors emphasized the probable importance of canonical ER-α signaling. Interfering with paracrine signaling through fibroblast ER-α is worth exploiting as a targeted therapy in CxCa management.

Human papillomavirus oncogenes reprogram the cervical cancer microenvironment independently of and synergistically with estrogen

“…expression of ERα in the cervical stroma of HPV transgenic mice is required for the maintenance of neoplastic disease in the cervical epithelium (27). In human cervical cancers, expression of ERα is, in fact, retained in the stroma but is lost in epithelial cancer cells (28), and human cervical cancer-associated fibroblasts have been shown to mediate estrogen-dependent signaling (29). Moreover, stromal-epithelial interactions mediate the effects of estrogen on female reproductive tract morphogenesis, and stromal ERα facilitates the proliferative effects of estrogen on the adjacent epithelium (30)(31)(32)(33).…”

Functional association of oestrogen receptors with HPV infection in cervical carcinogenesis

“…Cervical cancer-associated fibroblasts under the control of ERα signalling exhibited properties of promoting tumour growth by supporting cell proliferation, angiogenesis, metabolism, epithelialto-mesenchymal transition, epithelial cell migration and inflammation (Kumar et al 2016). Kwasniewska and coworkers reported a strong expression of ERα and PR in the stromal compartment of human CC specimens.…”

“…Stromal ERα target genes such as INPP4B, ESPL1, ORC1L, SERPINE1, SHC4 and MAP2K1 were consistently downregulated by both ER antagonists. This study emphasised the probable importance of SERMs to regulate stromal ERα signalling in CC (Kumar et al 2016). To date, the majority of the information related to the possible utility of SERMs was obtained solely through in vitro and in vivo studies.…”

Research Article Synergic effect of oral contraceptives, GSTP1 polymorphisms, and high-risk HPV infection in development of cervical lesions.

“…Interestingly, according to Weyn et al (2011), the LCR contains response elements for progesterone and glucocorticoid, and Chen et al (1996) proposed that HPV-16 expression may be stimulated by estrogens and progesterone through the activation of nuclear receptors. The synthetic estrogens found in oral contraceptive have augmented estrogenic activity compared with endogenous estrogen in some tissues (Kumar et al, 2016).…”