Role of estrogen receptor alpha in human cervical cancer-associated fibroblasts: a transcriptomic study.
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.
Department of Microbiology, Kidwai Memorial Institute of Oncology, Room. No. 114, 1st Floor, Main Block, Hosur Road, Bangalore, 560029, Karnataka, India.
Mahesh M
MM
Kumar
Structural Biology Lab, Centre for Medical Research, School of Bio Sciences and Technology, Vellore Institute of Technology (VIT) University, Vellore, India.|Shodhaka Life Sciences Private Limited, Bangalore, India.
Sravanthi
S
Davuluri
Department of Radiotherapy, Kidwai Memorial Institute of Oncology, Bangalore, India.
Sridhar
S
Poojar
Department of Pathology, Kidwai Memorial Institute of Oncology, Bangalore, India.
Geetashree
G
Mukherjee
Structural Biology Lab, Centre for Medical Research, School of Bio Sciences and Technology, Vellore Institute of Technology (VIT) University, Vellore, India.|Shodhaka Life Sciences Private Limited, Bangalore, India.
Akhilesh Kumar
AK
Bajpai
Department of Gynecology, Kidwai Memorial Institute of Oncology, Bangalore, India.
Uttam Dungarmal
UD
Bafna
Department of Gynecology, Kidwai Memorial Institute of Oncology, Bangalore, India.
Uma K
UK
Devi
Department of Radiotherapy, Kidwai Memorial Institute of Oncology, Bangalore, India.
Pramod P R
PP
Kallur
Shodhaka Life Sciences Private Limited, Bangalore, India.|Institute of Bioinformatics and Applied Biotechnology, Bangalore, India.
Acharya K
AK
Kshitish
Department of Microbiology, Kidwai Memorial Institute of Oncology, Room. No. 114, 1st Floor, Main Block, Hosur Road, Bangalore, 560029, Karnataka, India. microjayshree@gmail.com.
R S
RS
Jayshree
D000072645:Cancer-Associated Fibroblasts / Q000378:metabolism*; D002294:Carcinoma, Squamous Cell / Q000378:metabolism* / Q000473:pathology; D016022:Case-Control Studies; D002478:Cells, Cultured; D002584:Cervix Uteri / Q000378:metabolism / Q000473:pathology; D047628:Estrogen Receptor alpha / Q000502:physiology*; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D063990:Gene Ontology; D006801:Humans; D009367:Neoplasm Staging; D015398:Signal Transduction; D059467:Transcriptome; D002583:Uterine Cervical Neoplasms / Q000378:metabolism* / Q000473:pathology
C506487:ESR1 protein, human; D047628:Estrogen Receptor alpha
Cancer-Associated Fibroblasts; Cervical cancer; Estrogen Receptor Alpha; Estrogen Receptor antagonists; ICI 182,780; MPP-Methyl Piperidino Pyrazole