Stromal factors involved in human prostate cancer development, progression and castration resistance
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To detect new predictive markers from the prostate cancer tissue, to study the expression by cultured cancer-associated fibroblasts (CAFs) of stromal factors implicated in prostate carcinogenesis, and to compare their expressions in localized, metastatic, castration-sensitive (CSCP), castration-resistant prostate tumors (CRCP) as well as in fibroblasts from benign prostatic hyperplasia (BPH).
Materials and methods
The genomic expression of 20 stroma-derived factors, including the androgen receptor (AR), growth factors (FGF2, FGF7, FGF10, HGF, TGFβ, PDGFB), protein implicated in invasion (MMP-2, MMP-9 and MMP-11), inflammation (IL-6, IL-17, STAT-3 and NFκB), stroma/epithelium interaction (CDH11, FAP, CXCL12 and CXCL14) and chaperones (HPA1A and HSF1), was evaluated in cultured fibroblasts both from BHP and prostate carcinomas (PCa). After isolation and culture of fibroblasts by biopsy specimens, RNA was isolated and genomic studies performed.
Finally, 5 BPH and 37 PCa specimens were selected: clinically localized (19), metastatic (5), CSCP (7) and CRPC (6). Interleukin-17 receptor (IL-17RB) was highly expressed in CAFs compared with fibroblasts from BPH. However, metalloproteinase-2 and chemokine ligand 14 (CXCL14) were expressed at higher levels by fibroblasts from BPH. The fibroblastic growth factor-7 was highly expressed by CAFs from localized tumors, but metalloproteinase-11 in metastatic tumors. MMP-11, androgen receptor (AR) and heat–shock-70kda-protein-1A (HSPA1A) expressions were significantly higher in CAFs from CRPC.
These results demonstrate a CAFs heterogeneity among prostate carcinomas with regard to some molecular profile expressions that may be relevant in tumor development (IL-17RB), progression (MMP-11) and castration resistance (AR, MMP-11 and HSPA1A).
KeywordsCancer-associated fibroblasts (CAFs) Tumor stroma Metastatic cancer Castration-resistant prostate cancer Androgen deprivation therapy
This work was supported by a grant from Abbvie Inc, Chicago (Study No: ACA-SPAI-10-24). The expert technical assistance of Sandra Cid was gratefully acknowledged.
Compliance with ethical standards
Conflict of interest
The authors declare that there are no conflicts of interest.
All procedures performed in this study were in accordance with the ethical standards of the institutional research committee and with the 1964 Helsinki Declaration and its later amendments or comparable ethical standards.
Informed consent was obtained from all individual participants included in the study.
- Eiro N, Fernandez-Garcia B, Vazquez J, Del Casar JM, Gonzalez LO, Vizoso FJ (2015) A phenotype from tumor stroma based on the expression of metalloproteases and their inhibitors, associated with prognosis in breast cancer. Oncoimmunology 4:e992222. doi: 10.4161/2162402X.2014.992222 CrossRefPubMedPubMedCentralGoogle Scholar
- Fernandez-Gomez J et al (2011) Relationship between metalloprotease expression in tumour and stromal cells and aggressive behaviour in prostate carcinoma: simultaneous high-throughput study of multiple metalloproteases and their inhibitors using tissue array analysis of radical prostatectomy samples. Scand J Urol Nephrol 45:171–176. doi: 10.3109/00365599.2010.545074 CrossRefPubMedGoogle Scholar
- Herranz-Amo F, Molina-Escudero R, Ogaya-Pinies G, Ramirez-Martin D, Verdu-Tartajo F, Hernandez-Fernandez C (2015) Prediction of biochemical recurrence after radical prostatectomy. New tool for selecting candidates for adjuvant radiation therapy. Actas Urol Esp. doi: 10.1016/j.acuro.2015.07.006 Google Scholar
- Karkoulis PK, Stravopodis DJ, Margaritis LH, Voutsinas GE (2010) 17-Allylamino-17-demethoxygeldanamycin induces downregulation of critical Hsp90 protein clients and results in cell cycle arrest and apoptosis of human urinary bladder cancer cells. BMC Cancer 10:481. doi: 10.1186/1471-2407-10-481 CrossRefPubMedPubMedCentralGoogle Scholar