Abstract
BackgroundChondrosarcomas are malignant cartilage-forming tumors which are highly resistant to conventional chemotherapy and radiotherapy. Estrogen signaling is known to play an important role in proliferation and differentiation of chondrocytes and in growth plate regulation at puberty. Our experiments focus on unraveling the role of estrogen signaling in the regulation of neoplastic cartilage growth and on interference with estrogen signaling in chondrosarcomas in vitro and in vivo.MethodsWe investigated the protein expression of estrogen receptor alpha (ESR1), androgen receptor (AR), and aromatase in tumor specimens of various chondrosarcoma subtypes, and (primary) chondrosarcoma cultures. Dose-response curves were generated of conventional central chondrosarcoma cell lines cultured in the presence of 17β-estradiol, dihydrotestosterone, 4-androstene-3,17 dione, 4-hydroxytamoxifen, fulvestrant and aromatase inhibitors. In a pilot series, the effect of anastrozole (n = 4) or exemestane (n = 2) treatment in 6 chondrosarcoma patients with progressive disease was explored.ResultsWe showed protein expression of ESR1 and aromatase in a large majority of all subtypes. Only a minority of the tumors showed few AR positive cells. The dose-response assays showed no effect of any of the compounds on proliferation of conventional chondrosarcoma in vitro. The median progression-free survival of the patients treated with aromatase inhibitors did not significantly deviate from untreated patients.ConclusionsThe presence of ESR1 and aromatase in chondrosarcoma tumors and primary cultures supports a possible role of estrogen signaling in chondrosarcoma proliferation. However, our in vitro and pilot in vivo studies have shown no effect of estrogen-signaling inhibition on tumor growth.
Highlights
Chondrosarcomas are malignant cartilage-forming tumors which are highly resistant to conventional chemotherapy and radiotherapy
Almost all well differentiated (97%) and dedifferentiated (89%) components of dedifferentiated chondrosarcoma were positive for aromatase
We demonstrated the presence of aromatase and ESR1 in a majority of various chondrosarcoma subtypes, our in vitro data on conventional chondrosarcoma and our patient trial including one dedifferentiated chondrosarcoma patient suggest that effects of estrogen-signaling inhibition in other chondrosarcoma subtypes, if present at all, will be very small and that estrogen-signaling inhibition is unlikely to play a major role in chondrosarcoma management
Summary
Chondrosarcomas are malignant cartilage-forming tumors which are highly resistant to conventional chemotherapy and radiotherapy. Chondrosarcomas of bone are malignant cartilage-forming tumors which are highly resistant to conventional chemotherapy and radiotherapy [1,2]. Dedifferentiated chondrosarcoma (10%) is a tumor containing a highgrade dedifferentiated non-cartilaginous sarcoma next to a usually low-grade malignant well-differentiated cartilage-forming tumor, with a sharply defined junction between the two components. It bears a poor prognosis and no targets for therapy have been reported so far [6]. Clear cell chondrosarcoma (2%) is a low-grade malignant tumor, which rarely metastasizes, but commonly recurs after curettage. The lack of efficacious treatment for all different subtypes of chondrosarcomas emphasizes the need to identify new treatment strategies
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