Expression of aromatase and estrogen receptor alpha in chondrosarcoma, but no beneficial effect of inhibiting estrogen signaling both in vitro and in vivo

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.

Bone cancer incidence by morphological subtype: a global assessment

“…Estrogen is involved in cartilage metabolism and plays an important role in human growth [50]. Estrogen receptor alpha is present in CS tumors supporting a possible role of estrogen signaling in CS proliferation [51]. Furthermore, estrogen has been shown to stimulate vascular endothelial growth factor, which is a characteristic trait of progression of CS [16].…”

NY-ESO-1 (CTAG1B) expression in mesenchymal tumors

“…16 From MDACC, myxoid liposarcoma tissue microarrays contained untreated tumors and tumors pre-treated with chemotherapy, radiation, or a combination of both. 17,18 From the LUMC, tissue microarrays were selected containing chondrosarcomas, 19,20 osteosarcomas, 21 myxoid liposarcomas, and a variety of benign and malignant soft tissue tumors. 22,23 Immunohistochemistry Immunohistochemical staining was performed with an autostainer for tissue microarrays of the UBC and MDACC following protocols as described previously.…”

Chondrosarcoma of the tibial head during pregnancy: a challenging diagnosis

“…Placental and fetal metastasising of chondrosarcomas of the extremities has not been reported to date. An adverse effect of altered maternal hormone levels on tumour growth however cannot be ruled out until today 5 6. Therefore, a treatment with the least achievable delay appears to be necessary.…”

“…As a result there are neither rich experiences nor common treatment rationale for women diagnosed with chondrosarcoma of the extremities during pregnancy. In addition it still remains unclear whether chondrosarcoma may show progression or dedifferentiation according to the patient's hormone status 2 5 6…”