Aldoketoreductasis 1 B10 (AKR1B10) Expression in Tissues and Tumors Showing Notochordal Differentiation. A Role as a Neoplastic Biomarker and a Potential Therapeutic Target
Roberto Tirabosco, Nischalan Pillay, Fitim Berisha, Fernanda M Amary, Adrienne M Flanagan. Royal National Orthopaedic Hospital, London, England, United Kingdom; University College London, London, England, United Kingdom
Background: Chordoma is a malignant bone tumor which shows notochordal differentiation, sited almost exclusively in vertebrae and base of skull. Being chemoresistant, surgery is the key procedure, although this may be supported by proton-beam therapy. However, given the anatomical location, complete excision is rarely achieved and this accounts for a high incidence of recurrence and late metastasis. Consequently, there is a compelling need for new targeted therapy. It has previously been shown that brachyury, a key gene involved in notochord and chordoma development, indirectly regulates AKR1B10 expression in U-CH1 chordoma cell line. AKR1B10, an enzyme involved in the catabolism of aldehydes and ketones, has been implicated in the development of carcinoma of various organs and in the development of chemoresistance in these tumors. In this study we assessed the expression of AKR1B10 in normal and neoplastic tissues showing notochordal differentiation and in other bone and soft tissue tumors (BSTT).
Design: A TMA of 120 brachyury-positive vertebral chordomas and the full sections of 6 brachyury-positive benign notochordal tumors (BNT) were stained with AKR1B10. To assess the expression of this marker in non-neoplastic notochordal tissues, 10 human embryonic notochords and 2 incidental notochordal rests in intervertebral discs (brachyury-positive) were immunostained with AKR1B10. To assess the brachyury-AKR1B10 link, TMAs including a total of 1,765 BSTT of various types (brachyury-negative), were also tested. Standard immunohistochemistry was performed.
Results: None of the embryonic notochords and notochordal rests showed immunoreactivity for AKR1B10; conversely, all BNT and chordomas were diffusely positive for this marker. Apart from 1/17 Ewing sarcoma and 2/213 myxofibrosarcomas, AKR1B10 was negative in all BSTT.
Conclusions: We show that AKR1B10 is expressed in all benign and malignant notochordal tumors, but not in embryonic notochord or notochordal rests. Nor it is expressed in other BSTT. These findings argue that unlike during embryonic development, in neoplasia brachyury regulates AKR1B10 expression, implicating it in the development of notochordal tumors. Moreover, as AKR1B10 expression is widely reported in a variety of carcinomas and has been associated with chemoresistance, the expression of this enzyme in chordomas may contribute to the chemoresistance observed in these tumors. AKR1B10-inhibitors may therefore have a role in adjuvant therapy.
Category: Bone & Soft Tissue
Tuesday, March 5, 2013 1:00 PM
Poster Session IV # 10, Tuesday Afternoon