A potential role for Dkk-1 in the pathogenesis of osteosarcoma predicts novel diagnostic and treatment strategies

Abstract

Canonical Wnt signalling is an osteoinductive signal that promotes bone repair through acceleration of osteogenic differentiation by progenitors. Dkk-1 is a secreted inhibitor of canonical Wnt signalling and thus inhibits osteogenesis. To examine a potential osteoinhibitory role of Dkk-1 in osteosarcoma (OS), we measured serum Dkk-1 in paediatric patients with OS (median age, 13.4 years) and found it to be significantly elevated. We also found that Dkk-1 was maximally expressed by the OS cells at the tumour periphery and in vitro, Dkk-1 and RANKL are coexpressed by rapidly proliferating OS cells. Both Dkk-1 and conditioned media from OS cells reduce osteogenesis by human mesenchymal cells and by immunodepletion of Dkk-1, or by adding a GSK3b inhibitor, the effects of Dkk-1 were attenuated. In mice, we found that the expression of Dkk-1 from implanted tumours was similar to the human tumour biopsies in that human Dkk-1 was present in the serum of recipient animals. These data demonstrate that systemic levels of Dkk-1 are elevated in OS. Furthermore, the expression of Dkk-1 by the OS cells at the periphery of the tumour probably contributes to its expansion by inhibiting repair of the surrounding bone. These data demonstrate that Dkk-1 may serve as a prognostic or diagnostic marker for evaluation of OS and furthermore, immunodepletion of Dkk-1 or administration of GSK3b inhibitors could represent an adjunct therapy for this disease.

FUS-CHOP Fusion Protein Expression Coupled to p53 Deficiency Induces Liposarcoma in Mouse but Not in Human Adipose-Derived Mesenchymal Stem/Stromal Cells

“…Wnt signaling also controls the growth and transformation of MSCs. Thus, the expression of the Wnt signaling inhibitor Dkk-1 in hMSCs induced the formation of undifferentiated pleiomorphic sarcomas in vivo [38] and, likewise, this inhibitor is overexpressed in human osteosarcoma [54]. In addition, Dkk-1 is required for BM-MSCs entry into the cell cycle [55].…”

Osteosarcoma

“…Dkk-1 and RANKL also were noted to be coexpressed by rapidly proliferating osteosarcoma cells. (22) In the majority of malignancies, activation of the Wnt pathway and b-catenin promotes tumorigenesis, in contrast to the aforementioned line of evidence in osteosarcoma. (23) Indeed, even in osteosarcoma, a number of experiments have been performed downregulating the Wnt pathway using genetic or drug-treatment approaches, and in contrast to the prior observations, enhanced invasion and motility were observed, with the related clinical observations being an increased frequency of pulmonary metastases or decreased survival.…”

The role of Dickkopf-1 in bone development, homeostasis, and disease

“…79 Finally, DKK1 serum levels in pediatric patients with osteosarcoma (OS) were significantly elevated, and DKK1 was maximally expressed by the OS cells at the tumor periphery, suggesting that DKK1 contributes to tumor expansion by inhibiting repair of surrounding bone. 80 In vitro, DKK1 and RANKL are coexpressed by rapidly proliferating human OS cells. 80 Both DKK1 and conditioned media from OS cells reduced osteogenesis by human MSCs, and immunodepletion of DKK1 or adding a GSK3␤ inhibitor reduced the DKK1 effects.…”

“…80 Both DKK1 and conditioned media from OS cells reduced osteogenesis by human MSCs, and immunodepletion of DKK1 or adding a GSK3␤ inhibitor reduced the DKK1 effects. 80 Given that autologous HSC transplantation plays such a pivotal role in the management of MM, it is possible that the irreversible loss of reconstitution capabilities of HSC exposed to high levels of DKK1 may account for the poor engraftment and reconstitution of hematopoiesis that can occur. Given that HSCs isolated from DKK1-transgenic mice had fewer quiescent HSCs compared with normal controls, it will be interesting to investigate whether HSC mobilized from patients with MM also exhibit shifts in the ratios of p21Cip1-expressing and quiescent HSC that is correlated with DKK1 levels.…”