Abstract
Osteosarcoma (OS) is among the most frequently occurring primary bone tumors, primarily affecting adolescents and young adults. This malignant osteoid forming tumor is characterized by its metastatic potential, mainly to lungs. We recently demonstrated that WW domain-containing oxidoreductase (WWOX) is frequently inactivated in human OS and that WWOX restoration in WWOX-negative OS cells suppresses tumorigenicity. Of note, WWOX levels are reduced in paired OS samples of post-treatment metastastectomies as compared to pre-treatment biopsies suggesting that decreased WWOX levels are associated with a more aggressive phenotype at the metastatic site. Nevertheless, little is known about WWOX function in OS metastasis. Here, we investigated the role of tumor suppressor WWOX in suppressing pulmonary OS metastasis both in vitro and in vivo. We demonstrated that ectopic expression of WWOX in OS cells, HOS and LM-7, inhibits OS invasion and cell migration in vitro. Furthermore, WWOX expression reduced tumor burden in vivo and inhibited metastases’ seeding and colonization. Mechanistically, WWOX function is associated with reduced levels of RUNX2 metastatic target genes implicated in adhesion and motility. Our results suggest that WWOX plays a critical role in determining the aggressive phenotype of OS, and its expression could be an attractive therapeutic target to combat this devastating adolescent disease.
Highlights
Osteosarcoma (OS) is an aggressive malignant tumor arising from primitive transformed cells that exhibit osteoblastic differentiation and produce malignant osteoid tissue[1,2]
We previously demonstrated that WWOX levels are reduced in most OS cells[12]
Our previous data and others showed that WWOX expression is absent or reduced in the majority of OS12–14,27 and that restoring WWOX levels in OS cell lines results in inhibition of tumorigenicity[12]
Summary
Osteosarcoma (OS) is an aggressive malignant tumor arising from primitive transformed cells that exhibit osteoblastic differentiation and produce malignant osteoid tissue[1,2]. Careful investigation of Wwox mutant mice prior to their death revealed that WWOX possesses tumor suppressor functions[15,17,19,20] In this respect, we demonstrated that loss of both alleles of Wwox results in lesions resembling OS in juvenile mice[12,15,17] whereas Wwox-heterozygous mice develop spontaneous and chemically-induced tumors[15,19,21].
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