An unexpected role for a Wnt-inhibitor: Dickkopf-1 triggers a novel cancer survival mechanism through modulation of aldehyde-dehydrogenase-1 activity

It is widely accepted that canonical Wnt (cWnt) signaling is required for the differentiation of osteoprogenitors into osteoblasts. Furthermore, tumor-derived secretion of the cWnt-antagonist Dickkopf-1 (Dkk-1) is known to cause bone destruction, inhibition of repair and metastasis in many bone malignancies, but its role in osteosarcoma (OS) is still under debate. In this study, we examined the role of Dkk-1in OS by engineering its overexpression in the osteochondral sarcoma line MOS-J. Consistent with the known role of Dkk-1 in osteoblast differentiation, Dkk-1 inhibited osteogenesis by the MOSJ cells themselves and also in surrounding tissue when implanted in vivo. Surprisingly, Dkk-1 also had unexpected effects on MOSJ cells in that it increased proliferation and resistance to metabolic stress in vitro and caused the formation of larger and more destructive tumors than controls upon orthotopic implantation. These effects were attributed in part to upregulation of the stress response enzyme and cancer stem cell marker aldehyde-dehydrogenase-1 (ALDH1). Direct inhibition of ALDH1 reduced viability under stressful culture conditions, whereas pharmacological inhibition of cWnt or overexpression of ALDH1 had a protective effect. Furthermore, we observed that ALDH1 was transcriptionally activated in a c-Jun-dependent manner through a pathway consisting of RhoA, MAP-kinase-kinase-4 and Jun N-terminal Kinase (JNK), indicating that noncanonical planar cell polarity-like Wnt signaling was the mechanism responsible. Together, our results therefore demonstrate that Dkk-1 enhances resistance of OS cells to stress by tipping the balance of Wnt signaling in favor of the non-canonical Jun-mediated Wnt pathways. In turn, this results in transcriptional activation of ALDH1 through Jun-responsive promoter elements. This is the first report linking Dkk-1 to tumor stress resistance, further supporting the targeting of Dkk-1 not only to prevent and treat osteolytic bone lesions but also to reduce numbers of stress-resistant tumor cells

Atypical spindle cell lipoma: a clinicopathologic, immunohistochemical, and molecular study emphasizing its relationship to classical spindle cell lipoma

We studied a series of spindle cell lipomas arising in atypical sites and showing unusual morphologic features (which we called atypical spindle cell lipoma) to assess if these lesions have the same chromosomal alterations as classical spindle cell lipoma but different from those found in atypical lipomatous tumor/well-differentiated liposarcoma. We investigated alterations of different genes in the 13q14 region and the amplification status of the MDM2 and CDK4 genes at 12q14-15 by multiplex ligation-dependent probe amplification (MLPA) and fluorescence in situ hybridization (FISH) analysis. In the atypical spindle cell lipomas, MLPA revealed deletions in the two nearest flanking genes of RB1 (ITM2B and RCBTB2) and in multiple important exons of RB1. In contrast, in classical spindle cell lipomas, a less complex loss of RB1 exons was found but no deletion of ITM2B and RCBTB2. Moreover, MLPA identified a deletion of the DLEU1 gene, a finding which has not been reported earlier. We propose an immunohistochemical panel for lipomatous tumors which comprises of MDM2, CDK4, p16, Rb, which we have found useful in discriminating between atypical or classical spindle cell lipomas and other adipocytic neoplasms, especially atypical lipomatous tumor/well-differentiated liposarcoma. Our findings strengthen the link between atypical spindle cell lipoma and classical spindle cell lipoma, and differentiate them from atypical lipomatous tumor/well-differentiated liposarcoma