Open AccessThe endochondral bone protein CHM 1 sustains an undifferentiated, invasive phenotype, promoting lung metastasis in Ewing sarcoma
Author(s) -
Heyking Kristina,
CalzadaWack Julia,
Göllner Stefanie,
Neff Frauke,
Schmidt Oxana,
Hensel Tim,
Schirmer David,
Fasan Annette,
Esposito Irene,
MüllerTidow Carsten,
Sorensen Poul H.,
Burdach Stefan,
Richter Günther H. S.
Publication year - 2017
Publication title -
molecular oncology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.332
H-Index - 88
eISSN - 1878-0261
pISSN - 1574-7891
DOI - 10.1002/1878-0261.12057
Subject(s) - cancer research , gene knockdown , ewing's sarcoma , biology , chondrogenesis , metastasis , pathology , sarcoma , mesenchymal stem cell , cell culture , microbiology and biotechnology , medicine , cancer , genetics
Ewing sarcomas ( ES ) are highly malignant, osteolytic bone or soft tissue tumors, which are characterized by EWS – ETS translocations and early metastasis to lung and bone. In this study, we investigated the role of the BRICHOS chaperone domain‐containing endochondral bone protein chondromodulin I ( CHM 1) in ES pathogenesis. CHM 1 is significantly overexpressed in ES , and chromosome immunoprecipitation (Ch IP ) data demonstrate CHM 1 to be directly bound by an EWS – ETS translocation, EWS ‐ FLI 1. Using RNA interference, we observed that CHM 1 promoted chondrogenic differentiation capacity of ES cells but decreased the expression of osteolytic genes such as HIF 1A , IL 6 , JAG 1 , and VEGF . This was in line with the induction of the number of tartrate‐resistant acid phosphatase ( TRAP + )‐stained osteoclasts in an orthotopic model of local tumor growth after CHM 1 knockdown, indicating that CHM 1‐mediated inhibition of osteomimicry might play a role in homing, colonization, and invasion into bone tissues. We further demonstrate that CHM 1 enhanced the invasive potential of ES cells in vitro . This invasiveness was in part mediated via CHM 1‐regulated matrix metallopeptidase 9 expression and correlated with the observation that, in an xenograft mouse model, CHM 1 was essential for the establishment of lung metastases. This finding is in line with the observed increase in CHM 1 expression in patient specimens with ES lung metastases. Our results suggest that CHM 1 seems to have pleiotropic functions in ES , which need to be further investigated, but appears to be essential for the invasive and metastatic capacities of ES .