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Journal of Bone and Mineral Research, Volume 22, Issue S1, 1 September 2007, Pages s2–s51,


04 March 2010

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Revision received:

04 March 2010


04 March 2010



Identification of a Novel TGF‐beta Dependent‐Prometastatic Signature Mediating Bone Colonization. I. Garcia‐Tunon*1, S. Vicent*1, D. Luis‐Ravelo*1, I. Anton*1, C. Zandueta*1, S. Martinez*1, J. De Las Rivas*2, F. Lecanda1. 1Division of Oncology, Center for Applied Medical Research, Pamplona, Spain, 2Bioinformatics, CIC, Salamanca, Spain.

Bone represents a frequent target organ of metastasis in a variety of solid tumors including lung. We have recently developed a rapid and selective model in which to identify genes implicated in bone metastasis of lung cancer. After intracardiac inoculation (i.c.) in nude mice, highly metastatic subpopulations (HMS) were selected with increase prometastatic activity. Microarray expression analysis revealed a novel metastatic gene signature of differentially expressed genes in HMS vs parental. Four overexpressed genes in all HMS were further validated by real time qPCR. These genes encode signaling molecules (such as TCF4 and PRKD3) and cell anchorage related proteins (MCAM, and putative adhesion molecule SUSD5). To delineate their functional contribution in metastatic activity we assessed metastatic area by X‐ray image analysis and μCT scan of retrovirally transduced simple, double and triple gene combinations. I.c. of single overexpressors TCF4, PRKD3 or SUSD5 induced a significant increase in metastatic area as compared to mock cells (p<0.01). Furthermore, i.c. of triple overexpressors in nude mice synergistically induced a dramatic increase in prometastatic activity, with prominent osteolytic lesions and metastatic area (p<0.001), whereas cell homing activity to bone was unaltered. This multigenic signature was also ineffective promoting cell proliferation and subcutaneous tumor growth. By contrast, intratibial injection of triple overexpressors induced aggressive bone colonization leading to overt osteolytic lesions as compared to mock cells (p<0.001). These results were correlated with high osteoclastogenic activity induced by conditioned medium of triple overexpressors. Furthermore, TCF4 and SUSD5 were strongly up‐regulated in a coculture system mimicking in vivo tumor‐stroma interactions, an effect that was further abrogated by an anti‐TGF‐β peptide. Interestingly, after i.c. of HMS, in vivo treatment with a specific anti‐TGF‐β peptide severely reduced tumor burden (X‐ray analysis and μCT scans) and osteolytic activity of tumor cells (osteoclast number) compared to an irrelevant peptide and vehicle treated animals. These studies identified a novel signature involving several genes that act cooperatively promoting strong osseous colonization, partially mediated by high osteoclastogenic activity. This multifunctional program is strongly enhanced by TGF‐β, which plays a critical role in perpetuating a “vicious cycle” involved in metastatic progression.

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