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TGFβ1-Endo180-dependent collagen deposition is dysregulated at the tumour-stromal interface in bone metastasis

Caley, Matthew P.; Kogianni, Giolanta; Adamarek, Adam; Gronau, Julian H.; Rodriguez-Teja, Mercedes; Fonseca, Ana-Violeta; Mauri, Francesco; Sandison, Ann; Rhim, Johng S.; Palmieri, Carlo; Cobb, Justin P.; Waxman, Jonathan; Sturge, Justin


Matthew P. Caley

Giolanta Kogianni

Adam Adamarek

Julian H. Gronau

Mercedes Rodriguez-Teja

Ana-Violeta Fonseca

Francesco Mauri

Ann Sandison

Johng S. Rhim

Carlo Palmieri

Justin P. Cobb

Jonathan Waxman


Cellular niches in adult tissue can harbour dysregulated microenvironments that become the driving force behind disease progression. The major environmental change when metastatic cells arrive in the bone is the destruction of mineralized type I collagen matrix. Once metastatic niches establish in bone, the invading tumour cells initiate a vicious cycle of osteolytic lesion formation via the dysregulation of paracrine signals and uncoupling of normal bone resorption and production. Here we report that the collagen receptor Endo180 (CD280, MRC2, uPARAP) participates in collagen deposition by primary human osteoblasts during de novo osteoid formation. This newly recognized function of Endo180 was suppressed in osteoblasts following heterotypic direct cell–cell contact in co-culture with prostate tumour cells. Reciprocal Endo180 up-regulation in osteolytic prostate tumour cells (PC3 and DU145) followed their direct contact with osteoblasts and promoted de novo collagen internalization, which is a previously characterized function of the constitutively recycling Endo180 receptor. The osteoblastic suppression and tumour cell-associated enhancement of Endo180 expression were equally sustained in these direct co-cultures. These findings are the first to demonstrate that increased tumour cell participation in collagen degradation and decreased collagen formation by osteoblasts in the osteolytic microenvironment are linked to the divergent regulation of a collagen-binding receptor. Immunohistochemical analysis of core biopsies from bone metastasis revealed higher levels of Endo180 expression in tumour cell foci than cells in the surrounding stroma. Additional experiments in prostate cell–osteoblast co-cultures indicate that divergent regulation of Endo180 is the result of dysregulated TGFβ1 signalling. The findings of this study provide a rationale for targeting collagen remodelling by Endo180 in bone metastases and other collagen matrix pathologies.


Caley, M. P., Kogianni, G., Adamarek, A., Gronau, J. H., Rodriguez-Teja, M., Fonseca, A., …Sturge, J. (2012). TGFβ1-Endo180-dependent collagen deposition is dysregulated at the tumour-stromal interface in bone metastasis. Journal of Pathology, 226(5), 775-783.

Journal Article Type Article
Acceptance Date Nov 1, 2011
Online Publication Date Dec 8, 2011
Publication Date 2012-04
Print ISSN 0022-3417
Electronic ISSN 1096-9896
Publisher Wiley
Peer Reviewed Peer Reviewed
Volume 226
Issue 5
Pages 775-783
Keywords Bone; Collagen; Endo180; Metastasis; Metastatic; Osteoblast; Osteolytic; Prostate cancer
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