| Literature DB >> 20194748 |
Sonia Vallet1, Siddhartha Mukherjee, Nileshwari Vaghela, Teru Hideshima, Mariateresa Fulciniti, Samantha Pozzi, Loredana Santo, Diana Cirstea, Kishan Patel, Aliyah R Sohani, Alex Guimaraes, Wanling Xie, Dharminder Chauhan, Jesse A Schoonmaker, Eyal Attar, Michael Churchill, Edie Weller, Nikhil Munshi, Jasbir S Seehra, Ralph Weissleder, Kenneth C Anderson, David T Scadden, Noopur Raje.
Abstract
Understanding the pathogenesis of cancer-related bone disease is crucial to the discovery of new therapies. Here we identify activin A, a TGF-beta family member, as a therapeutically amenable target exploited by multiple myeloma (MM) to alter its microenvironmental niche favoring osteolysis. Increased bone marrow plasma activin A levels were found in MM patients with osteolytic disease. MM cell engagement of marrow stromal cells enhanced activin A secretion via adhesion-mediated JNK activation. Activin A, in turn, inhibited osteoblast differentiation via SMAD2-dependent distal-less homeobox-5 down-regulation. Targeting activin A by a soluble decoy receptor reversed osteoblast inhibition, ameliorated MM bone disease, and inhibited tumor growth in an in vivo humanized MM model, setting the stage for testing in human clinical trials.Entities:
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Year: 2010 PMID： 20194748 PMCID： PMC2841922 DOI： 10.1073/pnas.0911929107
Source DB: PubMed Journal: Proc Natl Acad Sci U S A ISSN： 0027-8424 Impact factor: 11.205