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Blood, 15 September 2007, Vol. 110, No. 6, pp. 2041-2048.
Prepublished online as a Blood First Edition Paper on May 29, 2007; DOI 10.1182/blood-2007-04-082495.
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Submitted April 9, 2007
Accepted May 14, 2007
The syndecan-1 heparan sulfate proteoglycan is a viable target for myeloma therapy
Yang Yang, Veronica MacLeod, Yuemeng Dai, Yekaterina Khotskaya-Sample, Zachary Shriver, Ganesh Venkataraman, Ram Sasisekharan, Annamaria Naggi, Giangiacomo Torri, Benito Casu, Israel Vlodavsky, Larry J Suva, Joshua Epstein, Shmuel Yaccoby, John D Shaughnessy Jr, Bart Barlogie, and Ralph D Sanderson*
Department of Pathology, University of Alabama at Birmingham, Birmingham, AL, United States
Department of Pathology, University of Arkansas for Medical Sciences, Little Rock, AR, United States
Momenta Pharmaceuticals, Inc., Cambridge, MA, United States
Division of Bioengineering and Environmental Health, Massachusetts Institute of Technology, Cambridge, MA, United States
G. Ronzoni Institute for Chemical and Biochemical Research, Milan, Italy
Cancer and Vascular Biology Research Center, The Bruce Rappaport Faculty of Medicine, Technion, Haifa, Israel
Center for Orthopedic Research, Dept of Orthopedic Surgery, University of Arkansas for Medical Sciences, Little Rock, AR, United States
Myeloma Institute for Research and Therapy, University of Arkansas for Medical Sciences, Little Rock, AR, United States
* Corresponding author; email: sanderson{at}uab.edu.
The heparan sulfate proteoglycan syndecan-1 is expressed by myeloma cells and shed into the myeloma microenvironment. High levels of shed syndecan-1 in myeloma patient sera correlate with poor prognosis and studies in animal models indicate that shed syndecan-1 is a potent stimulator of myeloma tumor growth and metastasis. Overexpression of extracellular endosulfatases, enzymes which remove 6-O sulfate groups from heparan sulfate chains, diminishes myeloma tumor growth in vivo. Together these findings identify syndecan-1 as a potential target for myeloma therapy. Here three different strategies were tested in animal models of myeloma with the following results: (i) treatment with bacterial heparinase III, an enzyme that degrades heparan sulfate chains, dramatically inhibited the growth of primary tumors in the SCID-hu model of myeloma, (ii) treatment with an inhibitor of human heparanase, an enzyme that synergizes with syndecan-1 in promoting myeloma progression, blocked the growth of myeloma in vivo, and (iii) knockdown of syndecan-1 expression by RNAi diminished and delayed myeloma tumor development in vivo. These results confirm the importance of syndecan-1 in myeloma pathobiology and provide strong evidence that disruption of the normal function or amount of syndecan-1 or its heparan sulfate chains is a valid therapeutic approach for this cancer.
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