The syndecan-1 heparan sulfate proteoglycan is a viable target for myeloma therapy.
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, 3 different strategies were tested in animal models of myeloma with the following results: (1) treatment with bacterial heparinase III, an enzyme that degrades heparan sulfate chains, dramatically inhibited the growth of primary tumors in the human severe combined immunodeficient (SCID-hu) model of myeloma; (2) 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 (3) 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.
Yang
Yang
Y
Department of Pathology, University of Alabama at Birmingham, Birmingham, AL 35294, USA.
MacLeod
Veronica
V
Dai
Yuemeng
Y
Khotskaya-Sample
Yekaterina
Y
Shriver
Zachary
Z
Venkataraman
Ganesh
G
Sasisekharan
Ram
R
Naggi
Annamaria
A
Torri
Giangiacomo
G
Casu
Benito
B
Vlodavsky
Israel
I
Suva
Larry J
LJ
Epstein
Joshua
J
Yaccoby
Shmuel
S
Shaughnessy
John D
JD
Barlogie
Bart
B
Sanderson
Ralph D
RD
D000818:Animals; D001853:Bone Marrow / Q000378:metabolism; D001842:Bone and Bones / Q000166:cytology / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D005434:Flow Cytometry; D015972:Gene Expression Regulation, Neoplastic; D005966:Glucuronidase / Q000037:antagonists & inhibitors / Q000378:metabolism; D019812:Heparan Sulfate Proteoglycans / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D008297:Male; D051379:Mice; D016513:Mice, SCID; D009101:Multiple Myeloma / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D009374:Neoplasms, Experimental / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D034741:RNA, Small Interfering / Q000494:pharmacology; D053668:Syndecan-1 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D014057:Tomography, X-Ray Computed; D014407:Tumor Cells, Cultured; D000099175:Heparanase
D004791:Enzyme Inhibitors; D005966:Glucuronidase; D019812:Heparan Sulfate Proteoglycans; D034741:RNA, Small Interfering; D053668:Syndecan-1; D000099175:Heparanase; C508241:SDC1 protein, human