HSulf-1 and HSulf-2 are potent inhibitors of myeloma tumor growth in vivo.
To participate as co-receptor in growth factor signaling, heparan sulfate must have specific structural features. Recent studies show that when the levels of 6-O-sulfation of heparan sulfate are diminished by the activity of extracellular heparan sulfate 6-O-endosulfatases (Sulfs), fibroblast growth factor 2-, heparin binding epidermal growth factor-, and hepatocyte growth factor-mediated signaling are attenuated. This represents a novel mechanism for regulating cell growth, particularly within the tumor microenvironment where the Sulfs are known to be misregulated. To directly test the role of Sulfs in tumor growth control in vivo, a human myeloma cell line was transfected with cDNAs encoding either of the two known human endosulfatases, HSulf-1 or HSulf-2. When implanted into severe combined immunodeficient (SCID) mice, the growth of these tumors was dramatically reduced on the order of 5- to 10-fold as compared with controls. In addition to an inhibition of tumor growth, these studies revealed the following. (i) HSulf-1 and HSulf-2 have similar functions in vivo. (ii) The extracellular activity of Sulfs is restricted to the local tumor cell surface. (iii) The Sulfs promote a marked increase in extracellular matrix deposition within tumors that may, along with attenuated growth factor signaling, contribute to the reduction in tumor growth. These findings demonstrate that dynamic regulation of heparan sulfate structure by Sulfs present within the tumor microenvironment can have a dramatic impact on the growth and progression of malignant cells in vivo.
Dai
Yuemeng
Y
Department of Pathology and the Arkansas Cancer Research Center, University of Arkansas for Medical Sciences, Little Rock, Arkansas 72205, USA.
Yang
Yang
Y
MacLeod
Veronica
V
Yue
Xinping
X
Rapraeger
Alan C
AC
Shriver
Zachary
Z
Venkataraman
Ganesh
G
Sasisekharan
Ram
R
Sanderson
Ralph D
RD
D000818:Animals; D015153:Blotting, Western; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D018076:DNA, Complementary / Q000378:metabolism; D004187:Disaccharides / Q000737:chemistry; D018450:Disease Progression; D005109:Extracellular Matrix / Q000378:metabolism; D016222:Fibroblast Growth Factor 2 / Q000378:metabolism; D005434:Flow Cytometry; D006133:Growth Substances / Q000378:metabolism; D019812:Heparan Sulfate Proteoglycans / Q000737:chemistry; D006497:Heparan Sulfate / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D051379:Mice; D016513:Mice, SCID; D009101:Multiple Myeloma / Q000473:pathology*; D009368:Neoplasm Transplantation; D009369:Neoplasms / Q000378:metabolism / Q000473:pathology*; D011133:Polysaccharide-Lyases / Q000378:metabolism; D011485:Protein Binding; D015398:Signal Transduction; D013429:Sulfatases; D015238:Sulfotransferases / Q000502:physiology*; D013997:Time Factors; D014162:Transfection
D018076:DNA, Complementary; D004187:Disaccharides; D016222:Fibroblast Growth Factor 2; D006133:Growth Substances; D019812:Heparan Sulfate Proteoglycans; D006497:Heparan Sulfate; D011133:Polysaccharide-Lyases; D013429:Sulfatases; D015238:Sulfotransferases; C470791:SULF1 protein, human; C470792:SULF2 protein, human; C021349:heparitinsulfate lyase