Extracellular protease ADAMTS9 suppresses esophageal and nasopharyngeal carcinoma tumor formation by inhibiting angiogenesis.
ADAMTS metalloprotease family member ADAMTS9 maps to 3p14.2 and shows significant associations with the aerodigestive tract cancers esophageal squamous cell carcinoma (ESCC) and nasopharyngeal carcinoma (NPC). However, the functional impact of ADAMTS9 on cancer development has not been explored. In this study, we evaluated the hypothesized antiangiogenic and tumor-suppressive functions of ADAMTS9 in ESCC and NPC, in stringent tumorigenicity and Matrigel plug angiogenesis assays. ADAMTS9 activation suppressed tumor formation in nude mice. Conversely, knockdown of ADAMTS9 resulted in clones reverting to the tumorigenic phenotype of parental cells. In vivo angiogenesis assays revealed a reduction in microvessel numbers in gel plugs injected with tumor-suppressive cell transfectants. Similarly, conditioned medium from cell transfectants dramatically reduced the tube-forming capacity of human umbilical vein endothelial cells. These activities were associated with a reduction in expression levels of the proangiogenic factors MMP9 and VEGFA, which were consistently reduced in ADAMTS9 transfectants derived from both cancers. Taken together, our results indicate that ADAMTS9 contributes an important function in the tumor microenvironment that acts to inhibit angiogenesis and tumor growth in both ESCC and NPC.
Lo
Paulisally Hau Yi
PH
Department of Clinical Oncology and Center for Cancer Research, University of Hong Kong, Hong Kong SAR, People's Republic of China.
Lung
Hong Lok
HL
Cheung
Arthur Kwok Leung
AK
Apte
Suneel S
SS
Chan
Kwok Wah
KW
Kwong
Fung Mei
FM
Ko
Josephine Mun Yee
JM
Cheng
Yue
Y
Law
Simon
S
Srivastava
Gopesh
G
Zabarovsky
Eugene R
ER
Tsao
Sai Wah
SW
Tang
Johnny Cheuk On
JC
Stanbridge
Eric J
EJ
Lung
Maria Li
ML
D051722:ADAM Proteins / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D000071119:ADAMTS9 Protein; D000818:Animals; D015536:Down-Regulation; D042783:Endothelial Cells / Q000166:cytology; D004789:Enzyme Activation; D004938:Esophageal Neoplasms / Q000098:blood supply* / Q000201:enzymology* / Q000235:genetics; D005260:Female; D055785:Gene Knockdown Techniques; D006801:Humans; D020780:Matrix Metalloproteinase 9 / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009303:Nasopharyngeal Neoplasms / Q000098:blood supply* / Q000201:enzymology* / Q000235:genetics; D009389:Neovascularization, Pathologic / Q000201:enzymology / Q000235:genetics / Q000473:pathology; D014162:Transfection; D042461:Vascular Endothelial Growth Factor A / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism
C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D051722:ADAM Proteins; D000071119:ADAMTS9 Protein; C412869:ADAMTS9 protein, human; D020780:Matrix Metalloproteinase 9