BRAK/CXCL14 is a potent inhibitor of angiogenesis and a chemotactic factor for immature dendritic cells.
BRAK/CXCL14 is a CXC chemokine constitutively expressed at the mRNA level in certain normal tissues but absent from many established tumor cell lines and human cancers. Although multiple investigators cloned BRAK, little is known regarding the physiologic function of BRAK or the reason for decreased expression in cancer. To understand the possible significance associated with loss of BRAK mRNA in tumors, we examined the pattern of BRAK protein expression in normal and tumor specimens from patients with squamous cell carcinoma (SCC) of the tongue and used recombinant BRAK (rBRAK) to investigate potential biological functions. Using a peptide-specific antiserum, abundant expression of BRAK protein was found in suprabasal layers of normal tongue mucosa but consistently was absent in tongue SCC. Consistent with previous in situ mRNA studies, BRAK protein also was expressed strongly by stromal cells adjacent to tumors. In the rat corneal micropocket assay, BRAK was a potent inhibitor of in vivo angiogenesis stimulated by multiple angiogenic factors, including interleukin 8, basic fibroblast growth factor, and vascular endothelial growth factor. In vitro, rBRAK blocked endothelial cell chemotaxis at concentrations as low as 1 nmol/L, suggesting this was a major mechanism for angiogenesis inhibition. Although only low affinity receptors for BRAK could be found on endothelial cells, human immature monocyte-derived dendritic cells (iDCs) bound rBRAK with high affinity (i.e., K(d), approximately 2 nmol/L). Furthermore, rBRAK was chemotactic for iDCs at concentrations ranging from 1 to 10 nmol/L. Our findings support a hypothesis that loss of BRAK expression from tumors may facilitate neovascularization and possibly contributes to immunologic escape.
Shellenberger
Thomas D
TD
Department of Head and Neck Surgery, University of Texas M.D. Anderson Cancer Center, Houston, Texas 77030, USA.
Wang
Mary
M
Gujrati
Manu
M
Jayakumar
Arumugam
A
Strieter
Robert M
RM
Burdick
Marie D
MD
Ioannides
Constantin G
CG
Efferson
Clayton L
CL
El-Naggar
Adel K
AK
Roberts
Dianna
D
Clayman
Gary L
GL
Frederick
Mitchell J
MJ
D002294:Carcinoma, Squamous Cell / Q000098:blood supply / Q000378:metabolism; D002460:Cell Line; D019743:Chemokines, CXC / Q000235:genetics / Q000378:metabolism / Q000502:physiology*; D002630:Chemotactic Factors / Q000502:physiology*; D003315:Cornea / Q000098:blood supply; D003713:Dendritic Cells / Q000166:cytology*; D016222:Fibroblast Growth Factor 2 / Q000502:physiology; D006801:Humans; D016209:Interleukin-8 / Q000502:physiology; D009389:Neovascularization, Pathologic; D012333:RNA, Messenger / Q000235:genetics; D011994:Recombinant Proteins / Q000235:genetics / Q000378:metabolism; D014062:Tongue Neoplasms / Q000098:blood supply / Q000378:metabolism; D042461:Vascular Endothelial Growth Factor A / Q000502:physiology
C118056:CXCL14 protein, human; D019743:Chemokines, CXC; D002630:Chemotactic Factors; D016209:Interleukin-8; D012333:RNA, Messenger; D011994:Recombinant Proteins; D042461:Vascular Endothelial Growth Factor A; D016222:Fibroblast Growth Factor 2