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2014 ; 17
(4
): 897-907
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TM4SF1: a new vascular therapeutic target in cancer
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Lin CI
; Merley A
; Sciuto TE
; Li D
; Dvorak AM
; Melero-Martin JM
; Dvorak HF
; Jaminet SC
Angiogenesis
2014[Oct]; 17
(4
): 897-907
PMID24986520
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Transmembrane-4 L-six family member-1 (TM4SF1) is a small plasma membrane
glycoprotein that regulates cell motility and proliferation. TM4SF1 is an
attractive cancer target because of its high expression in both tumor cells and
on the vascular endothelial cells lining tumor blood vessels. We generated mouse
monoclonal antibodies against human TM4SF1 in order to evaluate their therapeutic
potential; 13 of the antibodies we generated reacted with extracellular loop-2
(EL2), TM4SF1's larger extracellular, lumen-facing domain. However, none of these
antibodies reacted with mouse TM4SF1, likely because the EL2 of mouse TM4SF1
differs significantly from that of its human counterpart. Therefore, to test our
antibodies in vivo, we employed an established model of engineered human vessels
in which human endothelial colony-forming cells (ECFC) and human mesenchymal stem
cells (MSC) are incorporated into Matrigel plugs that are implanted
subcutaneously in immunodeficient nude mice. We modified the original protocol by
(1) preculturing human ECFC on laminin, fibronectin, and collagen-coated plates,
and (2) increasing the ECFC/MSC ratio. These modifications significantly
increased the human vascular network in Matrigel implants. Two injections of one
of our anti-TM4SF1 EL2 monoclonal antibodies, 8G4, effectively eliminated the
human vascular component present in these plugs; they also abrogated human PC3
prostate cancer cells that were incorporated into the ECFC/MSC Matrigel mix.
Together, these studies provide a mouse model for assessing tumor xenografts that
are supplied by a human vascular network and demonstrate that anti-TM4SF1
antibodies such as 8G4 hold promise for cancer therapy.
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