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2017 ; 36
(36
): 5189-5198
Nephropedia Template TP
Muppala S
; Xiao R
; Krukovets I
; Verbovetsky D
; Yendamuri R
; Habib N
; Raman P
; Plow E
; Stenina-Adognravi O
Oncogene
2017[Sep]; 36
(36
): 5189-5198
PMID28481870
show ga
TGF-? is a multifunctional cytokine affecting many cell types and implicated in
tissue remodeling processes. Due to its many functions and cell-specific effects,
the consequences of TGF-? signaling are process-and stage-dependent, and it is
not uncommon that TGF-? exerts distinct and sometimes opposing effects on a
disease progression depending on the stage and on the pathological changes
associated with the stage. The mechanisms underlying cell- and process-specific
effects of TGF-? are poorly understood. We are describing a novel pathway that
mediates induction of angiogenesis in response to TGF-?1. We found that in
endothelial cells (EC) thrombospondin-4 (TSP-4), a secreted extracellular matrix
(ECM) protein, is upregulated in response to TGF-?1 and mediates the effects of
TGF-?1 on angiogenesis. Upregulation of TSP-4 does not require the synthesis of
new protein, is not caused by decreased secretion of TSP-4, and is mediated by
activation of SMAD3. Using Thbs4(-/-) mice and TSP-4 shRNA, we found that TSP-4
mediated pro-angiogenic functions in cultured EC and angiogenesis in vivo in
response to TGF-?1. We observed~3-fold increases in tumor mass and levels of
angiogenesis markers in animals injected with TGF-?1, and these effects did not
occur in Thbs4(-/-) animals. Injections of an inhibitor of TGF-?1 signaling
SB-431542 also decreased the weights of tumors and cancer angiogenesis. Our
results from in vivo angiogenesis models and cultured EC document that TSP-4
mediates upregulation of angiogenesis by TGF-?1. Upregulation of pro-angiogenic
TSP-4 and selective effects of TSP-4 on EC may contribute to stimulation of tumor
growth by TGF-? despite the inhibition of cancer cell proliferation.
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