Decorin suppresses tumor cell-mediated angiogenesis

Abstract

The progressive growth of most neoplasms is dependent upon the establishment of new blood vessels, a process regulated by tumor-secreted factors and matrix proteins. We examined the in vitro and in vivo angiogenic ability of conditioned media obtained from fibrosarcoma, carcinoma, and osteosarcoma cells and their decorintransfected counterparts. Human endothelial cells were investigated in vitro by evaluating three essential steps of angiogenesis: migration, attachment, and differentiation. On the whole, wild-type tumor cell-secretions enhanced endothelial cell attachment, migration, and differentiation, whereas their decorin-expressing forms inhibited these processes. Similarly, decorin-containing media suppressed endothelial cell sprouting in an ex vivo aortic ring assay. Since angiogenesis is an important component of tumor expansion, the growth rate of these cells as tumor xenografts was examined by implantation in nude mice. In vivo, the decorin-expressing tumor xenografts grew at markedly lower rates and showed a significant suppression of neovascularization. Immunohistochemical, Northern and Western blot analyses indicated that the decorin-expressing cells produced vascular endothelial growth factor (VEGF) at markedly reduced rates vis-a´-vis their wild-type counterparts. Specificity of this process was confirmed by experiments where addition of recombinant decorin to the wild-type tumor cells caused 80 -95% suppression of VEGF mRNA and protein. These results provide a novel mechanism of action for decorin, and indicate that decorin could adversely affect in vivo tumor growth by suppressing the endogenous tumor cell production of a powerful angiogenic stimulus.

Decorin is a secreted protein associated with obesity and type 2 diabetes

“…In contrast, decorin may also exhibit antiangiogenic effects under certain circumstances. [28][29][30][31][32] Clearly, further experiments are required to substantiate the role of decorin in adipose tissue angiogenesis. The effect of decorin deficiency on the vascularization of adipose depots in decorin-knockout mice fed a high-fat diet will be a key experiment in determining the role of decorin in obesity-associated angiogenesis within the adipose tissue.…”

Transcriptional profiling endometrial carcinomas microdissected from DES‐treated mice identifies changes in gene expression associated with estrogenic tumor promotion

“…27 DCN-EGFR interaction results in up-regulation of endogenous p21 expression and a concomitant suppression of human cancer cell line growth, angiogenesis and metastasis. [28][29][30] Given its established role as a suppressor of human tumorigenesis, it is possible that the proteoglycan also safeguards against endometrial cancer formation in the DES model. Additional studies to examine DCN levels in human endometrial carcinomas could shed light on DCN's role in endometrial cancers.…”

Effects of ectopic decorin in modulating intracranial glioma progression in vivo, in a rat syngeneic model

“…[1][2][3] Overexpression of decorin inhibits TGF-b-induced proliferation and slows growth of a Chinese hamster ovary cell line. 4 In gene transfer studies of human colon cancer, cells stably transfected with decorin exhibited reduced growth rates in vitro and failed to generate tumors in severe combined immunodeficiency (SCID) mice.…”

“…12 Additionally, it has been indicated that decorin could adversely affect in vivo tumor growth by suppressing the endogenous tumor cell production of angiogenic stimulus. 3 Finally, it has been shown that ectopic expression of decorin in C6 rat glioma cells resulted in the inhibition of tumor formation in vivo. 13 These unique features make decorin a very good candidate gene for many experimental cancer gene therapy applications.…”

“…38 In vivo studies using decorin have also provided evidence that decorin may act through a novel mechanism, where it suppresses vascular endothelial growth factor (VEGF), resulting in inhibition of tumor growth. 3 The differences in effectiveness seen in our studies using CNS-1 cells that were stably transfected with decorin, when compared to gene transfer of decorin using RAds, could be due to the fact that in the former, decorin is expressed from the time of tumor cell implantation and therefore its inhibiting effects are seen very early on, while in the latter model, decorin is being delivered using a RAd, which although efficient, does not infect 100% of the tumor mass. Also, delivery was performed 3 days post-tumor implantation, once the tumor is already established, and this might impair the effectiveness of decorin in inhibiting tumor progression.…”