Affiliation of authors: Laboratory of Cell Regulation and Carcinogenesis, Division of Basic Sciences, National Cancer Institute, Bethesda, MD.
Correspondence to: Anita B. Roberts, Ph.D., National Institutes of Health, Bldg. 41, Rm. C629, 41 Library Dr., MSC 505, Bethesda, MD 208925055 (e-mail: Robertsa{at}dce41.nci.nih.gov).
We welcome and appreciate the comments of Dr. Li and colleagues regarding the possibility that overexpression of endoglin/CD105 in tumor blood vessels may contribute to tumor angiogenesis. Indeed, this is especially exciting because it begins to define reciprocal relationships between tumor cells and stroma that create an environment permissive for tumor cell growth. Furthermore, it provides potentially a mechanism whereby the endothelial cell can selectively "protect" itself from inhibitory effects of transforming growth factor- (TGF-
) secreted by the tumor cell, while at the same time allowing suppression of immune surveillance and enhancement of desmoplasia. However, before we embrace this mechanism, we must be cautious to assure that the tumor endothelial cells actually express more endoglin per cell, as distinguished from a more intense staining for endoglin in a tumor, which might result simply from a greater capillary density. In this regard, Matsubara et al. (1) have shown that increasing numbers of endoglin-positive endothelial cells are found in sporadic cerebral arteriovenous malformations but that endoglin density was normal, suggesting that endoglin does not play a role in generation of these lesions.
It should also be mentioned that the endoglin homologue, betaglycan (the actual designated TGF- receptor type III [T
RIII]), likely plays quite a different role in tumorigenesis. Endoglin and betaglycan show limited homology in their N-terminal domains, but, in contrast to endoglin, betaglycan binds all isoforms of TGF-
(2). Comparison of the effects of overexpression of endoglin and betaglycan showed that overexpression of endoglin led to a decrease in TGF-
responses, while overexpression of betaglycan enhanced responsiveness to TGF-
, correlating with increased binding of ligand to TGF-
receptor type II (T
RII) (3). Similarly, overexpression of betaglycan in human breast cancer MCF-7 cells increased the autocrine activity of TGF-
and reduced the clonogenicity of the cells in soft agar (4); in another human breast cancer cell line, MDA-MB-231, it resulted in reduced tumorigenicity in vivo and could be shown to result in sequestration of TGF-
secreted by the cells (5). In contrast, recent studies indicate that, under certain conditions, betaglycan can enhance tumorigenicity. Thus, overexpression of oncogenic, but not wild-type, Ras results in conversion of HD64 colon cancer cells from being insensitive to TGF-
to being growth stimulated by TGF-
, giving rise to a more aggressive tumor phenotype. This has been shown to correlate specifically with post-translational modification of betaglycan(6).
Overall, it is clear that the entire TGF- signaling cascade from secretion of ligand, to activation or sequestration of ligand, to receptors and receptor-modulating proteins (such as endoglin and betaglycan), to the intracellular signal transducers and modulators, including mitogen-activated protein kinase (MAP) and small mothers against decapentaplegic (Smad) pathways, must all be considered in any analysis of the complex effects of TGF-
on carcinogenesis.
REFERENCES
1
Matsubara S, Bourdeau A, terBrugge KG, Wallace C, Letarte M. Analysis of endoglin expression in normal brain tissue and in cerebral arteriovenous malformations. Stroke 2000;31:265360.
2 Massague J. TGF-beta signal transduction. Annu Rev Biochem 1998;67:75391.[Medline]
3
Letamendia A, Lastres P, Botella LM, Raab U, Langa C, Velasco B, et al. Role of endoglin in cellular responses to transforming growth factor-beta. A comparative study with betaglycan. J Biol Chem 1998;273:330119.
4
C, Wang XF, Sun L. Expression of transforming growth factor beta (TGFbeta) type III receptor restores autocrine TGFbeta1 activity in human breast cancer MCF-7 cells. J Biol Chem 1997;272:128627.
5
Sun L, Chen C. Expression of transforming growth factor beta type III receptor suppresses tumorigenicity of human breast cancer MDA-MB-231 cells. J Biol Chem 1997;272:2536772.
6 Yan Z, Deng X, Friedman E. Oncogenic Ki-ras confers a more aggressive colon cancer phenotype through modification of transforming growth factor-beta receptor III. J Biol Chem 2000;276:155563.[Medline]
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