Loss of tuberin, the tuberous-sclerosis-complex-2 gene product is associated with angiogenesis.
BACKGROUND
Tuberous sclerosis complex (TSC) is an autosomal dominantly inherited disorder associated with an alteration of the TSC2 tumor suppressor gene which encodes for the protein product tuberin. The disease is characterized by the development of hamartomas, e.g. cutaneous angiofibromas which consist of vascular cells, interstitial cells, and normal components of the skin. The Eker rat model, an animal model of inherited cancer, has been shown to carry a mutation of TSC2.


METHODS
Immunohistochemical analyses of human angiofibromas were performed using antibodies directed against tuberin and angiogenic growth factors. Proliferation of human dermal microvascular endothelial cells (HDMEC) was determined after incubation with the supernatants of TSC2 (+/+) and TSC2 (-/-) rat embryonic fibroblasts (REF) that were derived from the Eker strain.


RESULTS
Loss of the expression of tuberin was observed in the interstitial cells of 13 of 39 angiofibromas. The expression of tuberin was retained in the vascular cells. In all analyzed angiofibromas, the angiogenic factors bFGF, PD-ECGF, VEGF and angiogenin were detected in the interstitial cells and/or vascular cells. Expression of PDGF-B and TGF-beta1 was weak. Tissue culture supernatants from TSC2 (-/-) REF stimulated the growth of HDMEC significantly more than supernatants from TSC2 (+/+) REF.


CONCLUSIONS
A functional loss of tuberin may stimulate vascular growth.
Nguyen-Vu
P A
PA
Department of Dermatology, Ludwig-Maximilians-University Munich, Munich, Germany.
Fackler
I
I
Rust
A
A
DeClue
J E
JE
Sander
C A
CA
Volkenandt
M
M
Flaig
M
M
Yeung
R S
RS
Wienecke
R
R
D018322:Angiofibroma / Q000473:pathology*; D000818:Animals; D002478:Cells, Cultured; D017077:Culture Media, Conditioned / Q000494:pharmacology; D016228:Endothelial Growth Factors / Q000032:analysis; D004727:Endothelium / Q000166:cytology / Q000187:drug effects; D016222:Fibroblast Growth Factor 2 / Q000032:analysis; D005347:Fibroblasts / Q000737:chemistry / Q000166:cytology; D006801:Humans; D007150:Immunohistochemistry; D008222:Lymphokines / Q000032:analysis; D009389:Neovascularization, Pathologic / Q000473:pathology*; D020574:Proto-Oncogene Proteins c-sis / Q000032:analysis; D051381:Rats; D011922:Rats, Mutant Strains; D012097:Repressor Proteins / Q000032:analysis*; D012259:Ribonuclease, Pancreatic / Q000032:analysis; D013939:Thymidine Phosphorylase / Q000032:analysis; D016212:Transforming Growth Factor beta / Q000032:analysis; D053773:Transforming Growth Factor beta1; D014402:Tuberous Sclerosis / Q000473:pathology*; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D019043:Vascular Neoplasms / Q000473:pathology*
D017077:Culture Media, Conditioned; D016228:Endothelial Growth Factors; D008222:Lymphokines; D020574:Proto-Oncogene Proteins c-sis; D012097:Repressor Proteins; C508960:TGFB1 protein, human; C000624653:TSC2 protein, human; C508962:Tgfb1 protein, rat; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; C000624655:Tsc2 protein, rat; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D016222:Fibroblast Growth Factor 2; D013939:Thymidine Phosphorylase; C046366:angiogenin; D012259:Ribonuclease, Pancreatic