Loss of Tsc1 or Tsc2 induces vascular endothelial growth factor production through mammalian target of rapamycin.
Mutation in either TSC1 or TSC2 causes the autosomal dominant disorder tuberous sclerosis, in which widespread hamartomas are seen, some of which have a high level of vascularization. Tuberous sclerosis complex (TSC) gene products negatively regulate mammalian target of rapamycin (mTOR) activity. We found that vascular endothelial growth factor (VEGF) is secreted by Tsc1- or Tsc2-null fibroblasts at high levels compared with wild-type cells. In Tsc1+/- mice, serum levels of VEGF were increased and appeared to be associated with the extent of tumor development. Rapamycin, a mTOR inhibitor, reduced the production of VEGF by Tsc1- and Tsc2-null fibroblasts to normal levels. Moreover, short-term treatment of Tsc1+/- mice with rapamycin at 20 mg/kg led to some changes in tumor morphology and a reduction in serum VEGF levels. These observations have three implications. First, TSC gene products regulate VEGF production through a mTOR signaling pathway. Second, serum VEGF levels may be a useful clinical biomarker to monitor the progression of TSC-associated lesions. Last, rapamycin or related inhibitors of mTOR may have therapeutic benefit in TSC both by direct tumor cell killing and by inhibiting the development of TSC lesions through impairment of VEGF production.
D000818:Animals; D002460:Cell Line; D016228:Endothelial Growth Factors / Q000096:biosynthesis* / Q000378:metabolism; D005260:Female; D005347:Fibroblasts / Q000378:metabolism; D007150:Immunohistochemistry; D036341:Intercellular Signaling Peptides and Proteins / Q000096:biosynthesis* / Q000378:metabolism; D008222:Lymphokines / Q000096:biosynthesis* / Q000378:metabolism; D008297:Male; D051379:Mice; D011494:Protein Kinases / Q000378:metabolism*; D011506:Proteins / Q000235:genetics*; D012097:Repressor Proteins / Q000235:genetics*; D058570:TOR Serine-Threonine Kinases; D000077004:Tuberous Sclerosis Complex 1 Protein; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors
D016228:Endothelial Growth Factors; D036341:Intercellular Signaling Peptides and Proteins; D008222:Lymphokines; D011506:Proteins; D012097:Repressor Proteins; C000624651:Tsc1 protein, mouse; C000624654:Tsc2 protein, mouse; D000077004:Tuberous Sclerosis Complex 1 Protein; D000077005:Tuberous Sclerosis Complex 2 Protein; D025521:Tumor Suppressor Proteins; D042461:Vascular Endothelial Growth Factor A; D042442:Vascular Endothelial Growth Factors; D011494:Protein Kinases; C546843:mTOR protein, mouse; D058570:TOR Serine-Threonine Kinases