Angiomyolipomas are tumors that show histologic evidence of smooth muscle, fat, and melanocytic markers. While these tumors are histologically benign, they are the major cause of morbidity and mortality in adults with tuberous sclerosis. Angiomyolipomas are notoriously susceptible to rapid hemorrhage, and multiple angiomyolipomas may obliterate the renal parenchyma, causing renal failure, and the need for renal transplantation. Currently, the only treatments for angiomyolipomas are excision or embolization.
Most of the neoplasms and hamartomas of tuberous sclerosis exhibit multilineage phenotypes. Cortical tubers of tuberous sclerosis, the major cause of seizures in affected children, exhibit a combined neuronalglial phenotype. Collagenomas exhibit a mixed population of fat, smooth muscle, and collagen deposition. Lymphangiomyomatosis, which may cause respiratory failure, exhibits a similar phenotype of smooth muscle and melanocytic lesions to angiomyolipoma. This clinical finding of multilineage phenotypes suggests that the signaling aberrations in tuberous sclerosis result from a perturbation of stem cell differentiation.
Smooth muscle cells arise from endoderm and neural crest. Specifically, a common neural crest precursor can differentiate into glia, smooth muscle, pericytes, cartilage, myofibroblast, and neurons. Platelet derived growth factor α (PDGFα) and pax family transcription factors are required for initial proliferation of neural crest stem cells, which migrate to peripheral tissues. Pax genes are expressed in neural crest prior to migration to the periphery, and the lack of pax3 expression in SV7tert angiomyolipoma cells is consistent with the known patterns of pax expression (24
). Maintenance and differentiation of these stem cell derivatives occurs through locally based trophic factors, such as platelet-derived growth factor α (PDGFα). Angiogenic vascular endothelium produces abundant PDGF-BB, and deficiency of PDGF-BB in knockout mice results in severe kidney defects due to the presence of angiogenic endothelium not being invested by smooth muscle and pericytes (19
). Of interest, angiomyolipoma cells express high levels of PDGF-BB, and proliferation of angiomyolipoma cells in vitro is inhibited by PDGFRb tyrosine kinase antagonists, including glivec. Activated (phosphorylated) PDGFRb is expressed in angiomyolipoma tumor tissue, indicating patho-physiologic activation of PDGF-BB/ PDGFRβ in vivo (26
Neural crest contributes to the development of the embryonic kidney. Neural crest cells expressing the L1 neural cell adhesion protein are present in the embryonic metanephric kidney rudiment, and their proliferation is enhanced by neurotropin 3 (NT-3) (27
). Of interest, a population of SV7tert cells and angiomyolipoma tumors express L1 in addition to NG2, supporting a neural crest origin for angiomyolipoma cells. NG2 also may play a role in maintenance of these tumors, as NG2 has been shown to sequester and inactivate angiostatin, thus permitting pathologic angiogenesis (29
Angiomyolipomas are the most common kidney neoplasms that express melanocytic markers. In melanocytes, MITF is the major transcriptional switch for the distinct metabolic pathways for melanin formation, but MITF appears to have antiapoptotic and oncogenic functions independent of this. MITF shares biochemical similarity to the TFE3/TFEB transcription factors, and this extends to protection against apoptosis and oncogenesis (30
). Previous mechanisms for activation of these transcription factors include translocation, which occurs in a subset of pediatric renal cell carcinomas and alveolar soft part sarcomas (19
). In addition, these factors are expressed in Ewing’s sarcoma through transcriptional activation. Our data suggests that angiomyolipoma, which is far more common than pediatric renal cell carcinoma, alveolar soft part sarcoma, and Ewing’s sarcoma, may arise from a similar neural crest precursor. Angiomyolipoma cells are sensitive to blockade of PDGFRβ, and pharmacologic blockade of PDGFRβ activation with drugs such as glivec, may be useful in the treatment of angiomyolipoma (36
). In addition, angiogenesis inhibition may serve to deprive angiomyolipoma cells of trophic PDGF-BB production, and avastin, a VEGF trap, has been shown to be efficacious in renal cell carcinoma. Finally, NG2 binding peptides have been made which target tumor vessels (34
). The presence of NG2 on angiomyolipoma cells may enhance tumor killing by peptides which bind NG2. Thus, an understanding of the embryonic basis of angiomyolipoma may be beneficial in therapy of this common tumor.