RETRACTED: Ultrastructural immunohistochemical study of L-type amino acid transporter 1–4F2 heavy chain in tumor microvasculatures of N-butyl-N-(4-hydroxybutyl) nitrosamine (BBN) induced rat bladder carcinoma

Abstract

Angiogenesis is essential for tumor growth, and an enhanced vasculature supplying nutrients and oxygen might reflect malignant potential. L-type amino acid transporter 1 (LAT1/4F2hc) comprises a major nutrient transport system responsible for the Na+-independent transport of large neutral amino acids. Seventy five to seventy eight percent N-butyl-N-(4-hydroxybutyl) nitrosamine-induced rat bladder carcinoma cells showed high LAT1/4F2hc expression. While the intracarcinoma microvasculatures of fenestrated endothelial cells highly expressing LAT1/4F2hc might progressively transport essential amino acids from the microvasculatures to the extracellular matrix, non-fenestrated endothelial cells and pericytes did not. The present study revealed that the tumor angiogenesis is one of target anti-L-type amino acid transporter 1 drug.

Amino acid transporter LAT1 in tumor-associated vascular endothelium promotes angiogenesis by regulating cell proliferation and VEGF-A-dependent mTORC1 activation

“…Our study revealed that amino acid transporter LAT1 expressed in tumor-associated endothelial cells is a novel key molecule in tumor angiogenesis. Extending previous studies with limited observations on a rat bladder carcinoma model [29] and human glioma tissues [30], we established the upregulation of LAT1 expression as a general characteristic of tumor-associated endothelial cells. The functional relevance of endothelial LAT1 to tumor angiogenesis was demonstrated in in vivo models by genetic and pharmacological inhibition of LAT1 (Fig.…”

“…Besides its well-recognized function in tumor cells, a yet unclarified role of LAT1 in tumor biology has been its implication to endothelial cell functions in tumors. An elevated expression of LAT1 in tumor-associated microvasculatures was reported in N-butyl-N-(4-hydroxybutyl) nitrosamineinduced rat bladder carcinoma model [29]. A clinicopathological study on human glioma showed LAT1 expression in both vascular endothelial cells and tumor cells, demonstrating significant correlations of LAT1 expression with the pathological grade and the intratumoral microvessel density [30].…”

Contribution of LAT1-4F2hc in Urological Cancers via Toll-like Receptor and Other Vital Pathways

“…Anti-vascular endothelial growth factor receptor (anti-VEGFR) is the first to realize the normalization and functional recovery of tumor vascular system by tissue perfusion and reducing intratumoral hypoxia [ 99 ]. In the current studies of cancers [ 71 , 101 , 102 ], angiogenesis in vitro/in vivo experiments was inhibited by eliminating the function or expression of LAT1. It regulates proliferation, translation, and angiogenesis VEGF-A signal [ 102 ].…”

“…These data help to understand the intracellular signal transduction of cell growth inhibition induced by LAT1 inhibitors and can be used as a candidate for anticancer drug therapy [ 109 ]. Later studies proposed the use of N-butyl-N- (4-hydroxybutyl) nitrosamine (BBN) treatment to induce high expression of LAT1/4F2hc in rat bladder cancer cells [ 101 ] and proposed some directions for anti-LAT1/4F2hc drugs. JPH203 was discovered by Oda in 2010 and was originally known as KYT-0353 [ 115 ].…”

“…Whether LAT1-4F2hc expression depends on endothelial cell structure is unclear. Fenestration of microvascular endothelial cells is not a stable event, because endothelial cells with fenestration in BBN-induced rat bladder cancer were transformed into endothelial cells without fenestration 5 min after injection of VEGF inhibitor, and fenestration recovered 30 min later [ 101 ]. The molecular mechanisms of amino acid transport in normal and tumor microvascular endothelial cells need further study.…”