Relation of LAT1/4F2hc expression with pathological grade, proliferation and angiogenesis in human gliomas

BackgroundLAT1/4F2hc heterodimeric complex is a major route for the transport of large neutral essential amino acids through the plasma membrane. Although it has been shown that LAT1/4F2hc is highly expressed in a variety of human tumors including gliomas, and LAT1 over-expression is associated with glioma grade and poor prognosis of glioma patients, the precise tissue location of LAT1/4F2hc in gliomas and the precise role of LAT1/4F2hc in glioma biological features remain unclear.MethodsIn the current study, the expressions of LAT1, 4F2hc, CD34 and Ki-67 were investigated by immunohistochemistry in 62 cases of human brain glioma; LAT1/4F2hc expression level, Ki-67 labeling index (Ki-67 LI) and microvessel density (MVD) were measured semi-quantitatively; and the correlation of LAT1/4F2hc expression with histopathological features, Ki-67 LI and MVD in gliomas was further analyzed.ResultsThe results showed that both LAT1 and 4F2hc were expressed in all examined specimens. LAT1 but 4F2hc expression levels significantly correlated with the pathological grade and both expression levels significantly correlated with Ki-67 LI of gliomas. We also demonstrated that both LAT1 and 4F2hc immunoreactivity were observed in tumor cells as well as vascular endothelia; furthermore, the LAT1 expression level was markedly associated with glioma MVD as well.ConclusionLAT1/4F2hc over-expression is closely correlates with the malignant phenotype and proliferation of gliomas, and LAT1 was associates with glioma angiogenesis. LAT1/4F2hc, especially LAT1, may become a novel potential molecular target for glioma biological therapy.

[1]  Eiji Takeda,et al.  Expression Cloning and Characterization of a Transporter for Large Neutral Amino Acids Activated by the Heavy Chain of 4F2 Antigen (CD98)* , 1998, The Journal of Biological Chemistry.

[2]  W. Pardridge,et al.  Selective expression of the large neutral amino acid transporter at the blood-brain barrier. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[3]  Y. Kanai,et al.  Expression of a system L neutral amino acid transporter at the blood–brain barrier , 2000, Neuroreport.

[4]  Bradley E. Enerson,et al.  Expression of Large Amino Acid Transporter LAT1 in Rat Brain Endothelium , 2000, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

[5]  Y. Kanai,et al.  Human L-type amino acid transporter 1 (LAT1): characterization of function and expression in tumor cell lines. , 2001, Biochimica et biophysica acta.

[6]  T. Takayama,et al.  Expression of L‐type amino acid transporter 1 (LAT1) in esophageal carcinoma , 2005, Journal of surgical oncology.

[7]  H. Zhen,et al.  Survivin expression and its relation with proliferation, apoptosis, and angiogenesis in brain gliomas , 2005, Cancer.

[8]  Y. Kanai,et al.  Amino acid transport system L is differently expressed in human normal oral keratinocytes and human oral cancer cells. , 2005, Cancer letters.

[9]  B. Fuchs,et al.  Amino acid transporters ASCT2 and LAT1 in cancer: partners in crime? , 2005, Seminars in cancer biology.

[10]  H. Nawashiro,et al.  L‐type amino acid transporter 1 as a potential molecular target in human astrocytic tumors , 2006, International journal of cancer.

[11]  M. Nagane,et al.  Enhanced tumor growth elicited by L-type amino acid transporter 1 in human malignant glioma cells. , 2008, Neurosurgery.

[12]  N. Sunaga,et al.  l‐type amino acid transporter 1 and CD98 expression in primary and metastatic sites of human neoplasms , 2008, Cancer science.

[13]  M. Gumbleton,et al.  Characterization and astrocytic modulation of system L transporters in brain microvasculature endothelial cells , 2008, Cell biochemistry and function.

[14]  D. Shennan,et al.  Inhibition of system L (LAT1/CD98hc) reduces the growth of cultured human breast cancer cells. , 2008, Oncology reports.

[15]  N. Sunaga,et al.  L‐type amino acid transporter 1 expression is a prognostic marker in patients with surgically resected stage I non‐small cell lung cancer , 2009, Histopathology.

[16]  V. Ganapathy,et al.  Nutrient transporters in cancer: relevance to Warburg hypothesis and beyond. , 2009, Pharmacology & therapeutics.

[17]  Y. Kanai,et al.  L‐type amino‐acid transporter 1 as a novel biomarker for high‐grade malignancy in prostate cancer , 2009, Pathology international.

[18]  N. Sunaga,et al.  L‐type amino acid transporter 1 (LAT1) is frequently expressed in thymic carcinomas but is absent in thymomas , 2009, Journal of surgical oncology.

[19]  Y. Kanai,et al.  System L amino acid transporter inhibitor enhances anti-tumor activity of cisplatin in a head and neck squamous cell carcinoma cell line. , 2009, Cancer letters.

[20]  T. Tamiya,et al.  Correlation of l-methyl-11C-methionine (MET) uptake with l-type amino acid transporter 1 in human gliomas , 2010, Journal of Neuro-Oncology.

[21]  K. Nakanishi,et al.  LAT1 expression in non-small-cell lung carcinomas: analyses by semiquantitative reverse transcription-PCR (237 cases) and immunohistochemistry (295 cases). , 2010, Lung cancer.

[22]  H. Arakawa,et al.  Impact of system L amino acid transporter 1 (LAT1) on proliferation of human ovarian cancer cells: a possible target for combination therapy with anti-proliferative aminopeptidase inhibitors. , 2010, Biochemical pharmacology.

[23]  A. Kurata,et al.  Divergent expression of L-type amino acid transporter 1 during uterine cervical carcinogenesis. , 2011, Human pathology.