Norihiro Nakada

High expression of L-type amino-acid transporter 1 (LAT1) in gastric carcinomas: Comparison with non-cancerous lesions

Amino acid transporters are essential for maintenance and proliferation of both normal and transformed cells. In the present study, L‐type amino‐acid transporter 1 (LAT1) immunoreactive expression was investigated in gastric carcinomas, in comparison with gastric adenomas and non‐neoplastic lesions, using our recently developed novel monoclonal antibody. In a total of 87 cases of advanced gastric cancer, high LAT1 expression was observed in carcinoma cells, predominantly at plasma membranes with greater intensity in non‐scirrhous than scirrhous carcinomas. Gastric carcinoma cases with lymph node metastasis showed significantly higher LAT1 expression than cases without lymph node metastasis. A positive correlation with Ki‐67 LI was observed and the highly expressing non‐scirrhous carcinomas showed a significantly poorer prognosis than the low LAT1 group. Cox hazard test revealed that TNM stage and LAT1 expression were independent prognostic factors in non‐scirrhous carcinoma group. Further, a significant poor prognosis was confirmed in high LAT1 expression group, when limited to undifferentiated carcinoma cases excluding scirrhous carcinoma. Lower levels were found in adenomas. In conclusion, LAT 1 expression may be linked with cell proliferation and prognosis of gastric carcinomas, and offers a potential target for future anticancer therapy by inhibitors.

High expression of L-type amino acid transporter 1 (LAT1) predicts poor prognosis in pancreatic ductal adenocarcinomas

Background and aims Molecular target therapy against L-type amino acid transporter 1 (LAT1) is unique and expected to be developed soon. LAT1 expression was investigated in pancreatic cancer as a prognostic predictor. Methods Surgically resected pancreatic ductal adenocarcinomas (PDAC, n=66) were investigated using immunohistochemistry. For reference, intraductal papillary mucinous carcinomas (IPMC, including intraductal papillary mucinous neoplasm (IPMN) with high-grade dysplasia or with an associated invasive carcinoma, n=13) and adenomas (IPMA, including IPMN with low- and intermediate-grade dysplasia, n=5) were also examined. Results LAT1 expression scores increased from PDAC to IPMA to IPMC. Kaplan–Meier analysis showed significant differences between LAT1-high and -low scores in PDAC. Even in each Ki-67-labelling index (LI) low and high PDAC group (cut off 40%), high LAT1 expression could also predict poor prognosis. Multivariable analysis showed that LAT1 expression, Ki-67 LI, tumour differentiation and size were individual prognostic factors. Conclusions LAT1 aberrant overexpression in PDAC predicts poor prognosis, independent of Ki-67 LI, and offers a potential target for future anticancer therapy with its inhibitors.

Unique and selective expression of L-amino acid transporter 1 in human tissue as well as being an aspect of oncofetal protein.

Dysregulated expression of L-type amino acid transporter 1 (LAT1), which transports large neutral amino acids, is a characteristic of various human cancers and possibly offers a molecular target for chemotherapy. LAT2, in contrast, shows lower expression in neoplasms. LAT1 is presumed to be a biomarker of many cancers, suggesting a kind of oncoprotein. However, no precise analysis of LAT1 and LAT2 expression has been performed in systemic normal tissues. To see characteristics of LAT1 and LAT2, immunohistochemical expression of LAT1 and LAT2 was assessed and compared in normal human systemic organs and tissues from 3 adults, 3 children and 3 fetuses in the present study. Cardiac muscles, hepatocytes, thymic epithelial cells and primitive neuroectodermal cells in fetus were positive with LAT1, whereas no expression was found in the respective adult tissues, indicating an aspect of oncofetal protein. In adult tissues, LAT1 was found to be expressed proximal to proliferative zones in gastrointestinal mucosa by double immunostaining of LAT1 and Ki-67. Testicular Sertoli cells, ovarian follicular cells, and pancreatic islet cells showed strong expression. Although the systemic capillary endothelium did not express LAT1, but did express LAT2, capillaries corresponding to the blood-brain, blood-follicle, and blood-retinal barriers demonstrated strong LAT1 immunoreactions. In conclusion, LAT1 was expressed in gonad tissues and several kinds of cells having special functions, as well as being discovered to be an aspect of oncofetal protein. In addition, ubiquitous LAT2 expression was confirmed immunohistochemically in systemic tissues, indicating constitutional function.

Invasive behavior of ulcerative colitis-associated carcinoma is related to reduced expression of CD44 extracellular domain: comparison with sporadic colon carcinoma

BackgroundTo elucidate relations of invasion of ulcerative colitis (UC)-associated carcinoma with its prognosis, the characteristics of invasive fronts were analyzed in comparison with sporadic colonic carcinomas.MethodsPrognoses of 15 cases of UC-associated colonic carcinoma were compared with those of sporadic colon carcinoma cases, after which 75 cases of sporadic invasive adenocarcinoma were collected. Tumor budding was examined histologically at invasive fronts using immunohistochemistry (IHC) of pancytokeratin. Expressions of beta-catenin with mutation analysis, CD44 extracellular domain, Zo-1, occludin, matrix matalloproteinase-7, laminin-5γ2, and sialyl Lewis X (LeX) were immunohistochemically evaluated.ResultsUC-associated carcinoma showed worse prognosis than sporadic colon carcinoma in all the cases, and exhibited a tendency to become more poorly differentiated when carcinoma invaded the submucosa or deeper layers than sporadic carcinoma. When the lesions were compared with sporadic carcinomas considering differentiation grade, reduced expression of CD44 extracellular domain in UC-associated carcinoma was apparent. Laminin-5γ2 and sialyl-LeX expression showed a lower tendency in UC-associated carcinomas than in their sporadic counterparts. There were no differences in the numbers of tumor budding foci between the two lesion types, with no apparent relation to nuclear beta-catenin levels in IHC.ConclusionsUC-associated carcinoma showed poorer differentiation when the carcinoma invaded submucosa or deeper parts, which may influence the poorer prognosis. The invasive behavior of UC-associated carcinoma is more associated with CD44 cleavage than with basement membrane disruption or sialyl-Lewis-antigen alteration.

High expression of L-type amino acid transporter 1 as a prognostic marker in bile duct adenocarcinomas

Oncocytic L‐type amino acid transporter (LAT) 1 may be a prognostic indicator and target of new molecular therapeutic agents against malignancies. To investigate whether LAT1 expression influence the outcomes of patients with bile duct cancer, the expression of LAT1, LAT2, CD98, and Ki‐67 was investigated immunohistochemically in 134 surgically resected bile duct adenocarcinomas, including 84 distal extrahepatic bile duct adenocarcinomas, 21 hilar cholangiocarcinomas, 15 intrahepatic cholangiocarcinomas, and 14 ampullary adenocarcinomas. LAT1 expression was weakly correlated with CD98 expression and Ki‐67 labeling index (LI). Kaplan–Meier analysis showed a significant difference in prognosis between patients with bile duct adenocarcinomas having LAT1‐high and ‐low scores, whereas LAT2 and CD98 expression and Ki‐67 LI were not predictive of poor prognosis. Prognosis tended to be worse in patients having tumors with LAT1‐high/LAT2‐low than LAT1‐low/LAT2‐high scores (P = 0.0686). Multivariable analyses revealed that LAT1 expression, surgical margin, pT stage were independent prognostic factors. In conclusion, aberrant overexpression of LAT1 in bile duct adenocarcinoma predicts poor prognosis, suggesting that LAT1 may be a potential target of anticancer therapy.

Tumor budding, myofibroblast proliferation, and fibrosis in obstructing colon carcinoma: the roles of Hsp47 and basic fibroblast growth factor.

This study was designed to assess the mechanism of obstruction in obstructing colorectal carcinomas. Thirty-five cases of obstructing colorectal carcinoma and 34 cases of non-obstructing carcinoma were studied. The lesions were immunohistochemically analyzed using antibodies for pan-cytokeratin, α-smooth muscle actin, matrix metalloproteinase-7, 47-kDa heat shock protein (Hsp47), basic fibroblast growth factor (bFGF), myeloperoxidase, and CD68. Compared with non-obstructing cases, obstructing carcinoma cases included lesions of poorer differentiation. A higher value of tumor budding was observed in obstructing than in non-obstructing carcinoma. A higher number of α-smooth muscle actin-positive myofibroblasts, a higher expression of Hsp47 in stromal spindle cells, and a higher expression of bFGF in inflammatory cells were also significant in obstructing carcinoma. Therefore, obstructing colon carcinomas were characterized by poorer differentiation of cancer cells, a high level of tumor budding, and stromal myofibroblast proliferation resulting in fibrosis. Correlative Hsp47 expression in fibroblasts with bFGF in inflammatory cells may contribute to stromal fibrosis.

Small gastrointestinal stromal tumor in the stomach: identification of precursor for clinical gastrointestinal stromal tumor using c-kit and α-smooth muscle actin expression ☆

Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors of the digestive tract. To find precursors for clinical GISTs of the stomach, small gastric stromal tumors of less than 3 cm were collected and examined immunohistochemically with analysis of the KIT mutation. Sixty-eight of 74 lesions were classified into 4 representative groups according to the expression of c-kit and α-smooth muscle actin (αSMA): group A, c-kit diffusely positive and αSMA negative (18 cases); group B, c-kit diffusely positive and αSMA focally positive (13); group C, c-kit focally positive and αSMA diffusely positive (27); and group D, c-kit negative and αSMA diffusely positive (10). Of the 4 groups, groups A and B of c-kit diffuse expression showed higher cellularity and labeling indices of p27(Kip1) and Ki-67 than did groups C and D of diffuse αSMA expression. Incidence of KIT exon 11 mutation in groups A and B was 86% (25/29), whereas that in groups C and D was 0% (0/20). Small gastric stromal tumors with c-kit diffuse expression were considered precursors for clinical GIST because they were significantly different from c-kit focally positive or negative tumors. The mutation of KIT is considered as an early event in tumorigenesis of GIST.

L-type amino acid transporter 1 (LAT1) expression in lymph node metastasis of gastric carcinoma: Its correlation with size of metastatic lesion and Ki-67 labeling

L-Type amino acid transporter 1 (LAT1) is one of the major amino acid transporters. High levels of LAT1 expression have been reported in various tumors, which can act as a novel prognostic marker. Previously, we demonstrated that LAT1 is highly expressed in advanced gastric carcinoma with lymph node metastasis, and proposed that LAT1 is an independent prognostic factor in non-scirrhous gastric carcinoma. The aim of the present study was to investigate the relationship between LAT1 expression and the size of lymph node metastatic lesions in gastric carcinoma. LAT1 and Ki-67 expression was immunohistochemically analyzed in 64 cases of advanced gastric carcinoma with lymph node metastasis. LAT1 expression in the metastatic lymph nodes was correlated with that in the primary lesions. The high LAT1 expression group showed a larger size of metastatic lesion and a higher Ki-67 labeling index than the low LAT1 expression group. LAT1 expression had a weak association with Ki-67 labeling index and tumor diameter of lymph nodes. These results suggest that LAT1 expression is associated with disease progression in gastric carcinoma. We proposed that LAT1 could be a potential therapeutic target for gastric carcinoma cases with large lymph node metastasis.

Nab-paclitaxel plus carboplatin as an effective and safe chemotherapy regimen for pulmonary carcinosarcoma with interstitial lung disease: A case report

Carcinosarcoma is a rare histological type of non-small cell carcinoma (NSCLC), and its prognosis has been reported to be worse compared with other NSCLCs. Nanoparticle albumin-bound paclitaxel (nab-PTX) + carboplatin (CBDCA) achieves a favorable response rate in patients with non-small cell lung cancer (NSCLC). We administered nab-PTX + CBDCA to a 68-year-old man with postoperative recurrent carcinosarcoma with interstitial lung disease (ILD). A partial response was evident after four cycles of chemotherapy. To the best of our knowledge, the present study is the first to report the safety and efficacy of nab-PTX + CBDCA for treating carcinosarcoma with ILD.