Takatoshi Kadowaki

Effect of epidermal growth factor on cadherin-mediated adhesion in a human oesophageal cancer cell line.

Epidermal growth factor (EGF) mediates many pleiotrophic biological effects, one of which is alteration of cellular morphology. In the present study, we examine the possibility that this alteration in cell morphology is caused in part by the dysfunction of cadherin-mediated cell-cell adhesion using the human oesophageal cancer cell line TE-2R, which expresses E-cadherin and EGF receptor. In the presence of EGF, TE-2R changed its shape from round to fibroblastic and its colony formation from compact to sparse. Vanadate, a tyrosine phosphatase inhibitor, further potentiated the EGF response, whereas herbimycin A, a tyrosine kinase inhibitor, interfered with it. Moreover, EGF enabled the cells to invade in organotypic raft culture. These phenomena were accompanied not by decreased expression of the E-cadherin molecule but by a change in its localisation from the lateral adhesion site to the whole cell surface. Both alpha- and beta-catenin, cadherin-binding proteins, were also expressed at the same level throughout these morphological changes. Finally, we examined tyrosine phosphorylation of E-cadherin and alpha- and beta-catenin, and observed tyrosine phosphorylation of beta-catenin induced by EGF. These results suggest that EGF counteracts E-cadherin-mediated junctional assembly through phosphorylation of beta-catenin and modulates tumour cell behaviour to a more aggressive phenotype.

Immunohistochemical evaluation of alpha-catenin expression in human gastric cancer

E-cadherin (E-cad) plays a major role in the maintenance of cell-cell adhesion in epithelial tissues, and impaired E-cad expression correlates with tumour invasion and metastasis. Alpha-catenin (α-cat), an undercoat protein of adherens junctions, binds to the cytoplasmic domain of E-cad and is essential for linking E-cad to actin-based cytoskeleton. We investigated E-cad and α-cat expression in 60 human gastric cancers immunohistochemically. The 60 gastric cancers were classified into 18 (30%) in which α-cat expression was preserved, and 42 (70%) reduced cases. The reduction of α-cat expression was significantly related to dedifferentiation, depth of invasion, infiltrative growth and lymph node metastasis. We also examined the co-expression of α-cat and E-cad. Seventeen (28%) tumours preserved both molecules [α-cat(+)/E-cad(+)] and 33 (55%) tumours reduced both [α-cat(−)/E-cad(−)], whereas 9 (15%) tumours exhibited α-cat(−)/E-cad(+). The frequency of lymph node metastasis in α-cat(−)/E-cad(+) tumour (67%) was significantly higher than that in α-cat(+)/E-cad(+) tumours (24%) and was close to that in α-cat(−)/E-cad(−) tumours (82%). The frequency of haematogenous liver metastasis in α-cat(−)/E-cad(+) tumours (44%) was significantly higher than that in α-cat(+)/E-cad(+) tumours (6%) or α-cat(−)/E-cad(−) tumours (9%). Thus, in all E-cad(+) tumours, the frequency of lymph node and liver metastasis was higher in α-cat(−) tumours than in α-cat(+) tumours. α-Cat expression is apparently better at predicting tumour invasion and metastasis than E-cad expression.

Diagnosis and Treatment for Mucosal Carcinoma of the Esophagus. With Special Reference to the Indication for Endoscopic Mucosal Resection.

食道粘膜癌17例25病巣, および微小なsm浸潤を示すsm癌 (sml癌) 6例, 明らかなsm層浸潤のあるsm癌 (sm2, 3癌) で長径2cm以下の8例の肉眼型, 病理学的因子を検討し治療法について考察した.粘膜癌ではリンパ節転移はなかったが, 粘膜筋板まで浸潤したmm癌の7病巣では長径2cm以上の2病巣でリンパ管侵襲を, またsm1癌では半数にリンパ節転移を認めた.肉眼型では粘膜癌はすべて0-II型で, このうち0-IIa病変を伴った5例は1pm中層以上の浸潤を示したが, 隆起病巣の大きさは1.3cm以下, 高さは4例で0.5mm以下であった.一方, sm1癌では5例に隆起を認め, 長径は平均2.7cmであった.長径2cm以下のsm2, 3癌では5例が0-I型, 2例が0-III型で, これらはmm癌と鑑別可能であったが0-II型の病変も1例認められた.以上より隆起を伴わない0-II型病変, 隆起を伴っていても2cm以下で高さが0.5mm程度のものは内視鏡的粘膜切除術が適応となり, その他の病変ではリンパ節郭清を伴う食道切除術が必要と思われた.

Investigation of Endoscopic Mucosal Resection for Early Esophagel Cancer.

当教室ではこれまでに早期食道癌が疑われた症例10例 (12病変) に対し内視鏡的粘膜切除術 (以下, EMRと略記) を施行してきたが, これらのうちで術後に癌と診断された7例 (8病変) を対象に, 食道早期癌に対するEMRの適応について, 特に深達度の面から検討した.8病変の切除後の深達度診断は, epが4病変, mm1およびmm3がそれぞれ2病変であった. mm3癌のうちの1病変ではリンパ管侵襲が疑われ, 追加治療として切除後2週目より縦隔に対する放射線照射を行った. 最長で2年9か月経過を見ているが, 全症例無再発生存中である.現在のところ, 深達度mm2までの早期癌がEMRの絶対的適応であると考えられ, mm3ではly (+) の可能性が高く相対的適応と思われるが, ly (+) 症例でも追加治療により十分根治が可能な症例も含まれており, 今後mm3癌に対してもEMRの適応拡大が期待できると考えられた.

Relationship between E-cadherin and .ALPHA.-catenin Expression and Lymphnode Metastasis of Esophageal and Gastric Cancer.

上皮細胞間接着因子であるE型カドヘリン (以下, E-cad) とカドヘリンの膜裏打ちタンパクでその機能を制御しているσ カテニン (以下, α-cat) の発現性を食道癌46例と胃癌54例につき免疫組織学的手法を用い調べた.また, 分化度, 浸潤様式, リンパ節転移との相関も検討した.食道癌でE-cad, α-catとも80.5%, 胃癌でE-cadが57.5%, α-catが70.4%と高頻度に発現の減弱・消失が見られ, 分化度と浸潤様式に有意の相関を認めた.リンパ節転移との相関は食道癌の転移陽性例でEtcad, α-catとも有意に低下していたが, 胃癌ではα-catとのみ有意差を認めた.E-cadとα-catのcoexpressionをみるとα-catがE-cadより減弱・消失が高度である症例は食道癌で45.7%, 胃癌で27.8%あり, このような症例で高いリンパ節転移率を示した.すなわちα-catはE-cadよりリンパ節転移とより高い相関を示し, 今後術前の転移の検索に有用な因子となりうることが示唆された.

Immunohistochemical Evaluation of E-Cadherin and α-Catenin Expression in Human Esophageal Cancer

Tumor metastasis is initiated by disaggregation of invasive cells from the primary tumor - a step that requires a breakdown of intercellular adhesion. To investigate the mechanism of dysfunction in cell-cell adhesion of cancerous tissues, we evaluated E-cadherin (E-cad) and α-catenin (α-cat) expression of human esophageal cancer immunohistochemically. Eighty percent of the tumors showed reduced expression of both of the molecules. The frequency of α-cat negative tumors was observed in 47%, but none of them were E-cad negative. These results suggest that esophageal cancers lose α-cat expression more frequently than E-cad, and the loss of α-cat mights cause dysfunction of E-cad-mediated intercellular adhesion.

Immunohistochemical Evaluation of α-Catenin, Cadherin-Associated Intercellular Protein, Expression in Human Gastric Cancer

Immunohistochemical study of α-catenin, cadherin associated intercellular protein, was performed in 36 human gastric cancer tissues. All normal epithelium strongly expressed α-catenin as well as E- cadherin, while 67% of the tumor had reduced expression of α-catenin. Compared to E-cadherin expression, α-catenin expression was similar in 26 cases (72%), but weaker in 9 cases (25%). The reduction of α-catenin expression was associated with dedifferentiation, and infiltrative growth. These results indicated that the reduction of α-catenin expression may play a crucial role for cancer invasion through down-regulation of E-cadherin function.

Endoscopic Examination for the Early Esophageal Cancer in Patients with Head and Neck Cancers

Endoscopic screening of the esophagus with Lugol-dye staining was performed on 304 patients with head and neck cancers at the Department of Surgery II, Osaka University Medical School between June 1987 and August 1992. We found 19 patients with esophageal cancer (6.3%) and 21 patients with esophageal dysplasia (6.9%). Fifteen (78%) of 19 esophageal cancer patients were early stages (within submucosal invasion) with no lymph node metastases. Twelve (63%) of 19 esophageal cancer patients coexisted with multiple areas of dysplasia and/or cancer. The esophageal epithelium in patients with head and neck cancers may have tendency of field cancerization and multicentric potency for carcinogenesis.

Correlation Between Expression of E-Cadherin and Metastasis and Invasion in Human Esophageal Cancer

Cadherins are Ca2+-dependent cell-cell adhesion molecules which are possibly involved in the process of metastasis in cancer cells. We have investigated the expression of E-cadherin (E-CD), which is a subclass of cadherin expressed on cell membranes in normal esophageal epithelium. Sixty-two human esophageal cancers were studied with immunoblotting (5 cases) and immunohistochemical staining (62 cases) using monoclonal antibody for human E-CD (HECD-1) on frozen surgical specimens, and the correlation between E-CD expression and incidence of clinical lymph node metastasis and cancer invasion was investigated.

Treatment of Benign Esophageal Stricture

Benign esophageal stricture is caused by a variety of conditions. Considering its benign character, conservative management should be attempted first, using various dilatation instruments, such as a Celestin dilator [1, 2] and a baloon catheter [3, 4]. If the conservative management is not successful, surgical treatment is required to relieve the stricture. This retrospective study was attempted to clarify the limitation of conservative management and the indications for surgical treatment for benign esophageal strictures.