Establishment of melecular-based diagnositics for esophageal cancer

在包括日本在内的东方国家，食管癌被认为是最具侵袭性的恶性肿瘤之一。早期发现肿瘤的发展以及肿瘤的复发一直是该疾病的关键课题。我们目前的研究目的是建立基于分子的食管癌诊断方法，为此我们进行了4项主要研究：1)检测患者血液或骨髓中的肿瘤细胞（微转移），用于术后疾病监测；2)建立大鼠食管癌化学诱导模型，阐明食管癌发生相关基因；3)检测辐射敏感相关基因；4)应用DNA微阵列方法检测肿瘤相关基因，应用于人食管癌标本。结果：1)采集了150例食管癌患者的血液和骨髓标本。目前未观察到早期肿瘤复发或转移的病例有显著差异。术后观察需要更长的时间进行更详细的研究。2)发现大鼠明胶酶A （MMP2）、角蛋白6a、Lyn B酪氨酸激酶等基因在癌变过程中高表达。比如ALDH基因。SLP在肿瘤发展过程中受到抑制。3) SPP1、CKS2等基因与肿瘤放射敏感性相关。4)转染MAL和FHIT基因可引起肿瘤细胞生物学的剧烈变化。对于FHIT基因，Ad-FHIT的凋亡活性机制是识别受Ad-FHIT治疗影响的候选癌症相关靶点。这些分子可能既是早期发现肿瘤发展的肿瘤标志物，也是治疗食管癌的良好分子靶点。

Esophageal cancer is considered to be one of the most aggressive malignacy in the Eastern countries, including Japan. Early detection of the tumor development as well as tumor recurences has been a key subject of the disease. The purpose of our current study is to establish molecular-based diagnositics for esophageal cancer and we have conveyed 4 major researches for this purpose : 1) the detection of the tumor cells (micrometastasis) in either blood or bone marrow of the patient for the postoperative disease surveillance, 2) the establishment of rat esophageal chemical-induced carcinoma model for the elucidation of the genes associated with esophageal carcinogenesis, 3) the detection of the genes responsible for radiation sensitivities, 4) the detection of tumor associated genes using DNA microarray methodology applied for the human esophageal tumor specimens. Results : 1) The blood and bone marrow samples were obtained from 150 patients with esophageal cancer. No significant differences were currently observed between the cases with early recurrence or metastasis of the tumor. More detailed-studies are needed for longer period of the postoperative observation. 2) Genes such as rat gelatinase A (MMP2), keratin 6a, Lyn B tyrosine kinase were found to be highly expressed in development of carcinoma. Genes such as ALDH. SLP were repressed along the tumor development. 3) Genes such as SPP1, CKS2 were found to be associated with tumor radio sensitivity. 4) Transfection of MAL and FHIT genes induce dramatic changes in tumor cell biology. For the gene FHIT, the mechanism of apoptotic activity by Ad-FHIT is to identify the candidate cancer associated targets affected by Ad-FHIT treatment. Those molecules may consider to be both tumor markers for the early detection of tumor development, and also a fine molecular target for the treatments of esophagel cancer.