Die Rolle von CD97 in der Entstehung, Invasion und Metastasierung kolorektaler Karzinome (CD97 - elucidating the role in colorectal carcinoma development, invasion and metastasis)

EGF-TM 7受体CD 97最初被我们描述为白细胞活化标志物。我们最近发现CD 97在未分化甲状腺癌和结直肠癌的造血系统外表达，但在相应的正常组织中不表达。在结直肠癌的浸润前沿存在高度CD 97阳性的散在肿瘤细胞与肿瘤微环境中CD 97配体CD 55的存在相关。临床上，CD 97的表达与肿瘤的高分期和淋巴管浸润一致。因此，我们的数据表明CD 97参与结直肠癌的进展。在这项研究合作中，对CD 97的分子和肿瘤生物学特别感兴趣的实验室将研究这种分子在结直肠癌的发展，侵袭性生长和转移中的作用。具体而言，将解决以下问题：A）将研究肿瘤细胞上CD 97上调的过程。我们将研究CD 97是否是通过Wnt途径调控的Tcf-4靶基因。B）将在原发性结直肠癌、转移和复发之间比较在侵袭前沿和实体瘤形成处的分散肿瘤细胞上的CD 97的分布，并将其与肿瘤微环境的特征相关。分散的肿瘤细胞形成的过程将在体外通过调节肿瘤环境来模拟。C）将在体内研究CD 97在肿瘤发生中的作用。我们将通过比较野生型和CD 97敲除小鼠来分析CD 97表达对已建立的结肠直肠小鼠肿瘤生长的影响。在转基因小鼠中，将研究肠细胞特异性CD 97表达对结直肠癌的发展、转移和侵袭的影响。D）将阐明所观察到的CD 97 EGF和CD 97茎部表位的表达/可及性差异的分子基础。该项目期间开展的工作将增加我们对CD 97作为肿瘤诊断和预后标志物以及新型治疗方法的潜在靶点的了解。

The EGF-TM7 receptor CD97 has been described originally by us as a leukocyte activation marker. We recently showed expression of CD97 outside the haematopoietic system on anaplastic thyroid and colorectal carcinomas but not in the corresponding normal tissues. The presence of highly CD97-positive scattered tumor cells at the invasion front of colorectal carcinomas correlates with the presence of the CD97 ligand, CD55, in the tumor microenvironment. Clinically, expression of CD97 coincides with high tumor stage and lymph vessel invasion. Thus, our data suggest the involvement of CD97 in colorectal cancer progression. Whithin this research collaboration, laboratories with a specific interest in the molecular and tumor biology of CD97 will investigate the role of this molecule in development, invasive growth and metastasis of colorectal carcinomas. Specifically, the following problems will be addressed: A) The process of CD97 upregulation on tumor cells will be studied. We will investigate whether CD97 is a Tcf-4 target gene regulated through the Wnt pathway. B) The distribution of CD97 on scattered tumor cells at the invasion front and solid tumor formations will be compared between primary colorectal carcinomas, metastases and recidives and related to characteristics of the tumor microenvironment. The process of scattered tumor-cell formation will be mimicked in vitro by modulation of the tumor environment. C) The role of CD97 in tumorigenesis will be studied in vivo. We will analyze the effect of CD97 expression on the outgrowth of established colorectal mouse tumors by comparing wild-type and CD97 knock-out mice. In transgenic mice, the consequences of enterocyte-specific CD97 expression on development, metastasis and invasion of colorectal carcinomas will be investigated. D) The molecular basis for the observed differences in the expression /accessibility of CD97EGF and CD97stalk epitopes will be clarified. Work carried out during this project will increase our knowledge about CD97 as a marker for tumor diagnosis and prognosis as well as a potential target for novel therapeutic approaches.