CD44 ALTERNATIVE SPLICING IN COLORECTAL CARCINOMAS

结直肠癌中的 CD44 替代剪接

• 批准号: 2458125
• 负责人: KENNETH K TANABE
• 金额: $ 12.16万
• 依托单位: MASSACHUSETTS GENERAL HOSPITAL
• 依托单位国家: 美国
• 财政年份: 1994
• 资助国家: 美国
• 起止时间: 1994-08-01 至 1999-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2458125
• 关键词: CD antigens; CD44 molecule; antisense nucleic acid; athymic mouse; cell adhesion molecules; chimeric proteins; colorectal neoplasms; feces; human tissue; immunoglobulins; laboratory mouse; leukocyte adhesion molecules; mass screening; metastasis; mucopolysaccharides; neoplasm /cancer diagnosis; pathology; prognosis; protein isoforms; surface property; transfection

The objective of this proposal is to investigate the role of an adhesion molecule, CD44, in human colorectal carcinoma metastasis with the goal of improving detection and treatment of patients with this disease. CD44 is a cell surface adhesion molecule that is normally present in several isoforms and is postulated to facilitate normal lymphocyte recirculation by modulating adhesion of lymphocytes to specialized lymph node endothelium. Experimental data support the notion that tumor cells may gain access to lymph nodes by mimicking lymphocytes in their cell surface expression of a specific CD44 isoform, CD44R1. By developing CD44R1 specific antibodies as well as experimentally manipulating CD44R1 expression in colorectal carcinoma cells, we propose to improve our understanding of colorectal carcinoma metastasis in a manner that 1) increases the clinically useful prognostic information obtained from primary colorectal tumors; 2) provides a model for treatment of colorectal carcinoma metastases; and 3) enhances detection of asymptomatic patients with colorectal carcinoma. First, we will measure CD44R1 transcript and protein expression in clinical specimens representing primary colorectal tumors, metastases, and normal colonic mucosa. CD44R1-specific antisera will be developed using recombinant fusion proteins for the protein measurements. CD44R1 expression levels will be correlated with clinical and pathological parameters of metastatic disease. Second, we will examine the function of CD44R1 in vivo in a human colorectal carcinoma cell line, KM12, implanted into nude mice. We will examine the ability to modulate metastatic potential by experimentally manipulating CD44R1 expression in these cells. We will also assess the ability to block metastasis in this model using CD44-immunoglobulin fusion proteins. Third, we will use the specific CD44 antisera to develop an assay to detect colorectal carcinoma cells shed into the stool by virtue of their abnormal CD44R1 expression. We will use these results to develop a screening test to detect patients with colorectal carcinomas by examining stool smears. The proposed project will shed new light on mechanisms of human colorectal carcinoma metastasis in a manner that will aid in the detection and therapy of patients with this disease.

该提案的目的是研究粘附的作用 分子，CD44，在人结直肠癌转移中的作用，其目标是 改善这种疾病患者的检测和治疗。 CD44是 细胞表面粘附分子，通常存在于多种细胞中 亚型并被假定促进正常淋巴细胞再循环 通过调节淋巴细胞与特殊淋巴结的粘附 内皮细胞。实验数据支持肿瘤细胞可能 通过模仿细胞表面的淋巴细胞来进入淋巴结 特定 CD44 同种型 CD44R1 的表达。 通过开发CD44R1 特异性抗体以及实验性操纵 CD44R1 在结直肠癌细胞中的表达，我们建议改善我们的 通过以下方式了解结直肠癌转移：1) 增加了从以下来源获得的临床有用的预后信息 原发性结直肠肿瘤； 2）为结直肠癌的治疗提供了模型 癌转移； 3）加强对无症状患者的检测 患有结直肠癌。 首先，我们将测量 CD44R1 转录本和蛋白质的表达 代表原发性结直肠肿瘤、转移瘤和转移瘤的临床标本 正常结肠粘膜。 CD44R1特异性抗血清将使用 用于蛋白质测量的重组融合蛋白。 CD44R1 表达水平与临床和病理相关 转移性疾病的参数。 其次，我们将检查 CD44R1 在人体体内的功能 结直肠癌细胞系KM12，植入裸鼠体内。我们将 通过实验检查调节转移电位的能力 操纵这些细胞中的 CD44R1 表达。我们还将评估 使用 CD44-免疫球蛋白融合阻断该模型中的转移的能力 蛋白质。 第三，我们将使用特定的 CD44 抗血清来开发一种检测方法 凭借其自身特性检测脱落到粪便中的结直肠癌细胞 CD44R1 表达异常。我们将利用这些结果来开发 通过检查发现结直肠癌患者的筛查测试 粪便涂片。 拟议的项目将为人类结直肠癌的机制提供新的线索 癌症转移的方式有助于检测和 对患有这种疾病的患者进行治疗。