ONCOGENES & GROWTH FACTORS IN HUMAN GYNECOLOGIC CANCERS

癌基因

• 批准号: 3458652
• 负责人: LUNDY A BRAUN
• 金额: $ 10.5万
• 依托单位: BROWN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1988
• 资助国家: 美国
• 起止时间: 1988-08-01 至 1993-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3458652
• 关键词: Papillomavirus; biopsy; cell growth regulation; cervix neoplasms; condyloma acuminatum; cytodiagnosis; cytogenetics; epidermal growth factor; female reproductive system neoplasm; gene expression; gene mutation; genetic manipulation; growth factor receptors; histopathology; human tissue; keratinocyte; molecular cloning; natural gene amplification; neoplasm /cancer genetics; neoplastic cell culture for noncancer research; nucleic acid hybridization; nucleic acid probes; oncogenes; preneoplastic state; protooncogene; tissue /cell culture; transfection; transforming growth factors; viral carcinogenesis; virus classification; virus cytopathogenic effect; vulva neoplasms

Certain human papillomavirus (HPV) types are consistently associated with squamous cell carcinoma of the female genital tract. However, these viruses are also detected in histologically normal tissues and only a small proportion of HPV-infected lesions progress to cancer which suggests that additional factors are involved in progression of this disease. In this proposal, the role of cellular oncogenes and growth factors in the pathogenesis of female genital tract cancers, particularly those of the vulva and cervix will be explored. Activated proto-oncogenes have been detected in a variety of tumor cell lines of human origin, as well as in primary human tumors. Yet whether oncogene activation is a necessary step in tumorigenesis is not known. We have analyzed 21 biopsies from 14 patients with colposcopic evidence of condyloma for amplification of the myc or Ha-ras proto- oncogenes by Southern blot hybridization. All specimens were HPV typed. Our results to date indicate that oncogene alterations a) are only detected in HPV-16, not HPV-6 or HPV-11 infected tissues, b) are not detected in premalignant lesions, and c) can occur simultaneously in two biopsies from one patient. We will expand this study to include approximately 100 cervical and vulvar intraepithelial neoplasias to determine if activation (mutation, amplification or rearrangement) of the ras, myc, and erbB/EGF receptor genes in a subset of HPV infected genital tract lesions is involved in the origin or progression of carcinoma of the female genital tract in vivo. We will also study the expression of these genes as well as that of two transforming growth factors, TGF-alpha and TGF-beta by Northern blot hybridization and in situ hybridization using antisense RNA probes. Finally, an in vitro model for papillomavirus-associated transformation using gene transfer techniques will be developed and alterations in the response of HPV-containing cervical epithelial cells to growth factors during carcinogenesis tested. These studies should give us a better understanding of the cellular response to HPV infection and help elucidate the role of human papilloma-viruses in the pathogenesis of genital tract malignancies.

人乳头瘤病毒（HPV）是一种常见的病毒。 与女性生殖器鳞状细胞癌相关 道。 然而，这些病毒也在组织学上被检测到。 正常组织和只有一小部分HPV感染的病变 癌症的进展，这表明其他因素是 参与了这种疾病的发展。 在本提案中，角色 细胞癌基因和生长因子的发病机制 女性生殖道癌症，特别是外阴癌， 将对宫颈进行探查。 激活的原癌基因 在多种人类起源的肿瘤细胞系中也检测到， 与原发性人类肿瘤一样。 然而，癌基因激活是否 肿瘤发生的必要步骤尚不清楚。 我们已经分析 来自14名患者的21份活检，阴道镜证据显示 尖锐湿疣的扩增myc或Ha-ras原， 通过Southern印迹杂交检测癌基因。 所有标本均 HPV分型。 我们的研究结果表明癌基因的改变 a）仅在HPV-16中检测到，而不是HPV-6或HPV-11感染 组织，B）在癌前病变中未检测到，和c）可以 同时发生在一个病人的两个活检中。 我们将 扩大这项研究，包括大约100个宫颈和 外阴上皮内瘤变，以确定是否激活 ras、myc和 生殖道HPV感染中erbB/EGF受体基因的研究 肿瘤的发生和发展与肿瘤的发生和发展有关 女性生殖道的一个重要组成部分 我们亦会研究 这些基因的表达以及两个转化基因的表达， 生长因子、TGF-α和TGF-β（北方印迹法） 使用反义RNA的杂交和原位杂交 probes. 最后，建立了乳头瘤病毒相关的体外模型 将开发利用基因转移技术的转化 以及含HPV宫颈癌细胞反应的改变 上皮细胞在致癌过程中的生长因子测试。 这些研究应该让我们更好地了解细胞 对HPV感染的反应，并帮助阐明人类 乳头瘤病毒在生殖道发病中的作用 恶性肿瘤。