ONCOGENES & GROWTH FACTORS IN HUMAN GYNECOLOGIC CANCERS

癌基因

• 批准号: 3458654
• 负责人: LUNDY A BRAUN
• 金额: $ 10.22万
• 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/3458654
• 关键词: Papillomavirus; antisense nucleic acid; 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.

某些人乳头瘤病毒 (HPV) 类型始终是 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中检测到。 正常组织和仅一小部分 HPV 感染病变 进展为癌症，这表明其他因素是 参与本病的进展。 在这个提案中，角色 细胞癌基因和生长因子在发病机制中的作用 女性生殖道癌症，特别是外阴和 将探查子宫颈。 已激活的原癌基因 在多种人类来源的肿瘤细胞系中检测到 如原发性人类肿瘤。 然而癌基因激活是否 肿瘤发生的必要步骤尚不清楚。 我们分析过 来自 14 名患者的 21 份活组织检查，有阴道镜证据 用于扩增 myc 或 Ha-ras 原型的尖锐湿疣 通过 Southern blot 杂交检测癌基因。 所有标本均 HPV 分型。 我们迄今为止的结果表明癌基因改变 a) 仅在 HPV-16 中检测到，在 HPV-6 或 HPV-11 感染中未检测到 组织，b) 在癌前病变中未检测到，并且 c) 可以 一名患者的两次活检同时发生。 我们将 将这项研究扩大到包括大约 100 个宫颈和 外阴上皮内瘤变以确定是否激活 ras、myc 和 的（突变、扩增或重排） HPV 感染生殖器子集中的 erbB/EGF 受体基因 导管病变参与癌症的起源或进展 体内的女性生殖道。 我们还将研究 这些基因以及两个转化基因的表达 通过 Northern blot 检测生长因子、TGF-α 和 TGF-β 使用反义RNA的杂交和原位杂交 探针。 最后，乳头瘤病毒相关的体外模型 将开发使用基因转移技术的转化 以及含有 HPV 的宫颈反应的改变 上皮细胞在致癌过程中对生长因子的影响进行了测试。 这些研究应该让我们更好地了解细胞 对 HPV 感染的反应并有助于阐明人类的作用 乳头瘤病毒在生殖道发病机制中的作用 恶性肿瘤。