ONCOGENES & GROWTH FACTORS IN HUMAN GYNECOLOGIC CANCERS

某些人类乳头瘤病毒(HPV)类型一直是 与女性生殖器鳞状细胞癌相关 一条小路。然而，这些病毒在组织学上也被检测到 正常组织和仅有一小部分HPV感染病变 癌症的进展，这表明其他因素是 参与了这种疾病的发展。在这个提案中，角色是 细胞癌基因和生长因子在肿瘤发病机制中的作用 女性生殖道癌，特别是外阴癌和 将对宫颈进行探查。激活的原癌基因已经被 在各种人类起源的肿瘤细胞系中也检测到 就像人类的原发肿瘤一样。然而，癌基因激活是否 肿瘤发生过程中的一个必要步骤尚不清楚。我们已经分析了 镜检查证实的14例患者的21例活检 用于Myc或Ha-ras原扩增的尖锐湿疣- 癌基因的Southern杂交分析。所有标本都是 HPV分型。到目前为止，我们的结果表明癌基因的改变 A)仅在HPV-16中检测到，而不是在感染HPV-6或HPV-11中检测到 组织，b)在癌前病变中未检测到，以及c)可以 同时发生在一名患者的两份活组织检查中。我们会 将这项研究扩大到包括大约100名宫颈和 外阴上皮内瘤变是否激活 (突变、扩增或重排)ras、myc和 人乳头瘤病毒感染生殖器中ErbB/EGF受体基因的研究 肠道病变与癌症的发生或发展有关。 活体内的女性生殖道。我们亦会研究 这些基因的表达以及两个转化株的表达 Northern印迹法检测生长因子、转化生长因子-α和转化生长因子-β 利用反义RNA进行杂交和原位杂交 探测器。最后，建立了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HPV阳性宫颈病变反应的改变 对癌变过程中的上皮细胞生长因子进行检测。 这些研究应该会让我们更好地理解细胞 对HPV感染的反应并有助于阐明人类的作用 乳头状瘤病毒在生殖道疾病发病中的作用 恶性肿瘤。

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.