STROMAL INFLUENCE ON EXPRESSION OF PRENEOPLASIA

认为癌的发生既涉及启动的上皮细胞， 其支持基质具有大量的临床间接支持， 实验研究和观察，但还没有很好地- 有特点的或者理解的。 例如，乳腺癌， 是女性的一种主要肿瘤性疾病，常具有较强的间质 但最近的数据表明，异常基质甚至可能 在家族性乳腺癌的恶性发展之前。 两 已经提出了关于基质在 上皮中的肿瘤过程。 一方面正常组织 相互作用，即细胞、细胞类型和细胞之间的相互作用。 细胞外基质（ECM），可以抑制启动上皮细胞形成 表达肿瘤前表型。 相反，异常的间质可能 促进癌前病变的表达和/或其进展， 肿瘤形成 拟议的研究解决了后一个假设。 的目的 该建议是为了确定异常基质对 启动了乳腺上皮细胞表达其改变的 表型。 考虑到细胞外环境在 维持正常的组织特异性功能，假设ECM 介导异常间质和起始细胞之间的相互作用 也将被审查。 将研究间质对癌前病变表达的影响 在体内使用清除的鼠乳腺脂肪垫;这种方法的优点 乳腺独特的结构使得 很容易将上皮与基质分离，使脂肪垫保持完整， 随后移植起始的上皮细胞。 建立 异常间质模型，受体间质将被照射 分级剂量的X射线。 辐射暴露已被证明会诱发 间质和基底膜ECM质量的变化。 随后，暴露于x射线或化学物质的上皮细胞 致癌物质7，12-二甲基苯并蒽会被移植到脂肪垫上 在不同的时间。 受损和正常间质脂肪中的上皮生长 将评价衬垫的癌前病变频率， 以克隆性扩张（增生）或局灶性病变为特征， 表现出异常的细胞学特征（发育异常）， 进展为瘤形成。 这些研究将对比 化学和辐射引发的肿瘤的进展和发生 在异常间质的情况下的上皮细胞。 ECM的特性 由体内经辐照的基质、培养的细胞和由重组 组织将使用组织学、免疫化学和分子生物学方法进行分析。 测定。 这些研究将阐明异常间质细胞的作用， 可能通过ECM介导的小鼠乳腺上皮相互作用 通过提供关于表达、进展和致瘤性的数据， 辐射和化学致癌物暴露的上皮细胞在辐射 基质。

The theory that carcinogenesis involves both the initiated epithelial cell and its supporting stroma has substantial indirect support from clinical observations and experimental studies but has not yet been well- characterized or understood. For example, carcinoma of the breast, which is a major neoplastic disease of women, often has a strong stromal component but recent data indicate that the abnormal stroma may even precede the development of malignancy in familial breast cancer. Two related hypotheses have been proposed regarding the role of stroma in neoplastic processes in epithelia. On the one hand normal tissue interactions, i.e. interactions between cells, cell types and the extracellular matrix (ECM), may inhibit initiated epithelial cells form expressing the preneoplastic phenotype. Conversely, an abnormal stroma may promote expression of preneoplastic lesions and/or their progression to neoplasia. The proposed studies address the latter hypothesis. The aim of this proposal is to determine the influence of an abnormal stroma on the initiated mammary epithelial cell's capacity to express its altered phenotype. Given the significance of the extracellular milieu in maintaining normal tissue-specific function, the hypothesis that the ECM mediates the interaction between the abnormal stroma and initiated cells will also be examined. Stromal influences on the expression of preneoplasia will be investigated in vivo using cleared murine mammary gland fat pads; the advantage of this is that the distinctive architecture of mammary gland makes it possible to easily separate epithelium from stroma, leaving the fat pad intact for subsequent transplantation of initiated epithelial cells. To establish a model of abnormal stroma the recipient stroma will be irradiated with graded doses of x-rays. Radiation exposure has been shown to induce changes in the quality of both interstitial and basement membrane ECMs. Subsequently, epithelial cells exposed to x-irradiation or the chemical carcinogen 7,12-dimethylbenzanthracene will be transplanted to the fat pad at various times. Epithelial outgrowths in damaged and normal stromal fat pads will be evaluated for the frequency of preneoplastic lesions as characterized by clonal expansion (hyperplasia) or focal lesions that exhibit abnormal cytological characteristics (dysplasia) and their progression to neoplasia. These studies will contrast the patterns of progression and tumorigenesis of chemically and radiation initiated epithelia in the context of an abnormal stroma. The character of the ECM produced by irradiated stroma in vivo, cultured cells and by recombinant tissues will be analyzed using histological, immunochemical and molecular assays. The studies proposed will clarify the role of abnormal stromal- epithelial interactions, mediated possibly through ECM, in mouse mammary gland by providing data on the expression, progression and tumorigenicity of radiation and chemical carcinogen exposed epithelia in an irradiated stroma.