LYMPHOKINE-TISSUE INTERACTIONS IN PRENEOPLASIA

正常乳腺中的组织相互作用是重要的调节因素 维持腺体内环境平衡的机制。在鼠标中，两者都 正常和癌前病变的乳腺上皮依赖于基质，即， 它们只在体内的乳房脂肪垫中生长，但它们受到 正常的上皮细胞。因此，为了生长，正常细胞和癌前细胞必须 注射到不含腺体成分的乳腺中。乳房 肿瘤细胞不再依赖于间质，但仍然是间质- 反应，因为乳房脂肪垫中的基质刺激了生长 皮下部位。与正常乳腺上皮的相互作用是， 另一方面，与癌前上皮相反的是自生长以来 对肿瘤细胞的刺激作用而不是抑制作用 正常乳腺上皮细胞。 明确上皮内和间质-上皮相互作用的作用 在乳房组织的动态平衡和随后的改变 进展，我们已经开发了一种检测弥漫性生长因子的方法 其中生产者和响应者细胞都以3维阵列生长 胶原蛋白凝胶基质。正常乳腺细胞在肿瘤发生中的作用 该方法能准确反映体内癌前病变细胞的生长情况。 事件；即正常乳腺上皮和正常乳腺间质 刺激乳腺肿瘤细胞生长，但不刺激正常乳腺生长 上皮细胞或癌前病变HAN(增生性肺泡结节)细胞。 然而，在使用单层培养的平行实验中，肿瘤 正常乳腺细胞在体外对细胞有抑制作用。因此，矩阵、单元 形状和/或多细胞结构对动态平衡至关重要 互动。胶原蛋白凝胶实验结果也表明 乳腺基质成纤维细胞株对乳腺肿瘤细胞的刺激作用 但癌前细胞需要额外的基质元素才能 刺激才会发生。我们已经开发了第二代 胶原蛋白检测，可检测依赖于合同的相互作用 以及由可溶性因子介导的那些，并建议定义 刺激乳腺上皮细胞生长的基质因子 细胞。此外，原位乳腺间质是一个复杂的结构。 成纤维细胞、脂肪细胞、血管和浸润性淋巴因子 乳腺上皮细胞在不同发育阶段的生长调控 进展将是这项提案的重点。

Tissue interactions in normal mammary gland are important regulatory mechanisms in homeostatic maintenance of the gland. In the mouse, both normal and preneoplastic mammary epithelia are stroma-dependent, that is, they only grow in mammary fatpads in vivo, but they are inhibited by normal epithelium. Thus, for growth, normal and preneoplastic cells must be injected into mammary glands free of glandular elements. Mammary tumor cells are no longer stroma-dependent but are still stroma- responsive since growth is stimulated by stroma in mammary fatpads versus subcutaneous sites. The interaction with normal mammary epithelium is, on the other hand, the opposite of preneoplastic epithelium since growth of neoplastic cells is stimulated rather than inhibited in the presence of normal mammary epithelium. To define the role of intraepithelial and stromal-epithelial interactions in breast tissue homeostasis and subsequent alterations during progression, we have developed an assay for diffusible growth factors in which both producer and responder cells grow in a 3-dimensional array in collagen gel matrix. The effect of normal mammary cells on neoplastic and preneoplastic cell growth in this assay accurately reflects in vivo events; that is, both normal mammary epithelium and normal mammary stroma stimulate growth of mammary tumor cells but not of normal mammary epithelium or preneoplastic HAN (hyperplastic alveolar nodules) cells. However, in parallel experiments using monolayer cultures, neoplastic cells are inhibited by normal mammary cells in vitro. Thus, matrix, cell shape, and/or multicellular architecture are critical to homeostatic interactions. Results with the collagen gel assay also indicate that mammary tumor cells are stimulated by a mammary stromal fibroblast line but that preneoplastic cells require additional stromal elements for stimulation to occur. We have developed a second generation of the collagen assay which allows detection of contract-dependent interactions as well as those mediated by soluble factors and propose to define stromal elements responsible for stimulating growth of mammary epithelial cells. Furthermore, the mammary stroma in situ is a complex structure of fibroblasts, lipocytes, vasculature, and infiltrating lymphokines in the growth regulation of mammary epithelial cells at different stages of progression will be the focus of this proposal.