LYMPHOKINE-TISSUE INTERACTIONS IN PRENEOPLASIA

肿瘤前期的淋巴因子与组织的相互作用

• 批准号: 3204700
• 负责人: FRED Raymond MILLER
• 金额: $ 19.77万
• 依托单位: BARBARA ANN KARMANOS CANCER INSTITUTE
• 依托单位国家: 美国
• 财政年份: 1993
• 资助国家: 美国
• 起止时间: 1993-07-01 至 1997-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3204700
• 关键词: adipocytes; athymic mouse; cell adhesion molecules; cell cell interaction; cell growth regulation; cellular oncology; clone cells; connective tissue stroma; cytotoxic T lymphocyte; fibroblasts; laboratory mouse; lymphocyte; lymphokines; mammary gland; molecular oncology; neoplasm /cancer immunology; neoplastic process; preneoplastic state; tissue /cell culture

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.

正常乳腺的组织相互作用是重要的调节 维持腺体稳态的机制。 在鼠标中，两者都 正常和癌前乳腺上皮是基质依赖性的，即， 它们只在体内的乳腺脂肪垫中生长，但它们被 正常上皮。 因此，正常和癌前细胞必须 注射到没有腺体成分的乳腺中。 乳腺 肿瘤细胞不再依赖于基质，但仍然是基质， 由于乳腺脂肪垫中的基质刺激生长， 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， 肿瘤细胞的生长受到刺激而不是抑制， 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 在乳腺组织内环境稳定和随后的变化， 进展，我们已经开发了一种测定扩散性生长因子， 生产细胞和应答细胞都以三维阵列生长， 胶原蛋白凝胶基质。 正常乳腺细胞在肿瘤发生中的作用 并且该测定中的癌前细胞生长准确地反映了体内 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，但不刺激正常乳腺细胞生长 上皮或癌前HAN（增生性肺泡结节）细胞。 然而，在使用单层培养物的平行实验中， 细胞在体外受到正常乳腺细胞的抑制。 因此，基质、细胞 形状和/或多细胞结构对体内平衡至关重要 交互. 胶原凝胶测定的结果还表明， 用乳腺基质成纤维细胞系刺激乳腺肿瘤细胞， 但是癌前细胞需要额外的基质成分， 刺激发生。 我们开发了第二代 可检测契约依赖性相互作用的胶原测定 以及由可溶性因子介导的那些，并提出定义 负责刺激乳腺上皮生长的基质成分 细胞 此外，原位乳腺间质是一种复杂的结构 成纤维细胞、脂肪细胞、脉管系统和浸润性淋巴因子在 不同发育阶段乳腺上皮细胞的生长调节 进步将是这项建议的重点。