NATURAL SITE PREFERENCE IN MAMMARY CANCER BIOLOGY

乳腺癌生物学中的自然位点偏好

• 批准号: 3168104
• 负责人: FRED Raymond MILLER
• 金额: $ 20.39万
• 依托单位: BARBARA ANN KARMANOS CANCER INSTITUTE
• 依托单位国家: 美国
• 财政年份: 1980
• 资助国家: 美国
• 起止时间: 1980-06-01 至 1994-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3168104
• 关键词: adipose tissue; breast neoplasms; cellular oncology; collagen; contact inhibition; embryo /fetus; extracellular matrix; growth factor; growth media; hormone related neoplasm /cancer; intercellular connection; laboratory mouse; lactation; mammary epithelium; mammary gland; mixed tissue /cell culture; neoplasm /cancer immunology; neoplasm /cancer pharmacology; neoplasm /cancer transplantation; neoplastic cell; neoplastic growth; neoplastic transformation; preneoplastic state; tissue /cell preparation

Mouse mammary tumors demonstrate a preference for growth in their natural anatomic site, the mammary fatpad. Immunological mechanisms do not adequately explain these site effects. We are focusing on the role of intraepithelial and stromal-epithelial cellular interactions. Our first specific aim is to determine the role of soluble factors in the growth interactions. 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 tumor cell and preneoplastic HAN 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 HAN cells are stimulated only by the stromal cells. Preliminary evidence suggests a reciprocal paracrine interaction in which tumor cells induce an element of normal mammary gland to produce a factor mitogenic for tumor cells. This induction involves a soluble factor produced by the tumor cells. A second specific aim is to determine if normal mammary stroma and epithelium also alter the growth of preneoplastic and neoplastic cells via contact-dependent mechanisms. By utilizing mammary tumor lines with drug resistance markers to study contact-dependent metabolic cooperation between mammary tissues, we have found that tumor cells are as able to communicate as normal mammary or preneoplastic HAN cells, but that tumor cells may be less responsive than normal or preneoplastic cells to regulators of gap junctional communication. A third specific aim is to explore further the possibility that tumor cells are refractory to regulators (coupler and uncouplers) of contact-mediated intercellular communication. Interactive homeostatic processes, which occur between cells from the time of blastula formation, are usually able to maintain tissue integrity throughout life and can be regarded as mechanisms of "non-immune surveillance" against neoplasia. Manipulation of tissue interactions could lead to new therapeutic strategies against cancer growth and progression. Our experimental approaches are based on the principles that cell shape, tissue architecture, extracellular matrix, and stromal- epithelial and intraepithelial interactions may all play significant roles in neoplastic progression as well as in the normal growth and development of the mammary gland.

小鼠乳腺肿瘤表现出对其生长的偏好 天然解剖部位，乳房脂肪垫。免疫学 机制不能充分解释这些场地效应。我们是 关注上皮内和间质上皮的作用 细胞间的相互作用。我们的第一个具体目标是确定 可溶性因子在生长互作中的作用。我们有 开发了一种可扩散生长因子的检测方法，其中既有 生产者和响应者细胞在3维阵列中生长 胶原蛋白凝胶基质。正常乳腺细胞对肿瘤的影响 本方法能准确测定汉族人细胞及癌前病变细胞生长 反映活体事件；也就是说，正常的乳腺上皮 正常乳腺间质刺激乳腺肿瘤细胞生长 但HAN细胞只受到基质细胞的刺激。 初步证据表明存在一种相互旁分泌作用 其中肿瘤细胞诱导正常乳腺的一种成分 为肿瘤细胞产生一种促分裂因子。这种归纳法 涉及一种由肿瘤细胞产生的可溶性因子。一秒钟 具体目的是确定正常的乳腺间质和 上皮细胞也改变癌前病变和肿瘤的生长 细胞通过接触依赖机制。利用乳腺肿瘤 携带耐药标记的品系研究接触依赖 乳腺组织之间的代谢合作，我们发现 肿瘤细胞的沟通能力与正常乳腺或 癌前韩氏细胞，但肿瘤细胞可能较少 比正常或癌前细胞对GAP调节因子的反应 交汇点通信。第三个具体目标是探索 此外，肿瘤细胞对 接触式调整器(耦合器和解偶器) 细胞间通信。互动的动态平衡过程， 从囊胚形成时起发生在细胞之间的 通常能够在一生中保持组织的完整性，并且可以 被视为“非免疫监视”机制 肿瘤。对组织相互作用的操纵可能带来新的 针对癌症生长和进展的治疗策略。我们的 实验方法基于这样的原理，即细胞 形状、组织结构、细胞外基质和基质- 上皮和上皮内的相互作用都可能起作用 在肿瘤进展中的重要作用以及在 乳腺的正常生长和发育。