NATURAL SITE PREFERENCE IN MAMMARY CANCER BIOLOGY

小鼠乳腺肿瘤表现出对生长的偏好， 自然解剖部位乳房脂肪垫 免疫 机制不能充分解释这些现场效应。 我们 重点研究上皮内和间质-上皮的作用 细胞相互作用 我们的第一个具体目标是确定 可溶性因子在生长相互作用中的作用。 我们有 开发了一种用于扩散生长因子的测定方法， 生产细胞和应答细胞以三维阵列生长， 胶原凝胶基质。 正常乳腺细胞对肿瘤的作用 细胞和癌前HAN细胞生长 反映体内事件;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HAN细胞仅受基质细胞刺激。 初步证据表明， 其中肿瘤细胞诱导正常乳腺的成分， 产生肿瘤细胞的促有丝分裂因子。 该诱导 涉及由肿瘤细胞产生的可溶性因子。 第二 具体目的是确定正常乳腺间质和 上皮细胞也改变癌前和肿瘤的生长， 细胞通过接触依赖机制。 利用乳腺肿瘤 具有耐药标记物的品系，以研究接触依赖性 乳腺组织之间的代谢合作，我们发现， 肿瘤细胞与正常乳腺细胞一样能够交流， 癌前HAN细胞，但肿瘤细胞可能较少 比正常或癌前细胞对间隙调节剂的反应更敏感 连接通信 第三个具体目标是探索 进一步证实了肿瘤细胞对 接触介导的调节剂（耦合剂和解耦合剂） 细胞间通讯 相互作用的自我平衡过程， 从囊胚形成时开始， 通常能够在整个生命过程中保持组织完整性， 被视为“非免疫监视”机制， 肿瘤形成 组织相互作用的操纵可能导致新的 针对癌症生长和进展的治疗策略。 我们 实验方法是基于细胞 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 在肿瘤进展中的重要作用， 乳腺的正常生长和发育。

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.