FATE OF TUMOR CELLS IN PULMONARY METASTASIS

肺转移中肿瘤细胞的命运

• 批准号: 6514823
• 负责人: RUTH J MUSCHEL
• 金额: $ 25.58万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2001
• 资助国家: 美国
• 起止时间: 2001-03-15 至 2006-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6514823
• 关键词: CD95 molecule; apoptosis; arterioles; cell adhesion; cell adhesion molecules; cell proliferation; fibrosarcoma; fluorescence microscopy; genetically modified animals; green fluorescent proteins; integrins; intravital microscopy; laboratory mouse; laboratory rat; lung neoplasms; lymphoma; melanoma; metastasis; peptides; pulmonary circulation; vascular endothelium

DESCRIPTION: (Adapted from the investigator's abstract) Malignant tumors disseminate throughout the body by hematogenous routes leading to distant tumor metastasis. The mechanisms that lead to colony formation after tumor cells have entered the circulation are only imperfectly understood. The lungs are a frequent site for metastasis by human tumors of most types and a common site in experimental murine models as well. The investigator has developed methods that allow direct visualization of tumor cells in the pulmonary circulation of mouse or rat lung cells during the process of hematogenous metastasis. In summary, metastatic tumor cells adhered to endothelia of the precapillary arterioles, and also to that of the capillaries. Extravasation occurred infrequently at 6-24h after introduction of the tumor cells, but colonies did not arise from the extravasated cells; instead the intravascular tumor cells attached to the endothelium gave rise to proliferating colonies that remained intravascular. The formulation of a model for metastasis in which tumor cells attach to the endothelium and initially proliferate within the circulation leads to the prediction that metastasis could be blocked by specific targeting of these steps. Metastatic inefficiency, the process whereby most circulating tumor cells fail to establish metastatic colonies was also revealed in this system. Although virtually all cells introduced into the circulation attached in the lungs, at later times many of these cells had disappeared. These tumor cells die by apoptosis leading the investigator to hypothesize that death by apoptosis is an important component of metastatic inefficiency and could be a rate-limiting step in metastasis. Although many non-metastatic, but tumorigenic cell lines have been isolated and described, it is not known which step is the barrier to metastasis. Better definition of the early rate limiting steps should lead to more precise means for designing anti-metastasis therapies.

描述：（改编自调查员的摘要）恶性肿瘤 通过血源路线传播到整个身体，导致远处肿瘤 转移。导致肿瘤细胞后菌落形成的机制具有 输入循环只有不完美的理解。肺是 大多数类型的人类肿瘤经常发生转移的位点，并且 实验鼠模型也是如此。研究人员开发了方法 允许在小鼠的肺循环中直接可视化肿瘤细胞 在血源转移过程中或大鼠肺细胞。总之， 转移性肿瘤细胞粘附在毛细管前动脉的内皮上， 以及毛细血管的。渗出很少发生 引入肿瘤细胞后的6-24h，但并非菌落来自 外内部细胞；相反，附着的血管内肿瘤细胞 内皮引起了血管内的增殖菌落。 肿瘤细胞附着于转移的模型的表述 内皮和最初在循环中增殖导致 预测可以通过特定靶向这些转移来阻止这些转移 步骤。 转移性效率低下，大多数循环肿瘤细胞失败的过程 在该系统中还揭示了建立转移性菌落。虽然 几乎所有引入肺部循环中的细胞，在 后来，许多细胞都消失了。这些肿瘤细胞死亡 凋亡导致研究者假设凋亡死亡是一种 转移性效率低下的重要组成部分，可能是限制速率 踏上转移。虽然许多非转移性但肿瘤细胞系 已经被隔离和描述了，尚不清楚哪个步骤是 转移。更好的早期限制步骤的定义应导致 更精确的手段用于设计抗碎裂疗法。