Engineering sensitive microfluidic multiplex technology for isolating circulating

描述(由申请人提供) 摘要：尽管在了解癌症的分子基础和癌症治疗方面取得了很大进展，但对转移过程的复杂性仍然知之甚少。尤其是在结直肠癌中，由于对导致疾病通过血流转移的细胞的有限了解，它受到了严重阻碍。多个谱系的循环细胞被认为参与血管生成、肿瘤生长和转移。其中，从原发癌和转移癌脱落的循环肿瘤细胞(CTCs)可能引起血液转移，其中来自成人骨髓的循环内皮祖细胞(CEPC)启动了转移前的生态位。因此，种子(CTCs)和土壤(CEPC)的概念。虽然目前的模型解释了转移的不同和重要的方面，但没有一个单一的模型可以解释人类癌症进展和转移过程中明显的细胞变化的总和。我将研究CTCs和CEPC之间千丝万缕的关系，以及它们在肿瘤发生和转移中的作用。我建议采取一种激进的、但集成的技术和生物学为基础的翻译方法，使用微流控工程工具来识别和研究这些外周血中稀有细胞的生物学相关性。这一方法将寻求(1)结肠癌早期和晚期的CEPC和CTCs水平是否与肿瘤体积和临床病程相互关联(2)在治疗过程中其负荷的动态变化可以预测治疗的临床结果(3)这些细胞的表型和生物学特性是否有任何变化来区分预后亚型(4)CEPC在共培养时对CTCs的影响及其相互作用的基础生物学(5)我们能否在体外扩增这些细胞以鉴定真正的“转移前体细胞”或“癌症干细胞”并确定血管生成和转移的生物标志物作为潜在的治疗靶点。 公共卫生相关性：可能不会给个别参与者带来直接的医疗利益。然而，通过这个研究项目，我希望能更多地了解新的转移标志物。利用一种新的集成微流控技术，将研究循环细胞在癌症发生和转移中的生物学意义。为了可能提高参与者和未来癌症患者的诊断、预后和治疗能力，参与研究项目的风险是合理的。

DESCRIPTION (Provided by the applicant) Abstract: Despite major strides in understanding of the molecular basis of cancer and cancer therapeutics, the complexities of metastatic process remain poorly understood. Especially in colorectal cancer, it has been severely hampered by limited knowledge about the cells that cause the disease to metastasize through the blood stream. Circulating cells of several lineages are thought to participate in angiogenesis, tumor growth and metastasis. Among these, circulating tumor cells (CTCs) shed from the primary and metastatic carcinomas presumably give rise to blood borne metastases, where as circulating endothelial progenitor cells (CEPCs) from adult bone marrow initiating the pre-metastatic niche. Hence the seed (CTCs) and soil (CEPCs) concept. Although current models explain distinct and important aspects of metastasis, no single model can explain the sum of the cellular changes apparent in human cancer progression and metastasis. I will investigate the inextricable relationship between CTCs, and CEPCs, and their roles in carcinogenesis and metastasis. I propose to take a radical, but integrated technology and biology based translational approach using microfluidic engineering tools to identify, and study the biological relevance of these rare cells in peripheral blood. This approach will seek the following (1) Does the levels of CEPCs and CTCs in early and late stages of colon cancer correlate with each other along with tumor volume and clinical course (2) Can dynamic changes in their load during the course of treatment plan can predict the clinical outcome of the therapy (3) Are there any changes to phenotypic and biological characteristics of these cells that distinguish prognostic subtypes (4) What is the effect of CEPCs on CTCs when cocultured and the fundamental biology of interaction (5) Can we expand these cells in vitro to identify the true "metastatic precursors" or "cancer stem cells" and to determine biomarkers of angiogenesis and metastasis as potential therapeutic targets. Public Health Relevance: There may not be a direct medical benefit to individual participants. However, through this research program, I expect to learn more about novel metastatic markers. Using a novel integrated microfluidic technology, the biological significance of circulating cells in carcinogenesis and metastasis will be investigated. The risks of participating in the research project are reasonable to assume in order to possibly improve diagnostic, prognostic and treatment capabilities for the participants and future patients with cancer.