Microfluidic Models of Metastatic Cancer

描述(申请人提供)：转移性疾病仍然是大多数类型癌症患者的主要死亡原因。转移是通过一系列相互关联的步骤发生的，包括癌细胞在循环中的存活，与血管内皮细胞的黏附，以及癌细胞的生长形成转移。成功阻断这些步骤中的任何一个都将阻止转移性疾病，并有可能治愈癌症。转移的研究主要集中在原发肿瘤和已有转移的器官。人们对血管系统中的癌细胞知之甚少，在这个环境中，恶性肿瘤细胞和血管内皮细胞之间的机械力和分子相互作用控制着循环中的肿瘤细胞的命运。转移中的血管内微环境是一个肥沃的研究领域，需要新的治疗策略来阻止这一致命的癌症步骤。然而，需要一种有效的方法来研究生理条件下的血管微环境，但又是有效的和系统可调的。为了满足癌症研究中的这一关键需求，我们开发了一种微流体设备来模拟转移过程中血管内微环境的关键物理、分子和细胞成分。我们将使用这个装置来检验两个中心假设：1)趋化因子受体CXCR4和新发现的趋化因子受体CXCR7具有相加或协同作用，促进血管内步骤的转移；2)包括CXCR4和CXCR7在内的内皮分子控制循环中乳腺癌细胞的组织特异性转移潜能。在目标1中，我们将设计一种微流控流动装置，以复制血管系统的机械应力，并产生化学吸引剂分子的空间受限梯度。在目标2中，我们将使用微流控流系统来研究CXCR4和CXCR7在乳腺癌细胞对促转移趋化因子CXCL12的反应中的整合功能。Aim 3将研究癌细胞黏附和增殖的内皮特异性调节，利用我们的能力将多种类型的内皮整合到一个流动系统中，然后快速回收细胞进行分析。转移的内皮调节因子是特别有吸引力的治疗靶点，因为这些细胞不太可能产生耐药性。总而言之，这项研究将开发创新的微流体流动模型，研究生理条件下转移的血管内步骤，使我们能够识别乳腺癌和内皮分子，这些分子可以作为治疗的靶点，以防止转移疾病。公共卫生相关性：这项研究将开发新的血管生理学细胞培养模型，以研究循环中的乳腺癌细胞和血管内皮细胞在转移过程中的相互作用。这些模型将极大地提高我们对转移性疾病的了解，并使治疗或预防转移性疾病的新癌症疗法能够更快地进行测试和验证。

DESCRIPTION (provided by applicant): Metastatic disease remains the primary cause of death for patients with most types of cancer. Metastasis occurs through a series of interrelated steps, including survival of cancer cells in the circulation, adhesion to endothelial cells lining blood vessels, and growth of cancer cells to form metastases. Successfully interrupting any one of these steps will stop metastatic disease and potentially cure cancer. Research on metastasis has focused on primary tumors and organs with established metastases. Very little is known about cancer cells in the vascular system, an environment where mechanical forces and molecular interactions between malignant cells and vascular endothelium control the fate of circulating tumor cells. The intravascular microenvironment in metastasis is a fertile research area ripe for new therapeutic strategies to block this fatal step in cancer. What is required, however, is an efficient method for investigating the vascular microenvironment under physiologic, yet efficient and systematically adjustable conditions. To meet this critical need in cancer research, we have developed a microfluidic device to model key physical, molecular, and cellular components of the intravascular microenvironment in metastasis. We will use this device to test two central hypotheses: 1) chemokine receptor CXCR4 and the newly identified chemokine receptor CXCR7 have additive or synergistic effects to promote intravascular steps in metastasis; and 2) endothelial molecules including CXCR4 and CXCR7 control tissue-specific metastatic potential of circulating breast cancer cells. In Aim 1, we will engineer a microfluidic flow device to reproduce mechanical stresses of the vasculature and generate spatially- restricted gradients of chemoattractant molecules. In Aim 2, we will use the microfluidic flow system to investigate integrated functions of CXCR4 and CXCR7 on breast cancer cells in responding to the pro- metastatic chemokine CXCL12. Aim 3 will investigate endothelial-specific regulation of cancer cell adhesion and proliferation, exploiting our capabilities to integrate multiple types of endothelium into one flow system and then rapidly recover cells for analysis. Endothelial regulators of metastasis are particularly appealing therapeutic targets because these cells are less likely to develop drug resistance. Collectively, this research will develop innovative microfluidic flow models to study intravascular steps in metastasis under physiologic conditions, allowing us to identify breast cancer and endothelial molecules that can be targeted therapeutically to prevent metastatic disease. PUBLIC HEALTH RELEVANCE: This research will develop new, physiologic cell culture models of blood vessels to study interactions between circulating breast cancer cells and vascular endothelium during metastasis. These models should greatly advance our knowledge of metastatic disease and enable more rapid testing and validation of new cancer therapeutics to treat or prevent metastatic disease.