Microfluidic Models of Metastatic Cancer

描述（由申请人提供）：转移性疾病仍然是大多数类型癌症患者的主要死亡原因。转移通过一系列相互关联的步骤发生，包括癌细胞在循环中的存活、粘附到血管内衬的内皮细胞以及癌细胞生长以形成转移。成功地中断这些步骤中的任何一个将阻止转移性疾病并可能治愈癌症。转移的研究主要集中在原发肿瘤和已确定转移的器官。对血管系统中的癌细胞知之甚少，血管系统是恶性细胞和血管内皮之间的机械力和分子相互作用控制循环肿瘤细胞命运的环境。转移中的血管内微环境是一个肥沃的研究领域，新的治疗策略已经成熟，可以阻止癌症中的这一致命步骤。然而，所需要的是一种有效的方法，用于研究生理条件下的血管微环境，但有效的和系统可调的条件。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装置，以模拟转移中血管内微环境的关键物理，分子和细胞成分。我们将使用该装置来测试两个中心假设：1）趋化因子受体CXCR 4和新鉴定的趋化因子受体CXCR 7具有促进转移中的血管内步骤的累加或协同效应;和2）包括CXCR 4和CXCR 7的内皮分子控制循环乳腺癌细胞的组织特异性转移潜力。在目标1中，我们将设计微流体流动装置以再现脉管系统的机械应力并产生化学引诱物分子的空间限制梯度。在目的2中，我们将使用微流体流动系统来研究CXCR 4和CXCR 7在乳腺癌细胞上响应促转移趋化因子CXCL 12的整合功能。目标3将研究癌细胞粘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。总的来说，这项研究将开发创新的微流体流动模型，以研究在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，这些分子可以在治疗上靶向预防转移性疾病。公共卫生相关性：这项研究将开发新的血管生理细胞培养模型，以研究转移过程中循环乳腺癌细胞和血管内皮之间的相互作用。这些模型应该大大提高我们对转移性疾病的认识，并使新的癌症治疗方法能够更快速地测试和验证，以治疗或预防转移性疾病。

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.