利用人源器官型乳腺癌细胞渗出模型阐明癌症-血管旁分泌信号转导。
Elucidating cancer-vascular paracrine signaling using a human organotypic breast cancer cell extravasation model.
机构信息
Department of Biomedical Engineering, University of Wisconsin- Madison, 1415 Engineering Drive, Madison, WI, 53706, USA; The University of Wisconsin Carbone Cancer Center, University of Wisconsin- Madison, WIMR I Room 6028 - 1111 Highland Ave, Madison, WI, 53705, USA.
Department of Biomedical Engineering, University of Wisconsin- Madison, 1415 Engineering Drive, Madison, WI, 53706, USA; The University of Wisconsin Carbone Cancer Center, University of Wisconsin- Madison, WIMR I Room 6028 - 1111 Highland Ave, Madison, WI, 53705, USA.
出版信息
Biomaterials. 2021 Mar;270:120640. doi: 10.1016/j.biomaterials.2020.120640. Epub 2021 Feb 6.
In cancer metastasis, extravasation refers to the process where tumor cells exit the bloodstream by crossing the endothelium and invade the surrounding tissue. Tumor cells engage in complex crosstalk with other active players such as the endothelium leading to changes in functional behavior that exert pro-extravasation effects. Most in vitro studies to date have only focused on the independent effects of molecular targets on the functional changes of cancer cell extravasation behavior. However, singular targets cannot combat complex interactions involved in tumor cell extravasation that affects multiple cell types and signaling pathways. In this study, we employ an organotypic microfluidic model of human vasculature to investigate the independent and combined role of multiple upregulated secreted factors resulting from cancer-vascular interactions during cancer cell extravasation. The device consists of a tubular endothelial vessel generated from induced pluripotent stem cell derived endothelial cells within a collagen-fibrinogen matrix with breast cancer cells injected through and cultured along the lumen of the vessel. Our system identified cancer-vascular crosstalk, involving invasive breast cancer cells, that results in increased levels of secreted IL-6, IL-8, and MMP-3. Our model also showed that upregulation of these secreted factors correlates with invasive/metastatic potential of breast cancer cells. We also used therapeutic inhibitors to assess the independent and combined role of multiple signaling factors on the overall changes in functional behavior of both the cancer cells and the endothelium that promote extravasation. Taken together, these results demonstrate the potential of our organotypic model in elucidating mechanisms through which cancer-vascular interactions can promote extravasation, and in conducting functional assessment of therapeutic drugs that prevent extravasation in cancer metastasis.
在癌症转移中，血管外渗是指肿瘤细胞通过穿过内皮细胞并侵入周围组织而从血液中逸出的过程。肿瘤细胞与内皮细胞等其他活跃参与者进行复杂的串扰，导致功能行为发生变化，产生促血管外渗作用。迄今为止，大多数体外研究仅关注分子靶点对肿瘤细胞血管外渗行为功能变化的独立影响。然而，单一靶点无法对抗肿瘤细胞血管外渗涉及的复杂相互作用，这些相互作用涉及多种细胞类型和信号通路。在这项研究中，我们采用了一种人血管的器官型微流控模型，研究了癌症-血管相互作用导致的多个上调分泌因子在肿瘤细胞血管外渗中的独立和联合作用。该设备由诱导多能干细胞衍生的内皮细胞在胶原纤维蛋白基质中生成的管状内皮血管组成，乳腺癌细胞通过并沿着血管腔培养。我们的系统确定了涉及侵袭性乳腺癌细胞的癌症-血管串扰，导致分泌的白细胞介素 6、白细胞介素 8 和基质金属蛋白酶 3 水平升高。我们的模型还表明，这些分泌因子的上调与乳腺癌细胞的侵袭/转移潜力相关。我们还使用治疗抑制剂来评估多个信号因子对促进血管外渗的癌细胞和内皮细胞整体功能行为变化的独立和联合作用。总之，这些结果表明我们的器官型模型在阐明癌症-血管相互作用如何促进血管外渗的机制以及对预防癌症转移中血管外渗的治疗药物进行功能评估方面具有潜力。
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