Department of Cell Biology, Center for Cell Dynamics, Johns Hopkins University School of Medicine, Baltimore, Maryland.
Institute for Nanobiotechnology (INBT), Johns Hopkins University, Baltimore, Maryland.
Cancer Res. 2020 Oct 1;80(19):4288-4301. doi: 10.1158/0008-5472.CAN-19-1564. Epub 2020 Jul 14.
In solid tumors, vascular structure and function varies from the core to the periphery. This structural heterogeneity has been proposed to influence the mechanisms by which tumor cells enter the circulation. Blood vessels exhibit regional defects in endothelial coverage, which can result in cancer cells directly exposed to flow and potentially promoting intravasation. Consistent with prior reports, we observed in human breast tumors and in a mouse model of breast cancer that approximately 6% of vessels consisted of both endothelial cells and tumor cells, so-called mosaic vessels. Due, in part, to the challenges associated with observing tumor-vessel interactions deep within tumors in real-time, the mechanisms by which mosaic vessels form remain incompletely understood. We developed a tissue-engineered model containing a physiologically realistic microvessel in coculture with mammary tumor organoids. This approach allows real-time and quantitative assessment of tumor-vessel interactions under conditions that recapitulate many features. Imaging revealed that tumor organoids integrate into the endothelial cell lining, resulting in mosaic vessels with gaps in the basement membrane. While mosaic vessel formation was the most frequently observed interaction, tumor organoids also actively constricted and displaced vessels. Furthermore, intravasation of cancer cell clusters was observed following the formation of a mosaic vessel. Taken together, our data reveal that cancer cells can rapidly reshape, destroy, or integrate into existing blood vessels, thereby affecting oxygenation, perfusion, and systemic dissemination. Our novel assay also enables future studies to identify targetable mechanisms of vascular recruitment and intravasation. SIGNIFICANCE: A tissue-engineered microdevice that recapitulates the tumor-vascular microenvironment enables real-time imaging of the cellular mechanisms of mosaic vessel formation and vascular defect generation.
在实体肿瘤中，血管结构和功能从核心到外围各不相同。这种结构异质性被认为会影响肿瘤细胞进入循环的机制。血管在内皮细胞覆盖方面存在区域性缺陷，这可能导致癌细胞直接暴露于血流中，并促进其浸润。与之前的报告一致，我们在人类乳腺癌肿瘤和乳腺癌小鼠模型中观察到，大约 6%的血管由内皮细胞和肿瘤细胞组成，即所谓的镶嵌血管。部分由于在实时观察肿瘤-血管相互作用方面存在挑战，镶嵌血管形成的机制仍不完全清楚。我们开发了一种组织工程模型，其中包含在共培养物中具有生理上真实的微血管的乳腺肿瘤类器官。这种方法允许在再现许多特征的条件下实时和定量评估肿瘤-血管相互作用。成像显示，肿瘤类器官整合到内皮细胞衬里中，导致镶嵌血管的基膜出现间隙。虽然镶嵌血管形成是最常观察到的相互作用，但肿瘤类器官也积极地收缩和移位血管。此外，在形成镶嵌血管后观察到癌细胞簇的浸润。总之，我们的数据表明，癌细胞可以迅速重塑、破坏或整合到现有血管中，从而影响氧合、灌注和全身播散。我们的新测定法还可以使未来的研究能够识别血管募集和浸润的靶向机制。意义：一种再现肿瘤-血管微环境的组织工程微器件，能够实时成像镶嵌血管形成和血管缺陷产生的细胞机制。
