Metastatic brain cancer has poor prognosis due to challenges in both detection and treatment. One contributor to poor prognosis is the blood–brain barrier (BBB), which severely limits the transport of therapeutic agents to intracranial tumors. During the development of brain metastases from primary breast cancer, the BBB is modified and is termed the ‘blood-tumor barrier’ (BTB). A better understanding of the differences between the BBB and BTB across cancer types and stages may assist in identifying new therapeutic targets. Here, we utilize a tissue-engineered microvessel model with induced pluripotent stem cell (iPSC)-derived brain microvascular endothelial-like cells (iBMECs) and surrounded by human breast metastatic cancer spheroids with brain tropism. We directly compare BBB and BTB in vitro microvessels to unravel both physical and chemical interactions occurring during perivascular cancer growth. We determine the dynamics of vascular co-option by cancer cells, modes of vascular degeneration, and quantify the endothelial barrier to antibody transport. Additionally, using bulk RNA sequencing, ELISA of microvessel perfusates, and related functional assays, we probe early brain endothelial changes in the presence of cancer cells. We find that immune cell adhesion and endothelial turnover are elevated within the metastatic BTB, and that macrophages exert a unique influence on BTB identity. Our model provides a novel three-dimensional system to study mechanisms of cancer-vascular-immune interactions and drug delivery occurring within the BTB.

中文翻译：

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转移性乳腺癌期间血肿瘤屏障的组织工程模型

由于检测和治疗方面的挑战，转移性脑癌的预后较差。血脑屏障（BBB）是导致预后不良的原因之一，它严重限制了治疗药物向颅内肿瘤的转运。在原发性乳腺癌脑转移的发展过程中，血脑屏障发生改变，被称为“血肿瘤屏障”(BTB)。更好地了解不同癌症类型和阶段的 BBB 和 BTB 之间的差异可能有助于确定新的治疗靶点。在这里，我们利用组织工程微血管模型，其中包含诱导多能干细胞（iPSC）衍生的脑微血管内皮样细胞（iBMEC），并被具有脑向性的人乳腺癌转移癌球体包围。我们直接比较 BBB 和 BTB 体外微血管，以揭示血管周围癌症生长过程中发生的物理和化学相互作用。我们确定癌细胞的血管共选择动态、血管变性模式，并量化抗体转运的内皮屏障。此外，我们利用大量 RNA 测序、微血管灌注液 ELISA 和相关功能测定，探测癌细胞存在时的早期脑内皮变化。我们发现转移性 BTB 内的免疫细胞粘附和内皮周转率升高，并且巨噬细胞对 BTB 身份具有独特的影响。我们的模型提供了一种新颖的三维系统来研究 BTB 内发生的癌症-血管-免疫相互作用和药物输送的机制。