UCL Institute of Orthopaedics and Musculoskeletal Sciences, UCL Division of Surgery and Interventional Science, Stanmore Campus, HA7 4LP, UK.
UCL Division of Surgery and Interventional Science, Royal Free Campus, London, NW3 2QG, UK.
Sci Rep. 2017 Mar 9;7:44045. doi: 10.1038/srep44045.
The hallmark of tumours is the ability of cancerous cells to promote vascular growth, to disseminate and invade to distant organs. The metastatic process is heavily influenced by the extracellular matrix (ECM) density and composition of the surrounding tumour microenvironment. These microenvironmental cues, which include hypoxia, also regulate the angiogenic processes within a tumour, facilitating the spread of cancer cells. We engineered compartmentalized biomimetic colorectal tumouroids with stromal surrounds that comprised a range of ECM densities, composition and stromal cell populations. Recapitulating tissue ECM composition and stromal cell composition enhanced cancer cell invasion. Manipulation of ECM density was associated with an altered migration pattern from glandular buds (cellular aggregates) to epithelial cell sheets. Laminin appeared to be a critical component in regulating endothelial cell morphology and vascular network formation. Interestingly, the disruption of vascular networks by cancer cells was driven by changes in expression of several anti-angiogenic genes. Cancer cells cultured in our biomimetic tumouroids exhibited intratumoural heterogeneity that was associated with increased tumour invasion into the stroma. These findings demonstrate that our 3D in vitro tumour model exhibits biomimetic attributes that may permit their use in studying microenvironment clues of tumour progression and angiogenesis.
肿瘤的标志是癌细胞促进血管生长、扩散和侵袭到远处器官的能力。转移过程受到周围肿瘤微环境中细胞外基质 (ECM) 密度和组成的强烈影响。这些微环境线索，包括缺氧，也调节肿瘤内的血管生成过程，促进癌细胞的扩散。我们设计了具有基质环绕的分区仿生结直肠肿瘤，其基质环绕具有一系列 ECM 密度、组成和基质细胞群体。重现组织 ECM 组成和基质细胞组成增强了癌细胞的侵袭。ECM 密度的操纵与从腺体芽（细胞聚集体）到上皮细胞片的迁移模式的改变有关。层粘连蛋白似乎是调节内皮细胞形态和血管网络形成的关键成分。有趣的是，癌细胞对血管网络的破坏是由几个抗血管生成基因表达的变化驱动的。在我们的仿生肿瘤中培养的癌细胞表现出肿瘤内异质性，这与肿瘤向基质的侵袭增加有关。这些发现表明，我们的 3D 体外肿瘤模型表现出仿生特性，这可能允许它们用于研究肿瘤进展和血管生成的微环境线索。
