1 Wake Forest Institute for Regenerative Medicine , Wake Forest School of Medicine, Winston-Salem, North Carolina.
2 Virginia Tech-Wake Forest School of Biomedical Engineering and Sciences, Wake Forest School of Medicine , Winston-Salem, North Carolina.
Tissue Eng Part A. 2017 Oct;23(19-20):1026-1041. doi: 10.1089/ten.tea.2017.0397.
The physical nature of the tumor microenvironment significantly impacts tumor growth, invasion, and response to drugs. Most in vitro tumor models are designed to study the effects of extracellular matrix (ECM) stiffness on tumor cells, while not addressing the effects of ECM's specific topography. In this study, we bioengineered submucosal organoids, using primary smooth muscle cells embedded in collagen I hydrogel, which produce aligned and parallel fiber topography similar to those found in vivo. The fiber organization in the submucosal organoids induced an epithelial phenotype in spheroids of colorectal carcinoma cells (HCT-116), which were embedded within the organoids. Conversely, unorganized fibers drove a mesenchymal phenotype in the tumor cells. HCT-116 cells in organoids with aligned fibers showed no WNT signaling activation, and conversely, WNT signaling activation was observed in organoids with disrupted fibers. Consequently, HCT-116 cells in the aligned condition exhibited decreased cellular proliferation and reduced sensitivity to 5-fluorouracil chemotherapeutic treatment compared to cells in the unorganized construct. Collectively, the results establish a unique colorectal tumor organoid model to study the effects of stromal topography on cancer cell phenotype, proliferation, and ultimately, chemotherapeutic susceptibility. In the future, such organoids can utilize patient-derived cells for precision medicine applications.
肿瘤微环境的物理性质显著影响肿瘤的生长、侵袭和对药物的反应。大多数体外肿瘤模型旨在研究细胞外基质（ECM）硬度对肿瘤细胞的影响，而不考虑 ECM 特定拓扑结构的影响。在这项研究中，我们使用原代平滑肌细胞嵌入胶原 I 水凝胶来生物工程化黏膜下类器官，其产生与体内相似的排列和平行纤维拓扑结构。黏膜下类器官中的纤维组织诱导结直肠癌细胞（HCT-116）球体呈现上皮表型，这些球体嵌入在类器官中。相反，无组织的纤维促使肿瘤细胞呈现间充质表型。在具有排列纤维的类器官中，HCT-116 细胞没有 WNT 信号激活，相反，在纤维紊乱的类器官中观察到 WNT 信号激活。因此，与无组织结构的构建体相比，排列纤维条件下的 HCT-116 细胞表现出细胞增殖减少和对 5-氟尿嘧啶化疗敏感性降低。总的来说，这些结果建立了一个独特的结直肠肿瘤类器官模型，用于研究基质拓扑结构对癌细胞表型、增殖以及最终化疗敏感性的影响。将来，这种类器官可以利用患者来源的细胞进行精准医学应用。
