Sahlgrenska Center for Cancer Research, Department of Laboratory Medicine, Institute of Biomedicine, Sahlgrenska Academy at University of Gothenburg, Gothenburg, Sweden.
Research Institutes of Sweden (RISE), Division Biosciences and Materials, Section for Medical Device Technology, Borås, Sweden.
Cancer Med. 2021 Feb;10(3):867-882. doi: 10.1002/cam4.3668. Epub 2020 Dec 23.
Colorectal cancer is the second most common cause of cancer-related death worldwide and standardized therapies often fail to treat the more aggressive and progressive types of colorectal cancer. Tumor cell heterogeneity and influence from the surrounding tumor microenvironment (TME) contribute to the complexity of the disease and large variability in clinical outcomes.
To model the heterogeneous nature of colorectal cancer, we used patient-derived scaffolds (PDS), which were obtained via decellularization of surgically resected tumor material, as a growth substrate for standardized cell lines.
After confirmation of native cell absence and validation of the structural and compositional integrity of the matrix, 89 colorectal PDS were repopulated with colon cancer cell line HT29. After 3 weeks of PDS culture, HT29 cells varied their gene and protein expression profiles considerably compared to 2D-grown HT29 cells. Markers associated with proliferation were consistently decreased, while markers associated with pluripotency were increased in PDS-grown cells compared to their 2D counterparts. When comparing the PDS-induced changes in HT29 cells with clinically relevant tumor information from individual patients, we observed significant associations between stemness/pluripotency markers and tumor location, and between epithelial-to-mesenchymal transition (EMT) markers and cancer mortality. Kaplan-Meier analysis revealed that low PDS-induced EMT correlated with worse cancer-specific survival.
The colorectal PDS model can be used as a simplified personalized tool that can potentially reveal important diagnostic and pathophysiological information related to the TME.
结直肠癌是全球第二大常见的癌症相关死因，标准化治疗往往无法治疗更具侵袭性和进展性的结直肠癌。肿瘤细胞异质性和周围肿瘤微环境（TME）的影响导致了疾病的复杂性和临床结果的巨大变异性。
为了模拟结直肠癌的异质性，我们使用患者来源的支架（PDS）作为标准化细胞系的生长基质，该支架是通过手术切除的肿瘤材料脱细胞化获得的。
在确认天然细胞缺失并验证基质的结构和组成完整性后，89 个结直肠 PDS 用结肠癌细胞系 HT29 重新填充。在 PDS 培养 3 周后，与 2D 培养的 HT29 细胞相比，HT29 细胞的基因和蛋白表达谱发生了很大变化。与增殖相关的标志物持续减少，而与多能性相关的标志物在 PDS 培养的细胞中增加，与它们的 2D 对应物相比。当将 PDS 诱导的 HT29 细胞变化与来自个体患者的临床相关肿瘤信息进行比较时，我们观察到干性/多能性标志物与肿瘤位置之间以及上皮-间充质转化（EMT）标志物与癌症死亡率之间存在显著关联。Kaplan-Meier 分析显示，低 PDS 诱导的 EMT 与癌症特异性生存率较差相关。
结直肠 PDS 模型可用作简化的个性化工具，可能揭示与 TME 相关的重要诊断和病理生理信息。
