Oshi Masanori, Huyser Michelle R, Le Lan, Tokumaru Yoshihisa, Yan Li, Matsuyama Ryusei, Endo Itaru, Takabe Kazuaki
Roswell Park Comprehensive Cancer Center, Department of Surgical Oncology, Buffalo, NY 14263, USA.
Department of Gastroenterological Surgery, Yokohama City University Graduate School of Medicine, Yokohama 236-0004, Japan.
Cancers (Basel). 2021 Mar 23;13(6):1477. doi: 10.3390/cancers13061477.
The generation of pathologic, immature, and dysfunctional vessels by angiogenesis is a mechanism of metastasis that has been a therapeutic target for colorectal cancer (CRC). In this study, we investigated the clinical relevance of intra-tumoral microvascular endothelial (mvE) cells in CRC using the xCell algorithm on transcriptome. A total of 1244 CRC patients in discovery and validation cohorts were analyzed. We found that an abundance of mvE cells did not mirror angiogenesis but reflected mature blood vessels because it was significantly associated with a high expression of vascular stability-related genes, including sphingosine-1-phosphate receptor genes and pericytes. Epithelial-mesenchymal transition and myogenesis gene sets were enriched in mvE cell abundant CRC, while mvE cell-less CRC enriched cell proliferation, oxidative phosphorylation, and protein secretion gene sets. mvE cell abundant CRC was associated with infiltration of M2 macrophages, dendritic cells, and less gamma-delta T cells (all < 0.001), but not with the interferon-γ response. mvE cell abundant CRC was significantly associated with worse patient survival in CRC. Interestingly, mvE cell abundant CRC was significantly associated with a high response rate to chemotherapy ( = 0.012) and worse patient survival for those that did not receive chemotherapy. However, there was no survival difference in patients who underwent chemotherapy. In conclusion, we estimated the abundance of mvE cells using the xCell algorithm on tumor transcriptome finding its association with the number of mature blood vessels in a tumor microenvironment and its ability to predict response to chemotherapy, thereby patient survival in CRC.
通过血管生成产生病理性、不成熟和功能失调的血管是一种转移机制，一直是结直肠癌（CRC）的治疗靶点。在本研究中，我们使用xCell算法对转录组进行分析，研究了CRC中肿瘤内微血管内皮（mvE）细胞的临床相关性。对发现队列和验证队列中的1244例CRC患者进行了分析。我们发现，mvE细胞的丰度并不反映血管生成，而是反映成熟血管，因为它与血管稳定性相关基因的高表达显著相关，包括鞘氨醇-1-磷酸受体基因和周细胞。上皮-间质转化和成肌基因集在mvE细胞丰富的CRC中富集，而mvE细胞较少的CRC中富集细胞增殖、氧化磷酸化和蛋白质分泌基因集。mvE细胞丰富的CRC与M2巨噬细胞、树突状细胞浸润以及较少的γδT细胞相关（均<0.001），但与干扰素-γ反应无关。mvE细胞丰富的CRC与CRC患者较差的生存率显著相关。有趣的是，mvE细胞丰富的CRC与化疗的高反应率显著相关（=0.012），而未接受化疗的患者生存率较差。然而，接受化疗的患者生存率没有差异。总之，我们使用xCell算法对肿瘤转录组进行分析，估计了mvE细胞的丰度，发现其与肿瘤微环境中成熟血管的数量相关，并且具有预测化疗反应的能力，从而可预测CRC患者的生存率。
