Zhang Peiyi, Ono Atsushi, Fujii Yasutoshi, Hayes Clair Nelson, Tamura Yosuke, Miura Ryoichi, Shirane Yuki, Nakahara Hikaru, Yamauchi Masami, Uchikawa Shinsuke, Uchida Takuro, Teraoka Yuji, Fujino Hatsue, Nakahara Takashi, Murakami Eisuke, Miki Daiki, Kawaoka Tomokazu, Okamoto Wataru, Makokha Grace Naswa, Imamura Michio, Arihiro Koji, Kobayashi Tsuyoshi, Ohdan Hideki, Fujita Masashi, Nakagawa Hidewaki, Chayama Kazuaki, Aikata Hiroshi
Department of Gastroenterology and Metabolism, Graduate School of Biomedical & Health Sciences, Hiroshima University, Hiroshima, Japan.
Cancer Treatment Center, Hiroshima University Hospital, Hiroshima, Japan.
Int J Cancer. 2022 Dec 15;151(12):2278-2290. doi: 10.1002/ijc.34247. Epub 2022 Sep 2.
Recently, a distinct vascular pattern in hepatocellular carcinoma (HCC) called vessels encapsulating tumor-forming clusters (VETC) has received attention because of its association with poor prognosis. However, little is known about the mechanism by which VETC promotes an aggressive phenotype at the molecular level. In our study, the association between differences in stepwise signal intensity in the HB phase and molecular subtypes and somatic mutations associated with the immune microenvironment were investigated using the International Cancer Genome Consortium (ICGC) cohort (66 patients). To our knowledge, this is the first study to analyze the molecular patterns of VETC using RNA-Seq data. The VETC+ HCC group showed significantly lower overall survival and higher cumulative incidence of extrahepatic metastasis after curative hepatic resection than the VETC- HCC group. The VETC+ group exhibited molecular features indicative of lower immune activation than the VETC- group, suggesting that tumor cells in the VETC+ group were more likely to escape from the immune response, which could lead to the shorter OS (Overall survival) and higher risk of metastasis. On the other hand, gene expression levels of fibroblast growth factor receptors were upregulated in VETC+ HCC, suggesting that VETC+ HCC might benefit from lenvatinib treatment. Our results demonstrate that VETC+ HCC was associated with the suppression of tumor immune responses at the molecular level.
最近，肝细胞癌（HCC）中一种独特的血管模式——包绕肿瘤形成簇的血管（VETC）因其与预后不良相关而受到关注。然而，关于VETC在分子水平上促进侵袭性表型的机制却知之甚少。在我们的研究中，利用国际癌症基因组联盟（ICGC）队列（66例患者）研究了HB期逐步信号强度差异与分子亚型以及与免疫微环境相关的体细胞突变之间的关联。据我们所知，这是第一项使用RNA测序数据分析VETC分子模式的研究。与VETC- HCC组相比，VETC+ HCC组在根治性肝切除术后的总生存率显著降低，肝外转移的累积发生率更高。VETC+组表现出比VETC-组更低免疫激活的分子特征，这表明VETC+组中的肿瘤细胞更有可能逃避免疫反应，这可能导致较短的总生存期（OS）和更高的转移风险。另一方面，VETC+ HCC中纤维母细胞生长因子受体的基因表达水平上调，这表明VETC+ HCC可能从乐伐替尼治疗中获益。我们的结果表明，VETC+ HCC在分子水平上与肿瘤免疫反应的抑制有关。
