Shiomi Akio, Kusuhara Masatoshi, Sugino Takashi, Sugiura Teiichi, Ohshima Keiichi, Nagashima Takeshi, Urakami Kenichi, Serizawa Masakuni, Saya Hideyuki, Yamaguchi Ken
Division of Colon and Rectal Surgery, Shizuoka Cancer Center, Shizuoka 411-8777, Japan.
Division of Gene Regulation Institute for Advanced Medical Research, Keio University School of Medicine, Tokyo 160-858, Japan.
Oncol Lett. 2021 Jun;21(6):466. doi: 10.3892/ol.2021.12727. Epub 2021 Apr 12.
Recent studies have revealed that colorectal cancer (CRC) displays intratumor genetic heterogeneity, and that the cancer microenvironment plays an important role in the proliferation, invasion and metastasis of CRC. The present study performed genomic analysis on paired primary CRC and synchronous colorectal liver metastasis (CRLM) tissues collected from 22 patients using whole-exome sequencing, cancer gene panels and microarray gene expression profiling. In addition, immunohistochemical analysis was used to confirm the protein expression levels of genes identified as highly expressed in CRLM by DNA microarray analysis. The present study identified 10 genes that were highly expressed in CRLM compared with in CRC, from 36,022 probes obtained from primary CRC, CRLM and normal liver tissues by gene expression analysis with DNA microarrays. Of the 10 genes identified, five were classified as encoding 'matricellular proteins' [(osteopontin, periostin, thrombospondin-2, matrix Gla protein (MGP) and glycoprotein nonmetastatic melanoma protein B (GPNMB)] and were selected for immunohistochemical analysis. Osteopontin was strongly expressed in CRLM (6 of 22 cases: 27.3%), but not in CRC (0 of 22: 0%; P=0.02). Periostin also exhibited strong immunoreactivity in CRLM (17 of 22: 68.2%) compared with in CRC (7 of 22: 31.8%; P=0.006). Thrombospondin-2 exhibited strong immunoreactivity in both CRC and CRLM (54.5% in CRC, 45.5% in CRLM; P=0.55). GPNMB and MGP were rarely positive for both CRC and CRLM. A comparison of immunoreactive positive factors for these five genes revealed the complexities of gene expression in CRLM. Of the cases examined, 16 (72.7%) cases of CRC showed zero or only one positive immunoreactive factor. By contrast, CRLM showed more frequent and multiple immunoreactive factors; for example, 16 cases (72.7%) shared two or more factors, which was statistically more frequent than in CRC (P=0.007). The present study revealed the genomic heterogeneity between paired primary CRC and CRLM, in terms of cancer cell microenvironment. This finding may lead to novel diagnostic and therapeutic targets in the era of genome-guided personalized cancer treatment.
近期研究表明，结直肠癌（CRC）存在肿瘤内基因异质性，且癌症微环境在CRC的增殖、侵袭和转移中发挥重要作用。本研究使用全外显子测序、癌症基因检测板和微阵列基因表达谱分析，对从22例患者收集的配对原发性CRC和同步性结直肠肝转移（CRLM）组织进行了基因组分析。此外，免疫组织化学分析用于确认通过DNA微阵列分析确定在CRLM中高表达的基因的蛋白表达水平。通过对原发性CRC、CRLM和正常肝组织进行基因表达分析，从36,022个探针中，本研究确定了10个与CRC相比在CRLM中高表达的基因。在确定的10个基因中，有5个被归类为编码“基质细胞蛋白”[骨桥蛋白、骨膜蛋白、血小板反应蛋白-2、基质Gla蛋白（MGP）和糖蛋白非转移性黑色素瘤蛋白B（GPNMB）]，并被选用于免疫组织化学分析。骨桥蛋白在CRLM中强烈表达（22例中的6例：27.3%），但在CRC中不表达（22例中的0例：0%；P = 0.02）。与CRC（22例中的7例：31.8%；P = 0.006）相比，骨膜蛋白在CRLM中也表现出强烈的免疫反应性（22例中的17例：68.2%）。血小板反应蛋白-2在CRC和CRLM中均表现出强烈的免疫反应性（CRC中为54.5%，CRLM中为45.5%；P = 0.55）。GPNMB和MGP在CRC和CRLM中均很少呈阳性。对这5个基因的免疫反应阳性因子进行比较，揭示了CRLM中基因表达的复杂性。在所检查的病例中，16例（72.7%）CRC病例显示零个或仅一个免疫反应阳性因子。相比之下，CRLM显示出更频繁和多个免疫反应因子；例如，16例（72.7%）共享两个或更多因子，这在统计学上比CRC更频繁（P = 0.007）。本研究揭示了配对原发性CRC和CRLM之间在癌细胞微环境方面的基因组异质性。这一发现可能会在基因组导向的个性化癌症治疗时代带来新的诊断和治疗靶点。
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