Neutrophils expressing lysyl oxidase-like 4 protein are present in colorectal cancer liver metastases resistant to anti-angiogenic therapy

Colorectal cancer liver metastases (CRCLM) that present with a replacement histopathological growth pattern (HGP) are resistant to neoadjuvant anti-angiogenic therapy. Surrogate biomarkers are not available to preoperatively identifypatients with these tumors. Here we identify differentially expressed genes between CRCLM with a replacement HGP and those with a desmoplastic HGP using RNA sequencing.We demonstrate that LOXL4 is transcriptionally upregulated in replacement HGP CRCLM compared with desmoplastic HGP CRCLM and the adjacent normal liver. Interestingly, lysyl oxidase-like 4 (LOXL4) protein was expressed by neutrophils present in the tumor microenvironment in replacement HGP CRCLM. We further demonstrate that LOXL4 expression is higher in circulating neutrophils of cancer patients compared with healthy control patients and its expression can be induced by stimulation with lipopolysaccharide and TNF-alpha. Our study is the first to show the expression of LOXL4 in neutrophils and reveals the potential for LOXL4-expressing neutrophils to support the replacement HGP phenotype and to serve as a surrogate biomarker for this subtype of CRCLM. Examination of RNA samples of Colorectal cancer liver metastases (CRCLM)

具有替换型组织学生长模式（HGP）的结直肠癌肝转移（CRCLM）对新辅助抗血管生成治疗具有耐药性。目前尚无可用的替代生物标志物，用于术前甄别这类肿瘤患者。本研究通过RNA测序，鉴定了替换型HGP与促纤维增生型HGP两类CRCLM之间的差异表达基因。我们证实，相较于促纤维增生型HGP的CRCLM及邻近正常肝组织，替换型HGP的CRCLM中赖氨酰氧化酶样4（lysyl oxidase-like 4, LOXL4）的转录水平上调。值得注意的是，赖氨酰氧化酶样4（LOXL4）蛋白由替换型HGP的CRCLM肿瘤微环境中的中性粒细胞表达。我们进一步证实，与健康对照受试者相比，癌症患者的循环中性粒细胞中LOXL4的表达水平更高，且其表达可通过脂多糖与肿瘤坏死因子-α（TNF-α）刺激诱导。本研究首次证实了LOXL4在中性粒细胞中的表达，并揭示了表达LOXL4的中性粒细胞可能参与维持替换型HGP表型，且可作为该亚型CRCLM的替代生物标志物。对结直肠癌肝转移（CRCLM）的RNA样本的检测