血管生成调节因子S100A4、富含半胱氨酸的酸性分泌蛋白（SPARC）和骨桥蛋白（SPP1）与巨噬细胞浸润相关，是结肠癌和直肠癌的预后生物标志物。
Angiogenesis regulators S100A4, SPARC and SPP1 correlate with macrophage infiltration and are prognostic biomarkers in colon and rectal cancers.
作者信息
Kazakova Elena, Rakina Militsa, Sudarskikh Tatiana, Iamshchikov Pavel, Tarasova Anna, Tashireva Liubov, Afanasiev Sergei, Dobrodeev Alexei, Zhuikova Lilia, Cherdyntseva Nadezhda, Kzhyshkowska Julia, Larionova Irina
机构信息
Laboratory of Translational Cellular and Molecular Biomedicine, Tomsk State University, Tomsk, Russia.
Cancer Research Institute, Tomsk National Research Medical Center, Russian Academy of Sciences, Tomsk, Russia.
出版信息
Front Oncol. 2023 Feb 21;13:1058337. doi: 10.3389/fonc.2023.1058337. eCollection 2023.
INTRODUCTION
Increasing evidence suggests that it is necessary to find effective and robust clinically validated prognostic biomarkers that can identify "high-risk" colorectal cancer (CRC) patients. Currently, available prognostic factors largely include clinical-pathological parameters and focus on the cancer stage at the time of diagnosis. Among cells of tumor microenvironment (TME) only Immunoscore classifier based on T lymphocytes showed high predictive value.
METHODS
In the present study, we performed the complex analysis of mRNA and protein expression of crucial regulators of tumor angiogenesis and tumor progression, expressed by tumor-associated macrophages (TAMs): S100A4, SPP1 and SPARC. Colon and rectal cancer patients were investigated independently and in a combined cohort (CRC). For mRNA expression, we analyzed RNA sequencing data obtained from TCGA (N=417) and GEO (N=92) cohorts of colorectal cancer patients. For protein expression, we performed IHC digital quantification of tumor tissues obtained from 197 patients with CRC treated in the Department of abdominal oncology in Clinics of Tomsk NRMC.
RESULTS
High S100A4 mRNA expression accurately predicted poor survival for patients with CRC independently of cancer type. SPARC mRNA level was independent prognostic factors for survival in colon but not in rectal cancer. SPP1 mRNA level had significant predictive value for survival in both rectal and colon cancers. Analysis of human CRC tissues revealed that S100A4, SPP1 and SPARC are expressed by stromal compartments, in particular by TAMs, and have a strong correlation with macrophage infiltration. Finally, our results indicate that chemotherapy-based treatment can change the predictive direction of S100A4 for rectal cancer patients. We found that S100A4 stromal levels were higher in patients with better response to neoadjuvant chemotherapy/chemoradiotherapy, and S100A4 mRNA levels predicted better DFS among non-responders.
DISCUSSION
These findings can help improve the prognosis of patients with CRC based on S100A4, SPP1 and SPARC expression levels.
引言
越来越多的证据表明，有必要找到有效且可靠的经过临床验证的预后生物标志物，以识别“高危”结直肠癌（CRC）患者。目前，可用的预后因素主要包括临床病理参数，且侧重于诊断时的癌症分期。在肿瘤微环境（TME）的细胞中，只有基于T淋巴细胞的免疫评分分类器显示出较高的预测价值。
方法
在本研究中，我们对肿瘤相关巨噬细胞（TAM）表达的肿瘤血管生成和肿瘤进展关键调节因子的mRNA和蛋白质表达进行了综合分析：S100A4、SPP1和SPARC。对结肠癌和直肠癌患者分别以及合并队列（CRC）进行了研究。对于mRNA表达，我们分析了从TCGA（N = 417）和GEO（N = 92）结直肠癌患者队列中获得的RNA测序数据。对于蛋白质表达，我们对托木斯克国立研究医学中心临床腹部肿瘤学部门治疗的197例CRC患者的肿瘤组织进行了免疫组化数字定量分析。
结果
高S100A4 mRNA表达准确预测了CRC患者的不良生存，与癌症类型无关。SPARC mRNA水平是结肠癌患者生存的独立预后因素，但在直肠癌中不是。SPP1 mRNA水平对直肠癌和结肠癌患者的生存均具有显著的预测价值。对人类CRC组织的分析表明，S100A4、SPP1和SPARC由基质成分表达，特别是由TAM表达，并且与巨噬细胞浸润密切相关。最后，我们的结果表明，基于化疗的治疗可以改变S100A4对直肠癌患者的预测方向。我们发现，对新辅助化疗/放化疗反应较好的患者，其S100A4基质水平较高，而S100A4 mRNA水平预测无反应者的无病生存期更好。
讨论
这些发现有助于根据S100A4；SPP1和SPARC的表达水平改善CRC患者的预后。
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