Center for Cancer Treatment, Sorlandet Hospital, Kristiansand, Norway.
Department of Clinical Science, University of Bergen, Bergen, Norway.
Front Immunol. 2023 Mar 17;14:1170443. doi: 10.3389/fimmu.2023.1170443. eCollection 2023.
Systemic inflammation, diagnostically ascribed by measuring serum levels of the acute phase reactant C-reactive protein (CRP), has consistently been correlated with poor outcomes across cancer types. CRP exists in two structurally and functionally distinct isoforms, circulating pentameric CRP (pCRP) and the highly pro-inflammatory monomeric isoform (mCRP). The aim of this pilot study was to map the pattern of mCRP distribution in a previously immunologically well-defined colon cancer (CC) cohort and explore possible functional roles of mCRP within the tumor microenvironment (TME).
Formalin-fixed, paraffin-embedded (FFPE) tissue samples from 43 stage II and III CC patients, including 20 patients with serum CRP 0-1 mg/L and 23 patients with serum CRP >30 mg/L were immunohistochemically (IHC) stained with a conformation-specific mCRP antibody and selected immune and stromal markers. A digital analysis algorithm was developed for evaluating mCRP distribution within the primary tumors and adjacent normal colon mucosa.
mCRP was abundantly present within tumors from patients with high serum CRP (>30 mg/L) diagnostically interpreted as being systemically inflamed, whereas patients with CRP 0-1 mg/L exhibited only modest mCRP positivity (median mCRP per area 5.07‰ (95%CI:1.32-6.85) vs. 0.02‰ (95%CI:0.01-0.04), p<0.001). Similarly, tissue-expressed mCRP correlated strongly with circulating pCRP (Spearman correlation 0.81, p<0.001). Importantly, mCRP was detected exclusively within tumors, whereas adjacent normal colon mucosa showed no mCRP expression. Double IHC staining revealed colocalization of mCRP with endothelial cells and neutrophils. Intriguingly, some tumor cells also colocalized with mCRP, suggesting a direct interaction or mCRP expression by the tumor itself.
Our data show that the pro-inflammatory mCRP isoform is expressed in the TME of CC, primarily in patients with high systemic pCRP values. This strengthens the hypothesis that CRP might not only be an inflammatory marker but also an active mediator within tumors.
系统性炎症可通过测量急性时相反应物 C 反应蛋白（CRP）的血清水平来诊断，在多种癌症类型中均与不良预后相关。CRP 有两种结构和功能不同的亚型，循环五聚体 CRP（pCRP）和高度炎症的单体型（mCRP）。本研究旨在绘制先前免疫定义明确的结肠癌（CC）队列中 mCRP 分布模式，并探讨 mCRP 在肿瘤微环境（TME）中的可能功能作用。
对 43 例 II 期和 III 期 CC 患者的福尔马林固定、石蜡包埋（FFPE）组织样本进行免疫组织化学（IHC）染色，使用针对构象特异性 mCRP 抗体和选定的免疫和基质标志物。开发了一种数字分析算法，用于评估原发性肿瘤和相邻正常结肠黏膜内 mCRP 的分布。
高血清 CRP（>30 mg/L）患者的肿瘤中 mCRP 大量存在，临床上被解释为全身性炎症，而 CRP 为 0-1 mg/L 的患者 mCRP 阳性程度仅适度（mCRP 每面积中位数为 5.07‰（95%CI：1.32-6.85）vs. 0.02‰（95%CI：0.01-0.04），p<0.001）。同样，组织表达的 mCRP 与循环 pCRP 呈强相关性（Spearman 相关系数 0.81，p<0.001）。重要的是，mCRP 仅在肿瘤中检测到，而相邻的正常结肠黏膜无 mCRP 表达。双重 IHC 染色显示 mCRP 与内皮细胞和中性粒细胞共定位。有趣的是，一些肿瘤细胞也与 mCRP 共定位，提示肿瘤本身可能存在直接相互作用或 mCRP 表达。
我们的数据表明，促炎 mCRP 亚型在 CC 的 TME 中表达，主要在高全身 pCRP 值的患者中表达。这加强了 CRP 不仅是炎症标志物，而且还是肿瘤内活性介质的假说。
