PO.CL01.17 · 临床研究

在结直肠癌患者中，GDF-15反映的是宿主生理应激而非肿瘤进展

GDF-15 reflects host physiological stress rather than tumor progression in colorectal cancer patients

编号 5378 展板 16 时间 4/21 09:00–12:00 区域 Section 47 主讲 Tasuku Kaise, MD

分会场 Prognostic Biomarkers 3

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作者与单位 Authors & Affiliations

Tasuku Kaise¹, Hideaki Karasawa¹, Keigo Murakami², Ichiro Ise¹, Tomoyuki Ono¹, Megumi Murakami¹, Yoshihiro Sato¹, Gumpei Yoshimatsu¹, Hideyuki Suzuki¹, Takaaki Abe³, Takashi Kamei¹, Shinobu Ohnuma¹, Toru Furukawa², Michiaki Unno¹

¹Department of Surgery, Tohoku University Graduate School of Medicine, Sendai, Japan,²Department of investigative Pathology, Tohoku Graduate School of Medicine, Sendai, Japan,³Department of Clinical Biology and Hormonal Regulation, Tohoku University Graduate School of Medicine, Sendai, Japan

摘要 Abstract

中文摘要

GDF-15（生长分化因子15）是TGF-beta（转化生长因子-beta）超家族中的一种应激反应性细胞因子，在组织损伤和细胞应激时分泌。它在多种病理状态下升高，包括心血管疾病、肾脏疾病和恶性疾病。在结直肠癌（CRC）中，血浆GDF-15水平较健康人升高，且较高浓度与较差的预后相关。然而，GDF-15反映的是肿瘤特征还是宿主生理状态仍不清楚。本研究旨在通过整合血浆水平、肿瘤组织表达和肠道菌群组成的分析，阐明GDF-15在CRC中的临床意义。共纳入70例于2021年11月至2023年9月间接受手术的CRC患者。分析了血浆GDF-15水平与年龄、血清白蛋白（Alb）、肿瘤分期以及其他综合营养和临床参数之间的关系。通过免疫组化评估肿瘤组织中的GDF-15表达，并使用数字病理软件QuPath计算半定量组化评分（H-score）。术前粪便样本通过16S rRNA测序进行分析。在菌群分析中，根据中位值将患者分为血浆GDF-15高组和低组，并比较两组间的微生物多样性和组成。血浆GDF-15与年龄呈正相关（r = 0.58，p < 0.001），与Alb呈负相关（r = -0.54，p < 0.0001）。在较晚的T分类（T3+4 对比 T1+2，p < 0.05）和较高分期（II-IV 对比 I，p < 0.05）中水平更高；然而，在校正年龄和Alb后，这些关联消失（T分类，p = 0.72；分期，p = 0.86）。这些发现表明，血浆GDF-15反映的是宿主生理应激而非肿瘤进展。通过H-score评估的肿瘤组织中GDF-15表达与血浆GDF-15（r = 0.06，p = 0.62）、年龄（r = 0.09，p = 0.47）或Alb（r = -0.09，p = 0.48）均无相关性，且不随肿瘤浸润深度（p = 0.97）或分期（p = 0.75）而变化。肠道菌群分析显示alpha多样性无差异。相比之下，在加权和非加权UniFrac分析中beta多样性均存在显著差异（p < 0.05），表明与血浆GDF-15升高相关的组成变化。总之，GDF-15是一种宿主来源的标志物，反映的是与衰老和营养不良相关的全身生理应激，而非肿瘤负荷。此外，GDF-15升高患者中同时出现的菌群改变提示，GDF-15有可能作为一种整合性生物标志物，将宿主生理应激与结直肠癌中肠道环境变化联系起来。

查看英文原文 English abstract

GDF-15 (growth differentiation factor 15) is a stress-responsive cytokine within the TGF-beta (transforming growth factor-beta) superfamily that is secreted in response to tissue injury and cellular stress. It increases under various pathological conditions, including cardiovascular, renal, and malignant diseases. In colorectal cancer (CRC), plasma GDF-15 levels are elevated compared with healthy individuals, and higher concentrations have been associated with worse prognosis. However, whether GDF-15 reflects tumor characteristics or host physiology remains unclear. This study aimed to clarify the clinical significance of GDF-15 in CRC by integrating analyses of plasma levels, tumor tissue expression, and gut microbiota composition. Seventy patients with CRC who underwent surgery between November 2021 and September 2023 were enrolled. Plasma GDF-15 levels were examined in relation to age, serum albumin (Alb), tumor stage, and other comprehensive nutritional and clinical parameters. GDF-15 expression in tumor tissue was evaluated by immunohistochemistry, and a semiquantitative histoscore (H-score) was calculated using the digital pathology software QuPath. Preoperative fecal samples were analyzed by 16S rRNA sequencing. For microbiota analysis, patients were classified into high and low plasma GDF-15 groups based on the median value, and microbial diversity and composition were compared between the groups. Plasma GDF-15 correlated positively with age (r = 0.58, p < 0.001) and negatively with Alb (r = -0.54, p < 0.0001). Levels were higher in advanced T categories (T3+4 vs. T1+2, p < 0.05) and higher stages (II-IV vs. I, p < 0.05); however, these associations disappeared after adjustment for age and Alb (T category, p = 0.72; stage, p = 0.86). These findings indicate that plasma GDF-15 reflects host physiological stress rather than tumor progression. GDF-15 expression in tumor tissue, assessed by H-score, showed no correlation with plasma GDF-15 (r = 0.06, p = 0.62), age (r = 0.09, p = 0.47), or Alb (r = -0.09, p = 0.48), and did not vary by tumor depth (p = 0.97) or stage (p = 0.75). Gut microbiota analysis revealed no difference in alpha-diversity. In contrast, beta-diversity differed significantly in both weighted and unweighted UniFrac analyses (p < 0.05), indicating compositional shifts associated with elevated plasma GDF-15. In conclusion, GDF-15 functions as a host-derived marker that reflects systemic physiological stress associated with aging and malnutrition rather than tumor burden. Furthermore, concurrent microbial alterations in patients with elevated GDF-15 suggest a potential role for GDF-15 as an integrative biomarker linking host physiological stress to intestinal environmental changes in colorectal cancer.

利益披露 Disclosure

T. Kaise, None.. H. Karasawa, None.. K. Murakami, None.. I. Ise, None.. T. Ono, None.. M. Murakami, None.. Y. Sato, None.. G. Yoshimatsu, None.. H. Suzuki, None.. T. Abe, None.. T. Kamei, None.. S. Ohnuma, None.. T. Furukawa, None.. M. Unno, None.

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