Nevler Avinoam, Khalilieh Saed, Lavu Harish, Bowne Wilbur, Yeo Charles J
From the Jefferson Pancreas, Biliary, and Related Cancer Center, Department of Surgery, Thomas Jefferson University, Philadelphia, PA.
J Am Coll Surg. 2023 Apr 1;236(4):913-922. doi: 10.1097/XCS.0000000000000552. Epub 2023 Jan 10.
Pancreatic ductal adenocarcinoma (PDAC) is an aggressive and lethal cancer. Hypercapnic tumor microenvironments were previously shown to promote cancer chemoresistance. In this study, we aimed to investigate the impact of tissue hypercapnia on PDAC prognosis.
PDAC cancer-cell lines were cultured in normocapnic (5% CO 2 ) and hypercapnic conditions (10% CO 2 ). RNA was extracted, and whole-exome transcriptome was sequenced. Differentially expressed genes were identified and used to construct a "hypercapnic gene set." PDAC transcriptomic patient data from the Tumor Cancer Genome Atlas was used to calculate single-sample gene set enrichment scores based on each patient's tissue expression of the hypercapnic gene set. Tissue hypercapnic scores (HSs) in PDAC patients (TMN stages Ia-IIb) were determined and correlated with clinicopathological parameters and overall survival.
A cohort of 135 resected stage I-II PDAC patients were assessed in this study. The average age was 65 ± 11.0 years, and the male:female ratio was 74:61. Median overall survival was 19.5 ± 1.4 months. High HSs were associated with increased tumor stage (p < 0.05) and higher lymph-node ratio (p < 0.05). In active smokers, high HS also correlated with smoking pack-years (p < 0.05). Cox regression analysis revealed high HS to be an independent prognostic factor for overall survival (hazard ratio [HR] 2.66, p = 0.004), along with lymph-node ratio (HR 4.2, p = 0.002) and age at diagnosis (HR 2.63, p = 0.01).
The pancreatic tumor microenvironment plays an integral role in tumor aggressiveness, and our previous in vitro data suggest that hypercapnia promotes an aggressive, more resistant phenotype. Herein, we show that in early-stage pancreatic cancer, hypercapnic tissue signatures corresponded with a worse overall survival.
胰腺导管腺癌（PDAC）是一种侵袭性强且致命的癌症。先前研究表明，高碳酸血症肿瘤微环境可促进癌症化疗耐药性。在本研究中，我们旨在探究组织高碳酸血症对PDAC预后的影响。
将PDAC癌细胞系分别在正常碳酸血症（5%二氧化碳）和高碳酸血症条件（10%二氧化碳）下培养。提取RNA，并对全外显子转录组进行测序。鉴定差异表达基因，并用于构建“高碳酸血症基因集”。利用来自肿瘤癌症基因组图谱的PDAC转录组患者数据，根据每个患者组织中高碳酸血症基因集的表达情况计算单样本基因集富集分数。确定PDAC患者（TMN分期Ia-IIb）的组织高碳酸血症评分（HSs），并将其与临床病理参数和总生存期进行关联分析。
本研究评估了135例接受手术切除的I-II期PDAC患者队列。平均年龄为65±11.0岁，男女比例为74:61。中位总生存期为19.5±1.4个月。高HSs与肿瘤分期增加（p<0.05）和较高的淋巴结比率（p<0.05）相关。在现吸烟者中，高HS也与吸烟包年数相关（p<0.05）。Cox回归分析显示，高HS是总生存期的独立预后因素（风险比[HR]2.66，p=0.004），同时还有淋巴结比率（HR 4.2，p=0.002）和诊断时年龄（HR 2.63，p=0.01）。
胰腺肿瘤微环境在肿瘤侵袭性中起着不可或缺的作用，我们之前的体外数据表明，高碳酸血症可促进侵袭性更强、更具耐药性的表型。在此，我们表明，在早期胰腺癌中，高碳酸血症组织特征与更差的总生存期相关。
