Department of Surgical Oncology, Tata Memorial Hospital, Tata Memorial Centre, Mumbai, India.
Hypoxia and Clinical Genomics Lab (Clinician Scientist Laboratory), Advanced Centre for Treatment, Research, and Education in Cancer, Tata Memorial Centre, Navi Mumbai, Maharashtra, India.
Mol Cancer Res. 2024 Jun 4;22(6):572-584. doi: 10.1158/1541-7786.MCR-23-0265.
Surgery exposes tumor tissue to severe hypoxia and mechanical stress leading to rapid gene expression changes in the tumor and its microenvironment, which remain poorly characterized. We biopsied tumor and adjacent normal tissues from patients with breast (n = 81) and head/neck squamous cancers (HNSC; n = 10) at the beginning (A), during (B), and end of surgery (C). Tumor/normal RNA from 46/81 patients with breast cancer was subjected to mRNA-Seq using Illumina short-read technology, and from nine patients with HNSC to whole-transcriptome microarray with Illumina BeadArray. Pathways and genes involved in 7 of 10 known cancer hallmarks, namely, tumor-promoting inflammation (TNF-A, NFK-B, IL18 pathways), activation of invasion and migration (various extracellular matrix-related pathways, cell migration), sustained proliferative signaling (K-Ras Signaling), evasion of growth suppressors (P53 signaling, regulation of cell death), deregulating cellular energetics (response to lipid, secreted factors, and adipogenesis), inducing angiogenesis (hypoxia signaling, myogenesis), and avoiding immune destruction (CTLA4 and PDL1) were significantly deregulated during surgical resection (time points A vs. B vs. C). These findings were validated using NanoString assays in independent pre/intra/post-operative breast cancer samples from 48 patients. In a comparison of gene expression data from biopsy (analogous to time point A) with surgical resection samples (analogous to time point C) from The Cancer Genome Atlas study, the top deregulated genes were the same as identified in our analysis, in five of the seven studied cancer types. This study suggests that surgical extirpation deregulates the hallmarks of cancer in primary tumors and adjacent normal tissue across different cancers.
Surgery deregulates hallmarks of cancer in human tissue.
手术使肿瘤组织暴露于严重的缺氧和机械应激之下，导致肿瘤及其微环境中的基因表达迅速发生变化，但这些变化的特征仍未得到充分描述。我们在手术开始时（A）、手术中（B）和手术结束时（C）从患有乳腺癌（n=81）和头颈部鳞状细胞癌（HNSC；n=10）的患者中活检肿瘤和相邻正常组织。来自 46/81 例乳腺癌患者的肿瘤/正常 RNA 使用 Illumina 短读长技术进行了 mRNA-Seq 分析，来自 9 例 HNSC 患者的 RNA 进行了全转录组微阵列分析，采用 Illumina BeadArray。在 10 个已知的癌症标志中，有 7 个标志所涉及的途径和基因（促进肿瘤的炎症（TNF-A、NFK-B、IL18 途径）、侵袭和迁移的激活（各种细胞外基质相关途径、细胞迁移）、持续的增殖信号（K-Ras 信号）、逃避生长抑制剂（P53 信号、细胞死亡的调节）、细胞能量代谢失控（对脂质、分泌因子和脂肪生成的反应）、诱导血管生成（缺氧信号、肌发生）以及逃避免疫破坏（CTLA4 和 PDL1）在手术切除过程中（时间点 A 与 B 与 C）明显失调。这些发现使用来自 48 例患者的独立术前/术中/术后乳腺癌样本的 NanoString 检测进行了验证。在对来自癌症基因组图谱研究的活检（类似于时间点 A）和手术切除样本（类似于时间点 C）的基因表达数据进行比较时，在研究的七种癌症类型中的五种中，上调最明显的基因与我们的分析相同。本研究表明，外科切除会使原发性肿瘤及其相邻正常组织中的癌症标志失调。
手术使人类组织中的癌症标志失调。
