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Surgical Tumor Resection Deregulates Hallmarks of Cancer in Resected Tissue and the Surrounding Microenvironment
Rohan Chaubal1,2,3, Nilesh Gardi2,3,4, Shalaka Joshi1,2,3
1Department of Surgical Oncology, Tata Memorial Hospital, Tata Memorial Centre, Mumbai, India.
Abstract:
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.
Implications:
Surgery deregulates hallmarks of cancer in human tissue.
Insights
Surgical stress significantly alters gene expression in tumors and surrounding tissues, impacting key cancer hallmarks. These changes, observed in breast and head/neck cancers, suggest surgery itself can promote cancer progression.
Area of Science:
- Oncology
- Molecular Biology
- Genomics
Background:
- Surgical procedures induce significant physical and biochemical stress on tumor tissues.
- The resulting gene expression changes in tumors and their microenvironment are not well understood.
- Understanding these changes is crucial for developing effective cancer therapies.
Purpose of the Study:
- To investigate the impact of surgical resection on the gene expression profiles of tumor and adjacent normal tissues.
- To identify specific cancer hallmarks that are deregulated during the surgical process.
- To validate findings in independent patient cohorts and compare with existing cancer genomic data.
Main Methods:
- Biopsied tumor and adjacent normal tissues from breast cancer and head/neck squamous cell carcinoma (HNSC) patients at multiple surgical time points.
- Analyzed gene expression using mRNA-Seq and whole-transcriptome microarray.
- Validated findings with NanoString assays and compared data with The Cancer Genome Atlas (TCGA) study.
Main Results:
- Surgical resection significantly deregulated genes and pathways associated with 7 out of 10 cancer hallmarks, including inflammation, invasion, proliferation, and immune evasion.
- Key deregulated pathways involved TNF-A, NFK-B, IL18, extracellular matrix interactions, K-Ras signaling, P53 signaling, lipid metabolism, hypoxia signaling, and immune checkpoints (CTLA4, PDL1).
- Findings were consistent across different cancer types and validated in independent samples and TCGA data.
Conclusions:
- Surgical extirpation profoundly impacts the molecular landscape of cancer by deregulating critical cancer hallmarks.
- These intraoperative molecular changes in both tumor and normal tissues may have significant implications for cancer recurrence and treatment strategies.
- Further research is warranted to explore therapeutic interventions targeting these surgery-induced molecular alterations.
