Radical gastric cancer surgery results in widespread upregulation of pro‐tumourigenic intraperitoneal cytokines

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Excerpt

Surgical resection remains the mainstay of curative treatment for gastric and oesophagogastric (OG) junctional carcinoma. Oncologic surgical resection is recommended to maximize the probability of complete tumour clearance, improve long‐term survival and reduce loco‐regional recurrence. However, recurrence rates post‐operatively are high even after radical resectional surgery with curative intent.1 A possible contributing factor to this could be the increased inflammatory reaction induced by surgical trauma as a potential mediator of worsened outcomes.
The systemic inflammatory response to surgical trauma has previously been described.2 Its role relating to the immediate post‐operative course and susceptibility to post‐operative infections has been well characterized.2 Intra‐operatively, an exaggerated local and systemic acute phase response occurs, resulting in profound immunological dysfunction.3
The causative link between inflammation and cancer has long been suspected. Inflammation plays a central role in the immune system's response to combat cancer,4 but paradoxically it is also a vital causative component in initiation, promotion and progression of a tumour.6 There is now substantial evidence supporting the role of systemic and infective inflammation in promotion of carcinogenesis, as well as poorer oncological outcome.4 Numerous laboratory and animal models have demonstrated the propensity for pro‐inflammatory cytokines to promote endothelial adhesion of colorectal, lung, gastric and ovarian cancer cells.9
There are some key cytokines that demonstrate properties that could lead to tumour implantation and dissemination. Interleukin‐1 (IL‐1) and IL‐6, tumour necrosis factor‐α (TNF‐α) and CC‐chemokine ligand‐2 (CCL‐2) play a major role in inflammation, tumour sustainability and progression.6 The IL‐1 family of cytokines, including IL‐1α and IL‐1β, perpetuates inflammation by inducing the expression of many pro‐inflammatory genes.12 TNF‐α is produced by macrophages and T‐cells, and plays a critical role in the maintenance and homeostasis of the physiologic immune system.14 Both TNF‐α and IL‐6 promote progression of tumour cells via activation of the nuclear transcription factor κB and other proliferative factors.14 Overall, upregulation in these factors are linked to increased angiogenesis, inflammatory cell infiltration and tumour invasiveness.12
OG cancer resections involve extensive and often prolonged surgery. There are few data in humans describing the pro‐tumourigenic local and systemic inflammatory response specific to this surgery. In particular, the intraperitoneal inflammatory reaction has not been previously described. Investigating this reaction may help to better understand a potential mechanism that facilitates tumour implantation, dissemination and early recurrence.
In this study, we aimed to establish potential immune and inflammatory markers that were altered during the course of surgery, which have been linked to the promotion of tumour implantation and dissemination on a basic science level. We aimed to explore these markers in intraperitoneal tissues, both adjacent and remote to the site of surgery, as well as serum during and after surgery.
We hypothesized that radical OG cancer surgery would induce a profound and prolonged local and systemic inflammatory response. We hypothesized that this response would globally affect intraperitoneal tissue and not be confined to the operative site.

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