The impact of CRS and HIPEC treatment on gastric cancer patients at the molecular level

Abstract

Introduction Gastric cancer is an aggressive malignancy and in 2023 was the third leading cause of cancerrelated death in Lithuania. Among gastrointestinal tumors, it most frequently leads to peritoneal dissemination. Tumor cells spread within the peritoneal cavity through direct contact, and surgical manipulation may further contribute to their dissemination. Moreover, gastric cancer often shows limited sensitivity to systemic chemotherapy due to poor drug penetration [1]. Hyperthermic intraperitoneal chemotherapy (HIPEC) is a localized treatment based on circulatory perfusion of a heated chemotherapy solution in the abdominal cavity. HIPEC is usually combined with cytoreductive surgery (CRS), which enhances drug absorption and elimination of metastasized cancer cells [2]. Some studies report improved survival rate among patients with metastatic gastric cancer who received HIPEC [3]. Aim To evaluate the effects of CRS and HIPEC on gene expression and protein levels in peripheral blood of gastric cancer patients. Methods Peripheral blood mononuclear cells (PBMCs) were obtained from 6 patients with confirmed gastric cancer undergoing CRS and HIPEC, as well as from 23 healthy controls without any surgery and cancer history. PBMCs were isolated from venous blood using Ficoll–Paque density gradient centrifugation. Blood samples were collected at three points: before surgery, on postoperative days 2–3, and on days 4–8 after surgery. Gene expression levels were evaluated by qRT-PCR. Soluble cytokines concentrations in serum were measured using a multiplex ELISA. Results Gene expression analysis revealed that AHR (77%), ELAVL1 (49%), IL12A (18%), IL12B (23%) and PD1 (30%) were downregulated in patients a few days after surgery compared to healthy controls. IL12A and IL12B expression remained low before HIPEC and during the early posttreatment period. Analysis of cytokine concentrations in serum, IL-6 levels were elevated in patients before (48,5 pg/ml) compared to healthy controls (35,5 pg/ml), reflecting tumourassociated and perioperative inflammatory activation [4]. After HIPEC, IL-6 concentrations gradually decreased over time, approaching control levels. IL-12/IL-23 p40 subunit concentration increased four days after HIPEC (140,5 pg/ml while before surgery was 98 pg/ml), which reflects total p40 secretion. The rise in p40 could be a non-specific inflammatory response rather than a specific activation of IL-12 signaling. Conclusions The findings indicate that CRS and HIPEC modulate immune-related pathways at both gene and protein levels in gastric cancer patients. Further studies incorporating comparison between CRS with HIPEC and CRS-only groups are needed to clarify the independent immunomodulatory impact of HIPEC and its relevance to postoperative recovery and therapeutic outcomes.