Effect of Hypercapnia, an Element of Obstructive Respiratory Disorders, on Pancreatic Cancer Chemoresistance and Progression.

Chronic obstructive respiratory disorders (ORD) are linked to increased rates of cancer related deaths. Little is known about the effects of hypercapnia (elevated CO₂) on pancreatic ductal adenocarcinoma (PDAC) development and drug-resistance.

Two PDAC cell-lines were exposed to normocapnic (5% CO₂) and hypercapnic (continuous/intermittent 10% CO₂) conditions, physiologically similar to patients with active ORD. Cells were assessed for proliferation rate, colony formation, and chemo/radiotherapeutic efficacy. In a retrospective clinical study design, patients with PDAC who have undergone pancreatic resection between the years of 2002-2014 were reviewed. Active smokers were excluded in order to remove possible smoking-related pro-tumorigenic influences. Clinical data, pathological findings, and survival endpoints were recorded. Kaplan-Meier and Cox regression analyses were performed.

Exposure to hypercapnia resulted in an increased colony formation and proliferation rate, in-vitro in both cell lines (MIA-PaCa-2:111% increase and Panc-1:114% increase, P<0.05). Hypercapnia exposure induced a 2.5-fold increase in oxaliplatin resistance (P<0.05) in both cell lines and increased resistance to ionizing radiation in MIA-PaCa-2 cells (P<0.05). Five hundred and seventy-eight patients were included [52% males, median age was 68.7 years (IQR 60.6-76.8 years)]. Cox regression analysis, assessing TNM-staging, age, gender and ORD status, identified ORD as an independent risk factor for both overall survival (HR 1.64, 95%CI 1.2-2.3, P<0.05) and disease-free survival (HR 1.68, 95%CI 1.06-2.67).PDAC cells exposed to hypercapnic environments, common to patients with ORD, showed tumor proliferation, radioresistance and chemoresistance. Patients with a history of ORD had a worse overall prognosis, suggesting that hypercapnic conditions play a role in the development and progression of PDAC and stressing the need for patient-tailored care.