TY - JOUR
T1 - Effect of Hypercapnia, an Element of Obstructive Respiratory Disorder, on Pancreatic Cancer Chemoresistance and Progression
AU - Nevler, Avinoam
AU - Brown, Samantha Z.
AU - Nauheim, David
AU - Portocarrero, Carla
AU - Rodeck, Ulrich
AU - Bassig, Jonathan
AU - Schultz, Christopher W.
AU - McCarthy, Grace A.
AU - Lavu, Harish
AU - Yeo, Theresa P.
AU - Yeo, Charles J.
AU - Brody, Jonathan R.
N1 - Publisher Copyright:
© 2020 American College of Surgeons
PY - 2020/4
Y1 - 2020/4
N2 - Background: Chronic obstructive respiratory disorders (ORDs) are linked to increased rates of cancer-related deaths. Little is known about the effects of hypercapnia (elevated CO2) on development of pancreatic ductal adenocarcinoma (PDAC) and drug resistance. Study Design: 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 had undergone pancreatic resection between 2002 and 2014 were reviewed. Active smokers were excluded to remove possible smoking-related protumorigenic influence. Clinical data, pathologic findings, and survival end points were recorded. Kaplan-Meier and Cox regression analyses were performed. Results: Exposure to hypercapnia resulted in increased colony formation and proliferation rates 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% were male, median age was 68.7 years [interquartile range 60.6 to 76.8 years]). Cox regression analysis, assessing TNM staging, age, sex, and ORD status, identified ORD as an independent risk factor for both overall survival (hazard ratio 1.64; 95% CI, 1.2 to 2.3; p < 0.05) and disease-free survival (hazard ratio 1.68; 95% CI, 1.06 to 2.67). Conclusions: PDAC cells exposed to hypercapnic environments, which is common in 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.
AB - Background: Chronic obstructive respiratory disorders (ORDs) are linked to increased rates of cancer-related deaths. Little is known about the effects of hypercapnia (elevated CO2) on development of pancreatic ductal adenocarcinoma (PDAC) and drug resistance. Study Design: 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 had undergone pancreatic resection between 2002 and 2014 were reviewed. Active smokers were excluded to remove possible smoking-related protumorigenic influence. Clinical data, pathologic findings, and survival end points were recorded. Kaplan-Meier and Cox regression analyses were performed. Results: Exposure to hypercapnia resulted in increased colony formation and proliferation rates 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% were male, median age was 68.7 years [interquartile range 60.6 to 76.8 years]). Cox regression analysis, assessing TNM staging, age, sex, and ORD status, identified ORD as an independent risk factor for both overall survival (hazard ratio 1.64; 95% CI, 1.2 to 2.3; p < 0.05) and disease-free survival (hazard ratio 1.68; 95% CI, 1.06 to 2.67). Conclusions: PDAC cells exposed to hypercapnic environments, which is common in 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.
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U2 - 10.1016/j.jamcollsurg.2019.12.033
DO - 10.1016/j.jamcollsurg.2019.12.033
M3 - Article
C2 - 32058016
AN - SCOPUS:85082123098
SN - 1072-7515
VL - 230
SP - 659
EP - 667
JO - Journal of the American College of Surgeons
JF - Journal of the American College of Surgeons
IS - 4
ER -