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

Avinoam Nevler; Samantha Z Brown; David Nauheim; Carla Portocarrero; Ulrich Rodeck; Jonathan Bassig; Christopher W Schultz; Grace A McCarthy; Harish Lavu; Theresa P Yeo; Charles J Yeo; Jonathan R Brody

doi:10.1016/j.jamcollsurg.2019.12.033

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

Avinoam Nevler, Samantha Z Brown, David Nauheim, Carla Portocarrero, Ulrich Rodeck, Jonathan Bassig, Christopher W Schultz, Grace A McCarthy, Harish Lavu, Theresa P Yeo, Charles J Yeo, Jonathan R Brody

Research output: Contribution to journal › Article › peer-review

9 Scopus citations

Abstract

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.

Original language	English
Pages (from-to)	659-667
Number of pages	9
Journal	Journal of the American College of Surgeons
Volume	230
Issue number	4
DOIs	https://doi.org/10.1016/j.jamcollsurg.2019.12.033
State	Published - Apr 2020
Externally published	Yes

Keywords

Aged
Carcinoma, Pancreatic Ductal/drug therapy
Cell Line, Tumor
Cell Proliferation
Chronic Disease
Disease Progression
Drug Resistance, Neoplasm
Female
Humans
Hypercapnia/complications
Lung Diseases, Obstructive/complications
Male
Middle Aged
Pancreatic Neoplasms/drug therapy
Retrospective Studies

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1016/j.jamcollsurg.2019.12.033

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Nevler, A., Brown, S. Z., Nauheim, D., Portocarrero, C., Rodeck, U., Bassig, J., Schultz, C. W., McCarthy, G. A., Lavu, H., Yeo, T. P., Yeo, C. J., & Brody, J. R. (2020). Effect of Hypercapnia, an Element of Obstructive Respiratory Disorder, on Pancreatic Cancer Chemoresistance and Progression. Journal of the American College of Surgeons, 230(4), 659-667. https://doi.org/10.1016/j.jamcollsurg.2019.12.033

@article{529701cbe24543bb839830fc6427124b,

title = "Effect of Hypercapnia, an Element of Obstructive Respiratory Disorder, on Pancreatic Cancer Chemoresistance and Progression",

abstract = "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.",

keywords = "Aged, Carcinoma, Pancreatic Ductal/drug therapy, Cell Line, Tumor, Cell Proliferation, Chronic Disease, Disease Progression, Drug Resistance, Neoplasm, Female, Humans, Hypercapnia/complications, Lung Diseases, Obstructive/complications, Male, Middle Aged, Pancreatic Neoplasms/drug therapy, Retrospective Studies",

author = "Avinoam Nevler and Brown, {Samantha Z} and David Nauheim and Carla Portocarrero and Ulrich Rodeck and Jonathan Bassig and Schultz, {Christopher W} and McCarthy, {Grace A} and Harish Lavu and Yeo, {Theresa P} and Yeo, {Charles J} and Brody, {Jonathan R}",

year = "2020",

month = apr,

doi = "10.1016/j.jamcollsurg.2019.12.033",

language = "English",

volume = "230",

pages = "659--667",

journal = "Journal of the American College of Surgeons",

issn = "1072-7515",

publisher = "Lippincott Williams and Wilkins",

number = "4",

}

Nevler, A, Brown, SZ, Nauheim, D, Portocarrero, C, Rodeck, U, Bassig, J, Schultz, CW, McCarthy, GA, Lavu, H, Yeo, TP, Yeo, CJ & Brody, JR 2020, 'Effect of Hypercapnia, an Element of Obstructive Respiratory Disorder, on Pancreatic Cancer Chemoresistance and Progression', Journal of the American College of Surgeons, vol. 230, no. 4, pp. 659-667. https://doi.org/10.1016/j.jamcollsurg.2019.12.033

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

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.

KW - Aged

KW - Carcinoma, Pancreatic Ductal/drug therapy

KW - Cell Line, Tumor

KW - Cell Proliferation

KW - Chronic Disease

KW - Disease Progression

KW - Drug Resistance, Neoplasm

KW - Female

KW - Humans

KW - Hypercapnia/complications

KW - Lung Diseases, Obstructive/complications

KW - Male

KW - Middle Aged

KW - Pancreatic Neoplasms/drug therapy

KW - Retrospective Studies

U2 - 10.1016/j.jamcollsurg.2019.12.033

DO - 10.1016/j.jamcollsurg.2019.12.033

M3 - Article

C2 - 32058016

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 -

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

Abstract

Keywords

UN SDGs

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