title: Tumor necrosis factor links chronic obstructive pulmonary disease and K-ras mutant lung cancer through induction of an immunosuppressive pro-tumor microenvironment.
abstract: Tumor necrosis factor (TNF) is known as an important regulator of tumor microenvironment and inflammation. TNF levels are markedly elevated in the bronchoalveolar lavage fluid (BALF) of patients with chronic obstructive pulmonary disease (COPD), which is an independent risk factor for lung cancer. We have previously shown that COPD-like airway inflammation promotes lung cancer in a K-ras mutant mouse model (CC-LR mouse). This was associated with a significant increase of neutrophils in BALF, accompanied by a marked increase in TNF level, suggesting a link between COPD, TNF, and lung cancer promotion. Therefore, we first overexpressed TNF in the airway epithelium of CC-LR mice, which promoted lung cancer by ∼2-fold. This was associated with increased numbers of Ki67 and CD31 positive cells in lung tumors of CC-LR/TNF-Tg mice. We also found a robust increase in NF-κB activation, and numbers of neutrophils and myeloid-derived suppressor cells (MDSCs) in lung. Accordingly, we depleted MDSCs in CC-LR/TNF-Tg mice, which lead to significant tumor suppression emphasizing on the role of TNF-induced MDSCs in K-ras induced lung tumorigenesis. Finally, we targeted TNF expression by crossing CC-LR mice with TNF knock-out mice (CC-LR/TNF-KO), which resulted in a significant decrease in lung tumor burden in the absence or presence of COPD-like airway inflammation. Interestingly, there were less MDSCs and lower Ki67 and CD31 expression in the lung of the CC-LR/TNF-KO mice. We conclude that TNF links COPD to lung cancer promotion by induction of an immunosuppressive MDSC response, and subsequent amplification of proliferation and angiogenesis in tumors.
authors.affiliation: Department of Pulmonary Medicine, The University of Texas M. D. Anderson Cancer Center, Houston, TX, USA; Department of Esophageal Cancer, Tianjin's Clinical Research Center for Cancer and Key Laboratory of Cancer Prevention and Therapy, National Clinical Research Center for Cancer, Tianjin Medical University Cancer Institute and Hospital, Tianjin, People's Republic of China.
authors.forename: Lei
authors.initials: L
authors.lastname: Gong
authors.affiliation: Department of Pulmonary Medicine, The University of Texas M. D. Anderson Cancer Center , Houston, TX, USA.
authors.forename: Mauricio
authors.initials: M
authors.lastname: da Silva Caetano
authors.affiliation: Department of Pulmonary Medicine, The University of Texas M. D. Anderson Cancer Center , Houston, TX, USA.
authors.forename: Amber M
authors.initials: AM
authors.lastname: Cumpian
authors.affiliation: Department of Pulmonary Medicine, The University of Texas M. D. Anderson Cancer Center , Houston, TX, USA.
authors.forename: Soudabeh
authors.initials: S
authors.lastname: Daliri
authors.affiliation: Tecnológico de Monterrey School of Medicine , Monterrey, Nuevo León, Mexico.
authors.forename: Alejandra
authors.initials: A
authors.lastname: Garza Flores
authors.affiliation: Department of Immunology, The University of Texas M. D. Anderson Cancer Center , Houston, TX, USA.
authors.forename: Seon Hee
authors.initials: SH
authors.lastname: Chang
authors.affiliation: Department of Pulmonary Medicine, The University of Texas M. D. Anderson Cancer Center, Houston, TX, USA; Tecnológico de Monterrey School of Medicine, Monterrey, Nuevo León, Mexico.
authors.forename: Cesar E
authors.initials: CE
authors.lastname: Ochoa
authors.affiliation: Division of Pulmonary Sciences and Critical Care Medicine, University of Colorado Denver School of Medicine , Aurora, CO, USA.
authors.forename: Christopher M
authors.initials: CM
authors.lastname: Evans
authors.affiliation: Department of Esophageal Cancer, Tianjin's Clinical Research Center for Cancer and Key Laboratory of Cancer Prevention and Therapy, National Clinical Research Center for Cancer, Tianjin Medical University Cancer Institute and Hospital , Tianjin, People's Republic of China.
authors.forename: Zhentao
authors.initials: Z
authors.lastname: Yu
authors.affiliation: Department of Pulmonary Medicine, The University of Texas M. D. Anderson Cancer Center, Houston, TX, USA; The University of Texas Graduate School of Biomedical Sciences, Houston, TX, USA.
authors.forename: Seyed Javad
authors.initials: SJ
authors.lastname: Moghaddam
keywords: COPD; K-ras; MDSC; NF-κB; TNF; lung cancer