Inflammation and lung carcinogenesis: applying findings in prevention and treatment.
Lung carcinogenesis is a complex process requiring the acquisition of genetic mutations that confer the malignant phenotype as well as epigenetic alterations that may be manipulated in the course of therapy. Inflammatory signals in the lung cancer microenvironment can promote apoptosis resistance, proliferation, invasion, metastasis, and secretion of proangiogenic and immunosuppressive factors. Here, we discuss several prototypical inflammatory mediators controlling the malignant phenotype in lung cancer. Investigation into the detailed molecular mechanisms underlying the tumor-promoting effects of inflammation in lung cancer has revealed novel potential drug targets. Cytokines, growth factors and small-molecule inflammatory mediators released in the developing tumor microenvironment pave the way for epithelial-mesenchymal transition, the shift from a polarized, epithelial phenotype to a highly motile mesenchymal phenotype that becomes dysregulated during tumor invasion. Inflammatory mediators within the tumor microenvironment are derived from neoplastic cells as well as stromal and inflammatory cells; thus, lung cancer develops in a host environment in which the deregulated inflammatory response promotes tumor progression. Inflammation-related metabolic and catabolic enzymes (prostaglandin E(2) synthase, prostaglandin I(2) synthase and 15-hydroxyprostaglandin dehydrogenase), cell-surface receptors (E-type prostaglandin receptors) and transcription factors (ZEB1, SNAIL, PPARs, STATs and NF-kappaB) are differentially expressed in lung cancer cells compared with normal lung epithelial cells and, thus, may contribute to tumor initiation and progression. These newly discovered molecular mechanisms in the pathogenesis of lung cancer provide novel opportunities for targeted therapy and prevention in lung cancer.
Peebles
Katherine A
KA
David Geffen School of Medicine at UCLA, Division of Pulmonary & Critical Care Medicine & Hospitalists, Department of Medicine, UCLA Lung Cancer Research Program, CA, USA. katherine.peebles@gmail.com
Lee
Jay M
JM
Mao
Jenny T
JT
Hazra
Saswati
S
Reckamp
Karen L
KL
Krysan
Kostyantyn
K
Dohadwala
Mariam
M
Heinrich
Eileen L
EL
Walser
Tonya C
TC
Cui
Xiaoyan
X
Baratelli
Felicita E
FE
Garon
Edward
E
Sharma
Sherven
S
Dubinett
Steven M
SM
D000818:Animals; D016588:Anticarcinogenic Agents / Q000008:administration & dosage / Q000627:therapeutic use; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage / Q000627:therapeutic use; D002274:Carcinogens, Environmental / Q000009:adverse effects; D002454:Cell Differentiation / Q000187:drug effects; D002471:Cell Transformation, Neoplastic / Q000187:drug effects / Q000235:genetics; D002908:Chronic Disease; D003043:Cocarcinogenesis; D051546:Cyclooxygenase 2 / Q000502:physiology; D052246:Cyclooxygenase 2 Inhibitors / Q000008:administration & dosage / Q000627:therapeutic use; D016207:Cytokines / Q000502:physiology; D015232:Dinoprostone / Q000378:metabolism; D044127:Epigenesis, Genetic; D006801:Humans; D007249:Inflammation / Q000139:chemically induced / Q000150:complications* / Q000517:prevention & control; D008175:Lung Neoplasms / Q000209:etiology / Q000276:immunology / Q000517:prevention & control* / Q000628:therapy; D051379:Mice; D016032:Randomized Controlled Trials as Topic; D012907:Smoking / Q000009:adverse effects; D019139:Tumor Escape
D016588:Anticarcinogenic Agents; D002274:Carcinogens, Environmental; D052246:Cyclooxygenase 2 Inhibitors; D016207:Cytokines; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; D015232:Dinoprostone