Abstract
Chronic inflammation has been linked to promotion of tumorigenesis and metastasis in lung. However, due to lack of a relevant animal model for characterization, the underlying mechanism remains elusive. Lung tumor suppressor gene Gprc5a-knockout (ko) mice are susceptible to lung inflammation, tumorigenesis and metastasis, which resembles the pathological features in human patients. Here, we showed that PTGES/PGE2 signaling was highly associated with lung tumorigenesis and metastasis in Gprc5a-ko mice. Interestingly, Ptges-knockout in mouse lung tumor cells, although reduced their stemness and EMT-like features, still formed tumors and lung metastasis in immune-deficient nude mice, but not in immune-competent mice. This suggests that the major role of PTGES/PGE2 signaling in tumorigenicity and lung metastasis is through immunosuppression. Mechanistically, PTGES/PGE2 signaling intrinsically endows tumor cells resistant to T-cell cytotoxicity, and induces cytokines extrinsically for MDSC recruitment, which is crucial for suppression of T-cell immunity. Importantly, targeting PGE2 signaling in Gprc5a-ko mice by PTGES inhibitor suppressed MDSC recruitment, restored T cells, and significantly repressed lung metastasis. Thus, PTGES/PGE2 signaling links immunosuppression and metastasis in an inflammatory lung microenvironment of Gprc5a-ko mouse model.
Publication types
-
Research Support, Non-U.S. Gov't
MeSH terms
-
4-Butyrolactone / analogs & derivatives
-
4-Butyrolactone / pharmacology
-
4-Butyrolactone / therapeutic use
-
Animals
-
Antineoplastic Agents / pharmacology
-
Antineoplastic Agents / therapeutic use
-
Carcinogenesis / drug effects
-
Carcinogenesis / genetics
-
Carcinogenesis / immunology
-
Cell Line, Tumor
-
Dinoprostone / metabolism*
-
Disease Models, Animal
-
Female
-
HEK293 Cells
-
Humans
-
Lung / immunology
-
Lung / pathology
-
Lung Neoplasms / drug therapy
-
Lung Neoplasms / genetics
-
Lung Neoplasms / immunology*
-
Lung Neoplasms / pathology
-
Mice
-
Mice, Knockout
-
Mice, Nude
-
Myeloid-Derived Suppressor Cells / drug effects
-
Myeloid-Derived Suppressor Cells / immunology
-
Myeloid-Derived Suppressor Cells / metabolism
-
Pneumonia / genetics
-
Pneumonia / immunology
-
Pneumonia / pathology
-
Primary Cell Culture
-
Prostaglandin-E Synthases / antagonists & inhibitors
-
Prostaglandin-E Synthases / metabolism*
-
Receptors, G-Protein-Coupled / genetics*
-
Signal Transduction / drug effects
-
Signal Transduction / immunology
-
T-Lymphocytes / drug effects
-
T-Lymphocytes / immunology
-
T-Lymphocytes / metabolism
-
Thiophenes / pharmacology
-
Thiophenes / therapeutic use
-
Tumor Escape / genetics*
-
Tumor Microenvironment / drug effects
-
Tumor Microenvironment / immunology
Substances
-
4-(benzo(b)thiophen-2-yl)-3-bromo-5-hydroxydihydrofuran-2(3H)-one
-
Antineoplastic Agents
-
GPRC5A protein, mouse
-
Receptors, G-Protein-Coupled
-
Thiophenes
-
Prostaglandin-E Synthases
-
Ptges protein, mouse
-
Dinoprostone
-
4-Butyrolactone