Altered purinergic signaling in the tumor associated immunologic microenvironment in metastasized non-small-cell lung cancer.
OBJECTIVE
Purines are well-known as intracellular sources for energy but they also act as extracellular signaling molecules. In the recent years, there has been a growing interest in the therapeutic potential of purinergic signaling for cancer treatment. This is the first study to analyze lung purine levels and purinergic receptors in non-small-cell lung cancer (NSCLC) patients.


METHODS
In this prospective clinical trial we enrolled 26 patients with NSCLC and 21 patients with chronic obstructive pulmonary disease (COPD) without signs of malignancy. The purine concentrations were analyzed in bronchoalveolar lavage fluid (BALF) using fluorescent/luminescent assays. Expression of purinergic receptors and ectonucleotidases were analyzed using real time quantitative polymerase chain reaction (RT-qPCR).


RESULTS
Patients with NSCLC have significantly lower ATP and ADP concentrations in BALF than patients with COPD (p=0.006 and p=0.009). Expression of the ectonucleotidase CD39 is significantly higher in BAL cells from cancer patients compared to COPD (p=0.001) as well as in metastasized tumors compared to non-metastasized tumors (p=0.009). Receptor-analysis revealed a higher expression of P2X4 (p=0.03), P2X7 (p=0.001) and P2Y1 (p=0.003) in BAL cells of tumors with distant metastasis.


CONCLUSIONS
Our data suggests a role for CD39 in lung cancer tumor microenvironment, influencing tumor invasiveness and metastasization. Potentially the increased degradation of ATP and ADP leads to a subversion of their anti-neoplastic effects. Furthermore P2Y1, P2X4 and P2X7 receptors are upregulated in BAL cells in metastatic disease. Our findings might facilitate the identification of new therapeutic targets for cancer immunotherapy.
University Medical Center Freiburg, Department of Thoracic Surgery, Freiburg, Germany. Electronic address: severin.schmid@uniklinik-freiburg.de.
Severin
S
Schmid
University Medical Center Freiburg, Department of Thoracic Surgery, Freiburg, Germany.
Markus
M
Kübler
University Medical Center Freiburg, Department of Pneumology, Freiburg, Germany.
C
C
Korcan Ayata
Semmelweis University, Department of Pneumology, Budapest, Hungary.
Zsofia
Z
Lazar
University Medical Center Freiburg, Department of Thoracic Surgery, Freiburg, Germany.
Benedikt
B
Haager
University Medical Center Freiburg, Department of Pneumology, Freiburg, Germany.
Madelon
M
Hoßfeld
University Medical Center Freiburg, Department of Pneumology, Freiburg, Germany.
Anja
A
Meyer
University Medical Center Freiburg, Department of Pneumology, Freiburg, Germany.
Sanja
S
Cicko
University Medical Center Freiburg, Department of Thoracic Surgery, Freiburg, Germany.
Mirjam
M
Elze
University Medical Center Freiburg, Department of Thoracic Surgery, Freiburg, Germany.
Sebastian
S
Wiesemann
University Medical Center Freiburg, Department of Pneumology, Freiburg, Germany.
Gernot
G
Zissel
University Medical Center Freiburg, Department of Thoracic Surgery, Freiburg, Germany.
Bernward
B
Passlick
University Medical Center Freiburg, Department of Pneumology, Freiburg, Germany.
Marco
M
Idzko
D000244:Adenosine Diphosphate / Q000378:metabolism; D000255:Adenosine Triphosphate / Q000378:metabolism; D000368:Aged; D015703:Antigens, CD / Q000378:metabolism; D001081:Apyrase / Q000378:metabolism; D001992:Bronchoalveolar Lavage Fluid; D002289:Carcinoma, Non-Small-Cell Lung / Q000235:genetics / Q000276:immunology* / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D005260:Female; D006801:Humans; D008175:Lung Neoplasms / Q000235:genetics / Q000276:immunology* / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D008297:Male; D008875:Middle Aged; D009362:Neoplasm Metastasis; D029424:Pulmonary Disease, Chronic Obstructive / Q000235:genetics / Q000276:immunology / Q000378:metabolism / Q000503:physiopathology; D011983:Receptors, Purinergic / Q000378:metabolism; D015398:Signal Transduction; D059016:Tumor Microenvironment / Q000276:immunology*
D015703:Antigens, CD; D011983:Receptors, Purinergic; D000244:Adenosine Diphosphate; D000255:Adenosine Triphosphate; D001081:Apyrase; C067869:CD39 antigen
CD39; Lung cancer; P2-receptor; Purinergic signaling; Tumor microenvironment