Activated coagulation factors in human malignant effusions and their contribution to cancer cell metastasis and therapy.
We have shown that the thrombin G-protein coupled receptors (GPCR) designated as protease-activated receptors (PAR-1) are expressed in primary cancer cells isolated from peritoneal and pleural malignant effusions. Here, our main goal was to evaluate several coagulation and thrombin activation effectors and markers in a series of 136 malignant effusions from cancer patients with gastrointestinal, lung and mammary carcinomas. All these patients present a highly activated coagulation system in blood and their malignant effusions, as indicated by high levels of prothrombin F1.2 fragments and D-dimers. Notably, we detected in the effusions all the coagulation factors of the tissue factor pathway inducing thrombin activation, namely factors VII, V, X and II, as well as high VEGF levels and IGF-II in mature and precursor forms. Fibrin clot formation also correlated with higher levels of free ionized calcium (iCa), suggesting that iCa and its binding protein albumin are regulatory factors for fibrinogenesis in effusions. Consequently, thrombin, VEGF and IGFII appear to converge in the promotion of survival and invasivity of the metastatic cancer cells from blood to the malignant effusions. Thus, we add new insights on the interconnections between blood coagulation disorders in cancer patients and thrombin activation in malignant effusions, including their functional interaction with PAR in metastatic cancer cells. Based on these data we propose to counteract the metastatic cascades by targeted invalidation of key effectors of the coagulation system. Therefore, potential therapeutic approaches include the application of thrombin protease inhibitors, VEGF-blocking antibodies, and drugs targeting the VEGF and thrombin signaling pathways, such as tyrosine kinase or GPCR inhibitors.
Gieseler
Frank
F
University Hospital of Kiel, Schittenhelmstr. 12, 24105 Kiel, Germany. gieseler@oncology.uni-kiel.de
Lühr
Inke
I
Kunze
Thomas
T
Mundhenke
Christoph
C
Maass
Nicolai
N
Erhart
Tobias
T
Denker
Momme
M
Beckmann
Dennis
D
Tiemann
Markus
M
Schulte
Christoph
C
Dohrmann
Peter
P
Cavaillé
Françoise
F
Godeau
François
F
Gespach
Christian
C
D000368:Aged; D000970:Antineoplastic Agents / Q000494:pharmacology / Q000627:therapeutic use; D000991:Antithrombins / Q000032:analysis; D001202:Ascitic Fluid / Q000737:chemistry* / Q000473:pathology; D001777:Blood Coagulation / Q000187:drug effects; D001779:Blood Coagulation Factors / Q000032:analysis* / Q000378:metabolism; D001943:Breast Neoplasms / Q000097:blood / Q000737:chemistry; D002118:Calcium / Q000032:analysis; D016022:Case-Control Studies; D005165:Factor V / Q000032:analysis; D005167:Factor VII / Q000032:analysis; D005170:Factor X / Q000032:analysis; D005260:Female; D005337:Fibrin / Q000032:analysis; D005338:Fibrin Fibrinogen Degradation Products / Q000032:analysis; D005770:Gastrointestinal Neoplasms / Q000097:blood / Q000737:chemistry; D006801:Humans; D007335:Insulin-Like Growth Factor II; D008175:Lung Neoplasms / Q000097:blood / Q000737:chemistry; D008297:Male; D008875:Middle Aged; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D009369:Neoplasms / Q000097:blood / Q000737:chemistry* / Q000188:drug therapy / Q000473:pathology; D010446:Peptide Fragments / Q000032:analysis; D010490:Pericardial Effusion / Q000737:chemistry* / Q000473:pathology; D016066:Pleural Effusion, Malignant / Q000737:chemistry* / Q000473:pathology; D011506:Proteins / Q000032:analysis; D011516:Prothrombin / Q000032:analysis; D012709:Serum Albumin / Q000032:analysis; D013917:Thrombin / Q000378:metabolism; D013925:Thromboplastin / Q000032:analysis; D042461:Vascular Endothelial Growth Factor A / Q000032:analysis
D000970:Antineoplastic Agents; D000991:Antithrombins; D001779:Blood Coagulation Factors; D005338:Fibrin Fibrinogen Degradation Products; C035170:IGF2 protein, human; D010446:Peptide Fragments; D011506:Proteins; D012709:Serum Albumin; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; C036309:fibrin fragment D; C045879:prothrombin fragment 1.2; D007335:Insulin-Like Growth Factor II; D005165:Factor V; D005167:Factor VII; D011516:Prothrombin; D005170:Factor X; D005337:Fibrin; D013925:Thromboplastin; D013917:Thrombin; D002118:Calcium