gms | German Medical Science

Appr. 30 % of tumor-patients develop malignant pleural effusions or ascites during the progression of their disease. The tumor cells within these effusions are difficult to treat due to their high resistance to chemotherapy. 86 % of these tumor cells express the thrombin receptors PAR-1 , PAR-3 or both as shown by FACS and PCR. Colorectal tumors (n=4) had a 100% expression of PAR-1 and 0% PAR-3. With NSCLC (n=6) 1 sample was negative, 1 each with only PAR-1 or PAR-3 expression and 3 that expressed both PAR-1 and PAR-3; with 2 PAR-1 positive and 1 PAR-3 positive samples for SCLC (n=3). Other tumors (gastric, pancreatic, melanoma, mammary and NHL with n=9) were 44,4% positive for both PAR-1 and PAR-3, 33.3% for PAR-1 alone and 22,2% were negative. Malignant effusions harbour active thrombin in high concentrations (Schiller, Gieseler, et al. Int J Clin Pharmacol Ther 2002). There was a mean avg. of 9,79 nmol/l F1+F2 fragments in pathological effusions (n=22) and 2,06 in serum (n=21). The normal range in blood serum being 0,4-1,1 nmol/l. The incubation of patient tumor cells that express PAR-1 receptors with malignant effusions or thrombin induces both adhesion and invasion capacity of these cells. E.g., non-small lung cancer tumor cells have been incubated in a fibronectin coated cell chamber. Thrombin induced cell adhesion in a dose-dependent manner with a peak value >50 % with 5 U thrombin/ml. Complementary, effusions from patients with stomach, colon and esophageal carcinoma induced the invasion of HCT8/S11 colon carcinoma cells in a dilution of 1:9 to 1:15 (invasion index range 12 - 20 %, Nguyen, Gieseler, Gespach, et al. Oncogene. 2005 Aug 8). Both adhesion and invasion are important characteristics of tumor cell progression and metastasation. Although we are aware that the thrombin/PAR-1/G-protein pathway is only one of several pathways resulting in the malignant phenotype of the cells, these results point out the importance of the microenvironment for proliferation, metastasation and resistance of tumor cells within malignant effusions. The therapeutical consequences are an issue for discussion.