Wewnątrzotrzewnowa inwazyjność raka jajnika z perspektywy komórkowej i molekularnej

Peritoneal cavity is the primary site of ovarian cancer metastasis. It is believed that the intraperitoneal invasiveness of the malignancy is determined by interactions between cancer cells and the normal peritoneal mesothelium. The nature of these interactions is, however, unclear, which is the reason of divergent opinions about the role of mesothelial cells in the progression of the disease. According to some authors, the mesothelium acts as a barrier that prevents the expansion of the tumor cells. According to others, however, these cells actively promote various elements of cancer cell invasiveness. The aim of this study was to present the Reader both the concepts on the role of mesothelial cells in the intraperitoneal development of ovarian cancer metastasis, with particular emphasis on mechanisms of reciprocal interaction between the normal and the cancer cells.Jama otrzewnowa jest głównym miejscem powstawania przerzutów raka jajnika. Uważa się, że wewnątrzotrzewnowa inwazyjność tego nowotworu jest uwarunkowana wzajemnymi oddziaływaniami pomiędzy komórkami rakowymi a prawidłowymi komórkami mezotelium otrzewnowego. Natura tych oddziaływań jest jednak niejasna, co jest powodem rozbieżnych opinii na temat roli komórek mezotelialnych w postępie choroby. Według części autorów, mezotelium pełni funkcję bariery, powstrzymującej ekspansję komórek nowotworowych. Według innych badaczy, natomiast, komórki te aktywnie promują różnego rodzaju wykładniki ich inwazyjności. Celem niniejszej pracy było przybliżenie Czytelnikowi obu koncepcji dotyczących roli mezotelium w powstawaniu wewnątrzotrzewnowych przerzutów raka jajnika, ze szczególnym uwzględnieniem mechanizmów wzajemnych oddziaływań między komórkami prawidłowymi a nowotworowymi

Synthetic Resveratrol Analogue, 3,3\u27,4,4\u27,5,5\u27-Hexahydroxy-trans-Stilbene, Accelerates Senescence in Peritoneal Mesothelium and Promotes Senescence-Dependent Growth of Gastrointestinal Cancers

3,3\u27,4,4\u27,5,5\u27-Hexahydroxy-trans-stilbene (M8) is a synthetic resveratrol derivative, advertised as a candidate drug highly effective against numerous malignancies. Because multiple tumors prone to M8 frequently metastasize into the peritoneal cavity, this study was aimed at establishing the effect of M8 on the growth and senescence of human peritoneal mesothelial cells (HPMCs), the largest cell population within the peritoneum, actively involved in the intraperitoneal spread of cancer. The study showed that M8, used at the highest non-toxic dose of 10 μM, impairs proliferation and accelerates senescence in cultured HPMCs via an oxidative stress-dependent mechanism. At the same time, soluble factors released to the environment by HPMCs that senesced prematurely in response to M8 promoted growth of colorectal and pancreatic carcinomas in vitro. These findings indicate that M8 may indirectly—through the modification of normal (mesothelial) cells phenotype—facilitate an expansion of cancer cells, which challenges the postulated value of this stilbene in chemotherapy

Higher Serum Hepatocyte Growth Factor Concentration is Associated with Better Preservation of GFR in Hemodialysis Patients

Background/Aims: Hemodialysis induces an intravascular inflammatory reaction which may further deteriorate renal function. We studied changes of serum interleukin 6 (IL6) and hepatocyte growth factor (HGF) concentrations during dialysis sessions, and at 12 month intervals. The synthesis of these cytokines in arterial endothelial cells in the presence of serum obtained from dialyzed patients was studied. Changes of the inflammatory reaction during 12 months of treatment were correlated with GFR. Methods: The study was performed on a group of 30 uremic patients treated with hemodialysis. Serum samples were collected before the start of dialysis, 15 minutes, and 4 hours later, when the session was finished. Serum levels of IL6 and HGF were measured with ELISA, as was the effect of serum samples on the synthesis of these cytokines in arterial endothelial cells. Results: At baseline hemodialysis induced an increase of serum IL6 (+10%) and HGF (+164%) levels at the end of the session. After 12 months of treatment predialysis serum IL 6 level was increased as compared to the beginning of the study (+22%), but no change in serum HGF level was observed. At that time the dialysis-induced rise of serum IL6 level was stronger than at the start (+18%), but the observed effect for HGF was weaker (+116%). An inverse correlation was observed between the dialysis-induced increase of HGF level and decrease of GFR after 12 months of study. The same relation was seen for HGF synthesis in the endothelium, but opposite for IL6 synthesis in the endothelium. Conclusions: We found that a higher HGF serum level during hemodialysis treatment is associated with a slower loss of residual renal function

Sulodexide Reduces the Proinflammatory Effect of Serum from Patients with Peripheral Artery Disease in Human Arterial Endothelial Cells

Background/Aims: Dysfunction of the arterial endothelial cells promotes the progression of atherosclerosis. We studied how exposure of human arterial endothelial cells to atherosclerotic serum from patients with peripheral artery disease changes the secretory activity of these cells, and whether that reaction is modified by sulodexide. Methods: Endothelial cells in in vitro culture were exposed to standard culture medium ± 100pg/mL Interleukin-1(IL-1) or to medium supplemented with 20% atherosclerotic serum. Afterwards, the expression of genes responsible for the synthesis of Interleukin-6 (IL-6), Vascular Cell Adhesion Protein-1 (VCAM-1) and Von Willebrand Factor (VWF) was evaluated, together with the secretion of these compounds. Additionally, the effect of sulodexide on these processes was studied. Results: Atherosclerotic serum stimulated the expression of IL6, VCAM-1 and VWF genes in endothelial cells, which was followed by increased secretion of these compounds by 179%, 121% and 116%, respectively. Sulodexide (0.5 LRU/mL) reduced atherosclerotic serum-induced increased expression of genes for IL-6 (-32%), VCAM-1 (-20%) and VWF (-42%), and lowered secretion of these molecules: IL-6 (-27%), VCAM-1(-27%), VWF (-25%). Sulodexide also reduced, in a dose- dependent manner, secretion of IL6 from unstimulated and stimulated with IL-1 endothelial cells. Conclusions: Atherosclerotic serum induces proinflammatory and prothrombotic phenotype in arterial endothelium, which is partially reduced by sulodexide, via inhibition of genes expression, and in consequence lower secretory activity

Serum from Varicose Patients Induces Senescence-Related Dysfunction of Vascular Endothelium Generating Local and Systemic Proinflammatory Conditions

Although the role of endothelium in varicose vein development is indisputable, the effect of the pathology on biological properties of endothelial cells remains unclear. Here we examined if the presence of varicose veins affects senescence of endothelial cells (HUVECs) and, if so, what will be the local and systemic outcome of this effect. Experiments showed that HUVECs subjected to serum from varicose patients display improved proliferation, increased expression of senescence marker, SA-β-Gal, and increased generation of reactive oxygen species (ROS), as compared with serum from healthy donors. Both increased SA-β-Gal activity and ROS release were mediated by TGF-β1, the concentration of which in varicose serum was elevated and the activity of which in vitro was prevented using specific neutralizing antibody. Senescent HUVECs exposed to varicose serum generated increased amounts of ICAM-1, VCAM-1, P-selectin, uPA, PAI-1, and ET-1. Direct comparison of sera from varicose and healthy donors showed that pathological serum contained increased level of ICAM-1, VCAM-1, P-selectin, uPA, and ET-1. Calendar age of healthy subjects correlated positively with serum uPA and negatively with P-selectin. Age of varicose patients correlated positively with ICAM-1, VCAM-1, and ET-1. Collectively, our findings indicate that the presence of varicose veins causes a senescence-related dysfunction of vascular endothelium, which leads to the development of local and systemic proinflammatory environment

Sulodexide Slows Down the Senescence of Aortic Endothelial Cells Exposed to Serum from Patients with Peripheral Artery Diseases

Background/Aims: Aging of the arterial endothelial cells results in the appearance of their inflammatory phenotype, which may predispose patients to the acceleration of arteriosclerosis. We studied the effect of serum from patients with peripheral artery disease (PAD) on the senescence of human aortic endothelial cells (HAEC) and how that process is modulated by sulodexide. Methods: HAEC replicative aging in vitro was studied in the presence of 10% PAD-serum (PAD Group) or10%PAD serum and Sulodexide 0.5 LRU/mL (PAD-SUL group). In control group cells were cultured in medium supplemented with 10% fetal bovine serum. All studied parameters were evaluated at the beginning and at the end of the study, in all experimental groups. Population doubling time (PDT) was studied from the cells growth rate after repeated passages, and senescence-associated beta- galactosidase activity (SA-β gal activity) was measured with the fluorescence flow cytometry. Expression of IL6, vWF, p21 and p53 genes was measured with the real-time polymerase chain reaction (Real-Time PCR). Concentrations of IL6 and vWF were measured with the standard ELISA kits. Results: PAD serum accelerated the senescence of HAEC as reflected by increased, compared to control, expression of the IL6 gene (+43%, p<0.05) vWF gene (+443%, p<0.01), p21 gene (+ 124%, p<0.01) and p53 gene (+ 85%, p<0.01). Secretion of IL6 and vWF was higher in that group: + 101%, p<0.01 and + 78%, p<0.01, respectively, as compared to control. Also, SA-β gal activity was higher in the PAD group (+33%, p<0.05) than in the control group. In the PAD group PDT was longer (+108%, p<0.01) as compared to control. Simultaneous use of Sulodexide with PAD serum significantly reduced all the above described senescent changes in HAEC. Conclusions: PAD serum accelerates the aging of HAEC which may result in the faster progression of arteriosclerosis. Sulodexide reduces PAD induced senescence of HAEC, which results in lower inflammatory and thrombogenic activity of these cells