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

Endovenous Laser Ablation of Varicose Veins Preserves Biological Properties of Vascular Endothelium and Modulates Proinflammatory Agent Profile More Favorably Than Classic Vein Stripping

Here we compared effect of serum from varicose patients undergoing endovenous laser ablation (EVLA) and classic vein stripping (CVS) on biological properties of endothelial cells and on the local and systemic profiles of proinflammatory agents. Results showed that serum from EVLA patients improved proliferation and reduced senescence and oxidative stress in the endothelial cells, as compared with the serum from CVS patients. These effects were related to a suppressed activity of TGF-β1, the level of which in the serum from the EVLA patients was decreased. Medium generated by the cells subjected to EVLA serum contained decreased amounts of ICAM-1, VCAM-1, and E-selectin and increased amount of uPA, whereas the serum itself contained decreased concentrations of ICAM-1, E-selectin, and P-selectin and increased concentrations of uPA, PAI-1, and TFPI. Both EVLA and CVS resulted in diversified patients’ reaction with respect to a direction of postprocedure changes in proinflammatory factors’ serum level. Analysis of proportions showed that the groups differed remarkably in case of ICAM-1 and ET-1, the level of which declined in a higher fraction of patients treated endovenously. Our findings indicate that EVLA preserves better than CVS the functionality of vascular endothelium and modulates better both local and systemic profile of proinflammatory mediators

A Unique Pattern of Mesothelial-Mesenchymal Transition Induced in the Normal Peritoneal Mesothelium by High-Grade Serous Ovarian Cancer

The study was designed to establish whether high aggressiveness of high-grade serous ovarian cancer cells (HGSOCs), which display rapid growth, advanced stage at diagnosis and the highest mortality among all epithelial ovarian cancer histotypes, may be linked with a specific pattern of mesothelial-mesenchymal transition (MMT) elicited by these cells in normal peritoneal mesothelial cells (PMCs). Experiments were performed on primary PMCs, stable and primary ovarian cancer cells, tumors from patients with ovarian cancer, and laboratory animals. Results of in vitro and in vivo tests showed that MMT triggered by HGSOCs (primary cells and OVCAR-3 line) is far more pronounced than the process evoked by cells representing less aggressive ovarian cancer histotypes (A2780, SKOV-3). Mechanistically, HGSOCs induce MMT via Smad 2/3, ILK, TGF-1, HGF, and IGF-1, whereas A2780 and SKOV-3 cells via exclusively Smad 2/3 and HGF. The conditioned medium from PMCs undergoing MMT promoted the progression of cancer cells and the effects exerted by the cells triggered to undergo MMT by the HGSOCs were significantly stronger than those related to the activity of their less aggressive counterparts. Our findings indicate that MMT in PMCs provoked by HGSOCs is stronger, proceeds via different mechanisms and has more procancerous characteristics than MMT provoked by less aggressive cancer histotypes, which may at least partly explain high aggressiveness of HGSOCs

High Potency of a Novel Resveratrol Derivative, 3,3′,4,4′-Tetrahydroxy-trans-stilbene, against Ovarian Cancer Is Associated with an Oxidative Stress-Mediated Imbalance between DNA Damage Accumulation and Repair

We explored the effect of a new resveratrol (RVT) derivative, 3,3′,4,4′-tetrahydroxy-trans-stilbene (3,3′,4,4′-THS), on viability, apoptosis, proliferation, and senescence of three representative lines of ovarian cancer cells, that is, A2780, OVCAR-3, and SKOV-3, in vitro. In addition, the mechanistic aspects of 3,3′,4,4′-THS activity, including cell redox homeostasis (the production of reactive oxygen species, activity of enzymatic antioxidants, and magnitude of DNA damage accumulation and repair), and the activity of caspases (3, 8, and 9) and p38 MAPK were examined. The study showed that 3,3′,4,4′-THS affects cancer cell viability much more efficiently than its parent drug. This effect coincided with increased generation of reactive oxygen species, downregulated activity of superoxide dismutase and catalase, and excessive accumulation of 8-hydroxy-2′-deoxyguanosine and its insufficient repair due to decreased expression of DNA glycosylase I. Cytotoxicity elicited by 3,3′,4,4′-THS was related to increased incidence of apoptosis, which was mediated by caspases 3 and 9. Moreover, 3,3′,4,4′-THS inhibited cancer cell proliferation and accelerated senescence, which was accompanied by the activation of p38 MAPK. Collectively, our findings indicate that 3,3′,4,4′-THS may constitute a valuable tool in the fight against ovarian malignancy and that the anticancer capabilities of this stilbene proceed in an oxidative stress-dependent mechanism

Correction: Pakuła et al. Deciphering the Molecular Mechanism of Spontaneous Senescence in Primary Epithelial Ovarian Cancer Cells. <i>Cancers</i> 2020, <i>12</i>, 296

In the original publication [...

Deciphering the Molecular Mechanism of Spontaneous Senescence in Primary Epithelial Ovarian Cancer Cells

Spontaneous senescence of cancer cells remains a puzzling and poorly understood phenomenon. Here we comprehensively characterize this process in primary epithelial ovarian cancer cells (pEOCs). Analysis of tumors from ovarian cancer patients showed an abundance of senescent cells in vivo. Further, serially passaged pEOCs become senescent after a few divisions. These senescent cultures display trace proliferation, high expression of senescence biomarkers (SA-β-Gal, γ-H2A.X), growth-arrest in the G1 phase, increased level of cyclins D1, D2, decreased cyclin B1, up-regulated p16, p21, and p53 proteins, eroded telomeres, reduced activity of telomerase, predominantly non-telomeric DNA damage, activated AKT, AP-1, and ERK1/2 signaling, diminished JNK, NF-κB, and STAT3 pathways, increased formation of reactive oxygen species, unchanged activity of antioxidants, increased oxidative damage to DNA and proteins, and dysfunctional mitochondria. Moreover, pEOC senescence is inducible by normal peritoneal mesothelium, fibroblasts, and malignant ascites via the paracrine activity of GRO-1, HGF, and TGF-β1. Collectively, pEOCs undergo spontaneous senescence in a mosaic, telomere-dependent and telomere-independent manner, plausibly in an oxidative stress-dependent mechanism. The process may also be activated by extracellular stimuli. The biological and clinical significance of pEOC senescence remains to be explored