Justyna Mikuła-Pietrasik

Serum from Hypertensive Patients Induces Cancer-Supporting Phenotype of Vascular Endothelium In Vitro

Background/Objectives: Large-scale epidemiological studies have established a bidirectional association between hypertension and cancer. However, the underlying mechanisms explaining this connection remain unclear. In our study, we investigated whether serum from patients with hypertension (HT) could enhance the aggressiveness of cancer cells in vitro through alterations in endothelial cell phenotype. Methods: Experiments were performed using EAhy926 endothelial cells and ovarian (SKOV-3), colorectal (SW480), pancreatic (PSN-1), breast (MCF-7), and lung (A549) cancer cell lines. Results: This study showed that conditioned medium (CM) produced by EAhy926 cells, when exposed to serum from patients with untreated hypertension (HT-CM), promotes the proliferation, migration, and invasion of every cancer cell line tested. In addition, endothelial cells subjected to HT serum promote the adhesion of all cancer cell types except PSN-1. An intensified transendothelial invasion of cancer cells was accompanied by decreased expression of junctional proteins (connexin 43, E-cadherin, occluding, desmoglein) in HT serum-treated endothelial cells. Quantitative analysis of the secretome of endothelial cells subjected to HT serum showed that they secrete increased amounts of CCL2, CXCL1, CXCL8, bFGF, HGF, IL-6, PAI-1, and TGF-β1. Moreover, cancer cells exposed to HT-CM display increased mRNA expression for several pro-cancerogenic agents, including CXCL8, tPA, and VEGF. Conclusions: Our report shows that hypertension may potentiate cancer cell aggressiveness by modulating endothelial cell phenotype. Further tests with antihypertensive drugs are required to assess whether effective treatment of hypertension can mitigate its cancer-promoting potential.

Malignant Ascites Promote Adhesion of Ovarian Cancer Cells to Peritoneal Mesothelium and Fibroblasts

Although malignant ascites (MAs) are known to contribute to various aspects of ovarian cancer progression, knowledge regarding their role in the adhesion of cancer cells to normal peritoneal cells is incomplete. Here, we compared the effect of MAs and benign ascites (BAs) on the adhesion of A2780 and OVCAR-3 cancer cells to omentum-derived peritoneal mesothelial cells (PMCs) and peritoneal fibroblasts (PFBs). The results showed that MAs stimulated the adhesion of A2780 and OVCAR-3 cells to PMCs and PFBs more efficiently than did BAs, and the strongest binding occurred when both cancer and normal cells were exposed to the fluid. Intervention studies showed that MAs-driven adhesion of A2780 cells to PMCs/PFBs depends on the presence of TGF-β1 and HGF, whereas binding of OVCAR-3 cells was mediated by TGF-β1, GRO-1, and IGF-1. Moreover, MAs upregulated α5β1 integrin expression on PFBs but not on PMCs or cancer cells, vimentin expression in all cells tested, and ICAM-1 only in cancer cells. When integrin-linked kinase was neutralized in PMCs or PFBs, cancer cell adhesion to PMCs and PFBs decreased. Collectively, our report shows that MAs may contribute to the early stages of ovarian cancer metastasis by modulating the proadhesive interplay between normal and cancer cells.

Pro-cancerogenic effects of spontaneous and drug-induced senescence of ovarian cancer cells in vitro and in vivo: a comparative analysis

Abstract Background Clinical outcomes of cancer cell senescence are still elusive. Here, we reveal and compare pro-cancerous activity of spontaneously and drug-inducible senescent ovarian cancer cells. Experiments were performed on tumors and tumor-derived primary epithelial ovarian cancer cells (pEOCs) that were obtained from chemotherapy-naïve patients and from patients who received carboplatin (CPT) and paclitaxel (PCT) before cytoreduction. Results The analysis of tumors showed that senescent cancer cells are present in patients from both groups, albeit most frequently and covering a greater area in tissues from chemotherapy-positive women. This in vivo senescence of pEOCs translated to an expression of senescence markers in early-passage cells in vitro. A conditioned medium from senescent pEOCs fueled the cancer progression, including adhesion of non-senescent pEOCs to normal peritoneal cells, and their increased proliferation, migration, invasion, and EMT. Senescent pEOCs’ secretome promoted angiogenic activity of vascular endothelium, induced senescence of normal peritoneal cells, reprogrammed their secretome towards hypersecretion of cancer-promoting proteins, and stimulated motility of cancer cells subjected to a mesothelium- and fibroblast-derived medium. The most striking finding was, however, that spontaneously senescent pEOCs supported all the above pro-cancerous effects more efficiently than drug-inducible senescent cells, which was plausibly related to augmented release of several cancer spread mediators by these cells. The prevalence of spontaneously senescent pEOCs was most evident in experiments on mice when they were able, unlike the drug-inducible cells, to promote the development of drug-sensitive i.p. xenografts. Conclusions Our study shows that spontaneous senescence of pEOCs should be treated as an independent pathogenetic factor of cancer progression.