Various types of tumors, particularly those originating from the ovary and gastrointestinal tract, display a strong predilection for the peritoneal cavity as the site of metastasis. The intraperitoneal spread of a malignancy is orchestrated by a reciprocal interplay between invading cancer cells and resident normal peritoneal cells. In this review, we address the current state-of-art regarding colonization of the peritoneal cavity by ovarian, colorectal, pancreatic, and gastric tumors. Particular attention is paid to the pro-tumoral role of various kinds of peritoneal cells, including mesothelial cells, fibroblasts, adipocytes, macrophages, the vascular endothelium, and hospicells. Anatomo-histological considerations on the pro-metastatic environment of the peritoneal cavity are presented in the broader context of organ-specific development of distal metastases in accordance with Paget’s “seed and soil” theory of tumorigenesis. The activity of normal peritoneal cells during pivotal elements of cancer progression, i.e., adhesion, migration, invasion, proliferation, EMT, and angiogenesis, is discussed from the perspective of well-defined general knowledge on a hospitable tumor microenvironment created by the cellular elements of reactive stroma, such as cancer-associated fibroblasts and macrophages. Finally, the paper addresses the unique features of the peritoneal cavity that predispose this body compartment to be a niche for cancer metastases, presents issues that are topics of an ongoing debate, and points to areas that still require further in-depth investigations.

One of the most neglected aspects of chemotherapy are changes, and possible consequences of these changes, that occur in normal somatic cells. In this review, we summarize effects of selected drugs used to treat ovarian cancer (platin derivatives—cisplatin and carboplatin; and taxanes—paclitaxel and docetaxel) on cellular metabolism, acquisition of reactive stroma features, cellular senescence, inflammatory reactions, apoptosis, autophagy, mitophagy, oxidative stress, DNA damage, and angiogenesis in various types of normal cells, including fibroblasts, epithelial cells, endothelial cells, and neurons. The activity of these drugs against the normal cells is presented from a broader perspective of their desirable anti-tumoral effects.

Adhesion of ovarian cancer cells to the peritoneal mesothelium is a key step in the malignant progression of the disease. In an in vitro study, we showed that the adherence of ovarian cancer cells (of the OVCAR-3, SKOV-3, and A2780 cell lines) to senescent human omentum-derived peritoneal mesothelial cells (HOMCs) was greater than to early passage cells. The process was mediated primarily by the increased interaction of the ␣5␤1 integrin on cancer cells with HOMC-associated fibronectin (FN). In comparison with early passage HOMCs, senescent cells exhibited increased FN mRNA expression levels and produced significantly more FN. To assess the effect of senescence-associated oxidative stress on FN release, HOMCs were rendered senescent by exposure to an oxidant, tert-butyl hydroperoxide. Treatment with tert-butyl hydroperoxide resulted in a significant increase in HOMC FN mRNA and protein expression levels. The effect of oxidative stress on FN synthesis was found to be mediated by transforming growth factor-␤1, whose signaling pathway was controlled at upstream and downstream levels by p38 MAPK. The activity of p38 MAPK increased markedly in senescent HOMCs. Treatment of HOMCs with antioxidants significantly attenuated senescence-associated increases in p38 MAPK activity, production of both transforming growth factor-␤1 and FN, and ovarian cancer cell adhesion. These data indicate that oxidative stress that accompanies senescence may increase Ovarian cancer is still associated with high mortality. The poor outcome is related to a large extent to metastatic spreading of cancer cells within the peritoneal cavity. Attachment of malignant cells to the peritoneal mesothelium is thought to be a critical step in peritoneal dissemination of the disease. Available data indicate that the process is mediated by interactions between extracellular matrix components produced by mesothelial cells and the corresponding adhesion molecules on ovarian cancer cells. A key role is thought to be played by CD44 and ␤1 integrin receptors and their ligands-hyaluronan, fibronectin (FN), and vitronectin. [2][3][4][5][6] FN is a ubiquitous constituent of extracellular matrix. Secreted by cells as a soluble dimer, it is then processed and assembled into insoluble fibrils at the cell surface. 7 FN is involved in many cellular functions including the maintenance of cell shape, tissue repair, cell differentiation, adhesion, and migration. These processes are primarily mediated by binding of the Arg-Gly-Asp (RGD) sequence of the FN molecule to integrin receptors (especially to ␣5␤1 and ␣ V ␤3).8 It has been demonstrated that FN released by peritoneal mesothelial cells stimulates ovarian cancer cell motility in vitro.9 Moreover, competitive inhibition of FN by RGD-containing peptides has been reported to decrease peritoneal spreading of ovarian cancer cells in mice. 10 More recently it has been demonstrated that the attachment of ovarian cancer cells to the peritoneum results in up-regulation of their matrix metalloproteinase-2, which cleaves mesot...

In contrast to the well-recognized replicative and stress-induced premature senescence of normal somatic cells, mechanisms and clinical implications of senescence of cancer cells are still elusive and uncertain from patient-oriented perspective. Moreover, recent years provided multiple pieces of evidence that cancer cells may undergo senescence not only in response to chemotherapy or ionizing radiation (the so-called therapy-induced senescence) but also spontaneously, without any external insults. Since the molecular nature of the latter process is poorly recognized, the significance of spontaneously senescent cancer cells for tumor progression, therapy effectiveness, and patient survival is purely speculative. In this review, we summarize the most up-to-date research regarding therapy-induced and spontaneous senescence of cancer cells, by delineating the most important discoveries regarding the occurrence of these phenomena in vivo and in vitro. This review provides data collected from studies on various cancer cell models, and the narration is presented from the broader perspective of the most critical findings regarding the senescence of normal somatic cells.

Intercellular adhesion molecule-1 (ICAM-1) has been implicated in adhesion of colorectal and pancreatic cancer cells (of the SW480 and PSN-1 line, respectively) to the peritoneal mesothelium. It has been demonstrated that ICAM-1 expression increases with senescence in some cell types, however, the significance of this phenomenon in the context of malignant dissemination remains elusive. In this report we show that the adherence of SW480 and PSN-1 cells to senescent human omentum-derived mesothelial cells (HOMCs) in vitro is greater than to early-passage cells and that the effect is mediated by ICAM-1. Senescent HOMCs display increased expression of ICAM-1 mRNA and cell surface protein. The development of this phenotype is related to increased oxidative stress in senescent cells. The augmented ICAM-1 expression in HOMCs can be reduced by culturing cells with antioxidants; in contrast, exposure of HOMCs to an oxidant, t-BHP, leads to cellular senescence and increased ICAM-1 expression. The effect is partly mediated by activation of p38 MAPK and AP-1 signaling pathways. Finally, culture of HOMCs in the presence of a strong antioxidant, PBN, significantly reduces the senescence-associated increase in SW480 and PSN-1 cancer cell binding. These results indicate that increased oxidative stress and increased expression of ICAM-1 in senescent HOMCs may facilitate peritoneal adhesion of selected colorectal and pancreatic cancers.