fibrin and Peritoneal-Neoplasms

This chapter considered the observations that concern the spread of cancer emboli within the abdominal cavity. These collected observations begin to construct a pathophysiology that allows one to predict some important aspects of disease progression. The factors that should be considered are enumerated in Table 4. Taken together, these factors support an ordered phenomenon whose complete understanding will help design new and more effective treatment strategies.

Topics: Fibrin; Humans; Neoplasm Invasiveness; Neoplasm Seeding; Neoplastic Cells, Circulating; Peritoneal Neoplasms; Pseudomyxoma Peritonei

Peritoneal metastasis is one of the most frequent causes of death in several types of advanced cancers; however, the underlying molecular mechanisms remain largely unknown. In this study, we exploited multicolor fluorescent lineage tracking to investigate the clonality of peritoneal metastasis in mouse xenograft models. When peritoneal metastasis was induced by intraperitoneal or orthotopic injection of multicolored cancer cells, each peritoneally metastasized tumor displayed multicolor fluorescence regardless of metastasis sites, indicating that it consists of multiclonal cancer cell populations. Multicolored cancer cell clusters form within the peritoneal cavity and collectively attach to the peritoneum. In vitro, peritoneal lavage fluid or cleared ascitic fluid derived from cancer patients induces cancer cell clustering, which is inhibited by anticoagulants. Cancer cell clusters formed in vitro and in vivo are associated with fibrin formation. Furthermore, tissue factor knockout in cancer cells abrogates cell clustering, peritoneal attachment, and peritoneal metastasis. Thus, we propose that cancer cells activate the coagulation cascade via tissue factor to form fibrin-mediated cell clusters and promote peritoneal attachment; these factors lead to the development of multiclonal peritoneal metastasis and may be therapeutic targets.

Topics: Animals; Cluster Analysis; Fibrin; Fibrinogen; Humans; Mice; Peritoneal Neoplasms; Peritoneum; Thromboplastin

Cell-free and concentrated ascites reinfusion therapy (CART) is used for the treatment of diuretic-resistant ascites. An increase in circuit pressure and clogging of the filtration membrane often occur in CART for malignant ascites.. To clarify the precise mechanism of filter clogging, we performed an ultrastructural observation study of the filtration membrane after the filtration of malignant ascites.. The deposition on the filtration membrane was composed of blood cells, fibrin, or both. Cellular deposition was associated with a greater number of blood cells in the original ascites fluid. In contrast, fibrin deposition was associated with higher levels of interleukin-6, α1-antitrypsin, haptoglobin, and fibrinogen/fibrin degradation products.. Our results suggest that the specific pathophysiologies of malignancy (such as inflammation or coagulation/fibrinolysis) and characteristics of malignant ascites (highly concentrated and cell-rich) are associated with clogging of the filtration membrane during CART.

Topics: Ascites; Ascitic Fluid; Fibrin; Filtration; Humans; Peritoneal Neoplasms; Treatment Outcome

Peritoneal metastasis (PM) is a very serious complication of gastrointestinal and gynecological malignancies which is poorly documented. Modified mesothelial cell layer and their microenvironments can favor fibrin deposition for cancer cell adhesion. Scanning and transmission electron microscopy of peritoneal surface and cancer cell clusters from cancer patients was done. Ascites and its impact on mesothelial cells were assessed by cytokine array. Neprilysin, matrix metalloprotease, epithelial mesenchymal transition (EMT) related molecules (E-cadherin, Snail, Slug, Twist, Vimentin and Fibronectin), tissues factor (TF), endothelial protein C receptors (EPCR) were quantified by q-PCR. Fibrin in the simples were stained using anti fibrin F1E1 antibody. Migration ability was assessed by scratch assay. Cell viability and neprilysin activity were analyzed by bioluminescence. Cancer cells-fibrin interaction was investigated by scanning electron microscopy (SEM) and microcinematography (MCG). Mesothelial cells change their morphology after incubation with carcinomatosis peritoneal fluids in vitro. EMT associated with upregulation of neprilysin, matrix metalloproteinase-2, tissue factor and cytokines secretions such as interleukin-6, and 8, hepatocyte growth factor and granulocyte chemotactic protein-2 mRNA and protein were observed. EPCR expression as a natural anticoagulant was decreased. In parallel, carcinomatosis cell clusters extracted from peritoneal fluids were found to be associated with fibrin. Kinetic analysis of cancer cell-fibrin interaction in vitro studied by MCG showed that fiber filaments generated from clots inhibited cancer cell adhesion on fibrin clots. These results indicated that fibrin deposit on the peritoneal surface serve as niches for cancer expansion in carcinomatosis patients.

Topics: Biomarkers; Carcinoma; Cell Line, Tumor; Cells, Cultured; Cytokines; Epithelial-Mesenchymal Transition; Female; Fibrin; Gene Expression; Humans; Immunohistochemistry; Peritoneal Neoplasms; Peritoneum; Tumor Microenvironment

Although direct adhesion of cancer cells to the mesothelial cell layer is considered to be a key step for peritoneal invasion of ovarian cancer cell masses (OCM), we recently identified a different strategy for the peritoneal invasion of OCM. In 6 out of 20 cases of ovarian carcinoma, extraperitoneal growth of the OCM was observed along with the neovascularization of feeding vessels, which connect the intraperitoneal host stroma and extraperitoneal lesions through the intact mesothelial cell layer. As an early step, the OCMs anchor in the extraperitoneal fibrin networks and then induce the migration of CD34-positive and vascular endothelial growth factor A (VEGF-A)-positive endothelial cells, constructing extraperitoneal vascular networks around the OCM. During the extraperitoneal growth of OCM, podoplanin-positive and α smooth muscle actin (αSMA)-positive cancer-associated fibroblasts (CAF) appears. In more advanced lesions, the boundary line of mesothelial cells disappears around the insertion areas of feeding vessels and then extraperitoneal and intraperitoneal stroma are integrated, enabling the OCM to invade the host stroma, being associated with CAF. In addition, tissue factors (TF) are strongly detected around these peritoneal implantation sites and their levels in ascites were higher than that in blood. These findings demonstrate the presence of neovascularization around fibrin net-anchored OCMs on the outer side of the intact peritoneal surface, suggesting a novel strategy for peritoneal invasion of ovarian cancer and TF-targeted intraperitoneal anti-cancer treatment. We observed and propose a novel strategy for peritoneal implantation of ovarian cancer. The strategy includes the preinvasive growth of fibrin-anchored cancer cells along with neovascularization on the outer side of the intact peritoneal surface.

Topics: Adult; Aged; Ascites; Endothelial Cells; Epithelium; Female; Fibrin; Humans; Middle Aged; Neoplasm Invasiveness; Neovascularization, Pathologic; Ovarian Neoplasms; Peritoneal Neoplasms; Peritoneum; Vascular Endothelial Growth Factor A