Such a mechanism involving the expression of FAS-L on cancer cells and FAS on mesothelial cells has been shown for colon cancer cells (195)

Such a mechanism involving the expression of FAS-L on cancer cells and FAS on mesothelial cells has been shown for colon cancer cells (195). In disagreement with the concept that mesothelial cells shield the underlying ECM from invasion by ovarian cancer cells, prometastatic functions of mesothelial cells have also been described. particular activated mesothelial cells, which line the peritoneal cavity in huge numbers, as well as adipocytes of the omentum, the Ligustroflavone preferred site of metastatic lesions. Another crucial factor is the peritoneal fluid, which enables the transcoelomic spread of tumor cells to other pelvic and peritoneal organs, and occurs at more advanced stages as a malignancy-associated effusion. This ascites is usually rich in tumor-promoting soluble factors, extracellular vesicles and detached cancer cells as well as large Ligustroflavone numbers of T cells, TAMs, and other host cells, which cooperate with resident host cells to support tumor progression and immune evasion. In this review, we summarize and discuss our current knowledge of the cellular and molecular interactions that govern this interplay with a focus on signaling networks formed by cytokines, lipids, and extracellular vesicles; the pathophysiologial functions of TAMs and T cells; the mechanism of transcoelomic metastasis; and the cell type selective processing of signals from the TME. mutations (97%), germline and somatic mutations (~40%), as well as amplification and overexpression of ( Ligustroflavone 50%) (2). According to the prevailing opinion, HGSOCs arise from the fimbriated fallopian tube epithelium (3). There is some evidence to suggest that serous tubal intraepithelial carcinomas (STICs) are precursor lesion of HGSOC, although recent evidence obtained by next-generation sequencing suggests that lesions histologically identified as STICs may actually represent micrometastases (4). Several features contribute to the fatal nature of HGSOC, which distinguish it from other human cancers, in particular, the role of the peritoneal fluid in cancer cell spread: Tumor cells can be shed at a very early stage of the disease. Even at a stage when the primary tumor is still confined to the ovary, cancer cells can be detected in peritoneal lavage fluid. Besides hematogenous dissemination to the omentum (5), the spread of tumor cells to other pelvic and peritoneal organs is usually facilitated by the peritoneal fluid serving as a carrier (6). This transcoelomic dissemination is usually a major route for the adhesion of cancer cells to the omentum and serous membranes lining the peritoneal organs, giving rise to metastatic lesions growing into the peritoneal cavity rather than invading through the lamina propria (6, 7). The peritoneal environment, which is frequently formed by the effusion building up in the peritoneal cavity (ascites), is usually rich in tumor-promoting soluble factors (8), extracellular vesicles (9), highly tumorigenic cancer cells (10), and different types of immune cells, including large numbers of different types of T cells (11), tumor-associated macrophages (TAMs) (12, 13), and other Ligustroflavone MAPT host cells, supporting tumor cell proliferation, progression, chemoresistance, and immune evasion (14C16). In contrast to most other cancers, metastases at distant sites are confined to late stages (6). The most serious problem for most HGSOC patients is usually recurrent, aggressive growth of Ligustroflavone metastatic lesions within the peritoneal cavity. Mechanisms of Therapy Failure Although HGSOC is typically highly sensitive to chemotherapy, a small subgroup ( 10%) is usually refractory to first-line therapy, pointing to a mechanism of inherent resistance. However, even after a clinical remission, most patients suffer from a relapse of the disease (1). While some of these patients are refractory to chemotherapy due to acquired chemoresistance, the majority undergo remission under the same treatment regimen. This regrowth of lesions displaying a similar chemosensitivity as the primary disease points to a mechanism of therapy failure that is fundamentally different form intrinsic or acquired resistance. However, the mechanisms underlying this transient chemoresistance are unknown. A number of studies have associated chemoresistance with epithelialCmesenchymal transition (EMT), cell cycle arrest, blocked apoptosis, drug efflux, and several signaling pathways, including TGF, WNT, and NOTCH, but these observations did not yield a deep understanding of the mechanisms leading to relapse of the disease (17). It has also been a topic of intense research to clarify whether the regrowth of tumors after a complete clinical response is usually caused by a small populace of.