How Autophagy Shapes the Tumor Microenvironment in Ovarian Cancer.

Ovarian cancer (OC) is characterized by a high mortality rate due to the late diagnosis and the elevated metastatic potential. Autophagy, a lysosomal-driven catabolic process, contributes to the macromolecular turnover, cell homeostasis, and survival, and as such, it represents a pathway targetable for anti-cancer therapies. It is now recognized that the vascularization and the cellular composition of the tumor microenvironment influence the development and progression of OC by controlling the availability of nutrients, oxygen, growth factors, and inflammatory and immune-regulatory soluble factors that ultimately impinge on autophagy regulation in cancer cells. An increasing body of evidence indicates that OC carcinogenesis is associated, at least in the early stages, to insufficient autophagy. On the other hand, when the tumor is already established, autophagy activation provides a survival advantage to the cancer cells that face metabolic stress and protects from the macromolecules and organelles damages induced by chemo- and radiotherapy. Additionally, upregulation of autophagy may lead cancer cells to a non-proliferative dormant state that protects the cells from toxic injuries while preserving their stem-like properties. Further to complicate the picture, autophagy is deregulated also in stromal cells. Thus, changes in the tumor microenvironment reflect on the metabolic crosstalk between cancer and stromal cells impacting on their autophagy levels and, consequently, on cancer progression. Here, we present a brief overview of the role of autophagy in OC hallmarks, including tumor dormancy, chemoresistance, metastasis, and cell metabolism, with an emphasis on the bidirectional metabolic crosstalk between cancer cells and stromal cells in shaping the OC microenvironment.

Inflammation Associated Pancreatic Tumorigenesis: Upregulation of Succinate Dehydrogenase (Subunit B) Reduces Cell Growth of Pancreatic Ductal Epithelial Cells.

Pancreatic ductal adenocarcinoma (PDAC) is amongst the most fatal malignancies and its development is highly associated with inflammatory processes such as chronic pancreatitis (CP). Since the succinate dehydrogenase subunit B (SDHB) is regarded as tumor suppressor that is lost during cancer development, this study investigated the impact of M1-macrophages as part of the inflammatory microenvironment on the expression as well as function of SDHB in benign and premalignant pancreatic ductal epithelial cells (PDECs). Immunohistochemical analyses on pancreatic tissue sections from CP patients and control individuals revealed a stronger SDHB expression in ducts of CP tissues being associated with a greater abundance of macrophages compared to ducts in control tissues. Accordingly, indirect co-culture with M1-macrophages led to clearly elevated SDHB expression and SDH activity in benign H6c7-pBp and premalignant H6c7-kras PDECs. While siRNA-mediated SDHB knockdown in these cells did not affect glucose and lactate uptake after co-culture, SDHB knockdown significantly promoted PDEC growth which was associated with increased proliferation and decreased effector caspase activity particularly in co-cultured PDECs. Overall, these data indicate that SDHB expression and SDH activity are increased in PDECs when exposed to pro-inflammatory macrophages as a counterregulatory mechanism to prevent excessive PDEC growth triggered by the inflammatory environment.

Ovarian clear cell carcinoma with plasma cell-rich inflammatory stroma: Cytological Findings of a Case.

We report a case of clear cell carcinoma (CCC) of the ovary with plasma cell-rich inflammatory stroma, a recently proposed subtype of CCC, and present the cytological findings. The patient was a 48-year-old woman, who was incidentally found to have a right ovarian tumor during the preoperative work-up for an early-stage adenocarcinoma of the uterine cervix. Cytological examination of an imprint smear of the ovarian tumor and peritoneal washing revealed solid cell clusters of irregular, often dendritic shapes, which were intermingled with many inflammatory cells. "Raspberry bodies" were not found. Histopathological examination of the extirpated ovarian tumor showed the features of CCC with plasma cell-rich inflammatory stroma. This subtype of ovarian CCC poses cytological and histological diagnostic problems, and its differentiation from dysgerminoma is often difficult, because it mostly lacks the hyaline or mucoid stroma. Irregularly shaped clusters of large polyhedral cells, coarsely clumped nuclear chromatin, and plasma cell-rich inflammatory infiltrates suggest CCC, but the cytological differences between dysgerminoma and CCC are often subtle, and immunohistochemical examinations for cytokeratin 7 or epithelial membrane antigen may be necessary. Diagn. Cytopathol. 2017;45:128-132. © 2016 Wiley Periodicals, Inc.

Ovarian clear cell carcinoma with plasma cell-rich inflammatory stroma: a clear cell carcinoma subgroup with distinct clinicopathological features.

AIMS: Ovarian clear cell carcinoma has a unique stroma. Although a hyalinized or mucoid stroma is more common, the stroma sometimes shows a dense inflammatory infiltrate, simulating a dysgerminoma. The aim of this study was to analyse the character and significance of the inflammatory stroma. METHODS AND RESULTS: Twelve of 60 (20%) clear cell carcinomas showed an inflammatory stroma. The inflammatory stroma and hyalinized/mucoid stroma were mutually exclusive. Inflammatory cells were predominantly composed of CD138-positive plasma cells. As compared with the non-inflammatory cases, the epithelial component frequently showed a solid growth pattern and immunoreactivity for cyclooxygenase-2, one of the critical proinflammatory enzymes (P < 0.005). These findings were repeated after heterotransplantation of three clear cell carcinoma cell lines into athymic nude mice. In particular, xenografts of one cell line (JHOC-5) were infiltrated by mature plasma cells, indicating that plasma cell differentiation was stimulated by JHOC-5 cells, independently of T lymphocytes. Clinicopathologically, the frequency of International Federation of Gynaecology and Obstetrics stage III was higher in the cases with an inflammatory stroma than in those without it (P < 0.01). CONCLUSIONS: Clear cell carcinomas with an inflammatory stroma constitute a distinct clinicopathological subgroup. It is strongly suggested that tumour cells themselves are responsible for inducing inflammation and stimulating plasma cell differentiation in a paracrine manner.