Gram-negative bacterial infection increases lung cancer metastasis via Toll-like receptor 1 activation and increased cancer cell proliferation post-tumor adhesion

Background: Lung cancer is a leading cause of death partially due to high recurrence rates after surgical resection. Clinical data suggest that post-operative infections may increase the risk of recurrence. Our previous work indicated that increased adhesion of circulating tumors in the context of infection is partially responsible for this phenotype. However, cancer metastasis is a multi-step process, and it is likely that other events following tumor adhesion also play a role. Methods: In vivo intrasplenic injection of murine lung cancer cells into wild type (WT) and Toll-like receptor 4 knockout (TLR4-/-) mice followed by cecal-ligation and puncture (CLP) as a model of post-operative infection or sham surgery were used. H&E staining and immunohistochemistry analysis of Ki67+ cells in the livers of those mice were performed. In vitro proliferation assays were performed on human lung cancer cells using combinations of TLR blockade. Results: We found a 5-fold increase in hepatic metastases in WT CLP mice compared to WT sham mice. TLR4-/- CLP mice had a significant decreased tumor burden compared to WT CLP mice. This indicated an important mechanistic role for the TLR4-initiated host response to gram negative infection post-tumor cell adhesion. By analyzing the livers of those mice, we observed an increase in proliferation of tumor micrometastases in vivo in WT CLP mice as compared to WT sham mice. Here again, CLP TLR4 -/- mice had significantly fewer replicating micrometastases than CLP WT mice. Indeed, we found that direct stimulation of lung cancer cells with heat-inactivated E.Coli resulted in increased proliferation of tumor growth in vitro. These effects were partially abrogated by tumor TLR4 blockade; combined TLR2, 4 and 5 blockades led to a more prominent decrease. Conditioned media from bronchoalveolar epithelial cells treated with lipopolysaccharide lead to increased lung cancer proliferation; these changes were reversed with TLR blockade, indicating that the host response to infection is TLR mediated. Conclusions: Overall, these results imply a more complex mechanistic role of post-operative infection in metastasis. From a clinical standpoint, this evidence strengthens the case for the use of TLR blockade as a potential therapeutic target in the prevention of metastasis.

Systematic Analysis of the Expression and Prognostic Significance of P4HA1 in Pancreatic Cancer and Construction of a lncRNA-miRNA-P4HA1 Regulatory Axis

Objectives. Prolyl 4-hydroxylase subunit alpha 1 (P4HA1) plays a crucial role in modulating extracellular matrix component and promoting tumor progression by changing tumor adhesion, migration, and other biological behaviors in some cancers. However, its expression pattern, biological function, and underlying mechanism in pancreatic cancer remain largely unclear. Materials and Methods. In this study, a set of bioinformatics tools were used to analyze the expression of P4HA1 and its prognostic value in pancreatic cancer. In addition, the mechanism through which P4HA1 promotes the progression of pancreatic cancer was explored by constructing a competing endogenous RNA (ceRNA) regulatory axis. Results. It was found that the mRNA and protein expression of P4HA1 was significantly higher in pancreatic cancer tissues than in normal tissues. Its high P4HA1 expression correlated with poor clinicopathological features (T stage: P = 0.0078 ; N stage: P = 0.0124 ; TNM stage: P = 0.0013 ; pathological grade: P = 0.0108 ) and poor prognosis [OS: HR = 1 , 95% CI (1-1.01), P = 0.00028 ; DSS: HR = 1 , 95% CI (1-1.01), P = 0.00049 ; PFI: HR = 1.01 , 95% CI (1.01-1.02), P = 0.0057 ; and DFI: HR = 1 , 95% CI (1-1.01), P = 0.0034 ]. The LINC01503/miR-335-5p/P4HA1 axis might mediate the effects of P4HA1 in promoting the progression on pancreatic cancer. Conclusions. Collectively, our findings suggest that high expression of P4HA1 may be used as a promising prognostic biomarker and could be considered for the development of a novel therapeutic strategy for pancreatic cancer in the future.

Development of Peritoneal Carcinomatosis in Epithelial Ovarian Cancer: A Review

Epithelial ovarian cancer (EOC) metastasizes intra-abdominally with often numerous, superficial, small-sized lesions. This so-called peritoneal carcinomatosis is difficult to treat, and peritoneal recurrences are frequently observed, leading to a poor prognosis. Underlying mechanisms of interactions between EOC and peritoneal cells are incompletely understood. This review summarizes and discusses the development of peritoneal carcinomatosis from a cell-biological perspective, focusing on characteristics of EOC and peritoneal cells. We aim to provide insight into how peritoneum facilitates tumor adhesion but limits size of lesions and depth of invasion. The development of peritoneal carcinomatosis is a multistep process that requires adaptations of EOC and peritoneal cells. Mechanisms that enable tumor adhesion and growth involve cadherin restructuring on EOC cells, integrin-mediated adhesion, and mesothelial evasion by mechanical forces driven by integrin-ligand interactions. Clinical trials targeting these mechanisms, however, showed only limited effects. Other factors that inhibit tumor growth and deep invasion are virtually unknown. Future studies are needed to elucidate the exact mechanisms that underlie the development and limited growth of peritoneal carcinomatosis. This review on development of peritoneal carcinomatosis of EOC summarizes the current knowledge and its limitations. Clarification of the stepwise process may inspire future research to investigate new treatment approaches of peritoneal carcinomatosis.