Biology subjects

Zawieja, D. C.

Publications and source records attributed to Zawieja, D. C..

2 recordsLinked to original sources

bioRxiv2020

Inflammatory state of lymphatic vessels and miRNA profiles associated with relapse in ovarian cancer patients

Lymphogenic spread is associated with poor prognosis in epithelial ovarian cancer (EOC), yet little is known regarding roles of non-peri-tumoural lymphatic vessels (LVs) outside the tumour microenvironment that may impact relapse. The aim of this feasibility study was to assess whether inflammatory status of the LVs and/or changes in the miRNA profile of the LVs have potential prognostic and predictive value for overall outcome and risk of relapse. Samples of macroscopically normal human lymph LVs (n=10) were isolated from the external iliac vessels draining the pelvic region of patients undergoing debulking surgery. This was followed by quantification of the inflammatory state (low, medium and high) and presence of cancer-infiltration of each LV using immunohistochemistry. LV miRNA expression profiling was also performed, and analysed in the context of high versus low inflammation, and cancer-infiltrated versus non-cancer-infiltrated. Results were correlated with clinical outcome data including relapse with an average follow-up time of 13.3 months. The presence of a high degree of inflammation correlated significantly with patient relapse (p=0.033). Cancer-infiltrated LVs showed a moderate but non-significant association with relapse (p=0.07). Differential miRNA profiles were identified in cancer-infiltrated LVs and those with high versus low inflammation. In particular, several members of the let-7 family were consistently down-regulated in highly inflamed LVs (>1.8-fold, p<0.05) compared to the less inflamed ones. Down-regulation of the let-7 family appears to be associated with inflammation, but whether inflammation contributes to or is an effect of cancer-infiltration requires further investigation.

cancer biology↗

bioRxiv2020

Cdc42 is required for lymphatic branching, maturation and valve formation during embryonic development

Cdc42, a Ras-related GTPase that regulates the actin cytoskeleton, was recently shown to play an indispensable role in vasculogenesis and endothelial cell (EC) survival. Here, we determined whether Cdc42 also contributes to lymphatic development by generated two different Cdc42 knockout mice lines by crossing Cdc42/flox mice with either vascular endothelial cadherin-Cre (Cdh5-Cre) mice or Prox1-CreERT2 mice. Our results demonstrated that depleting ECs of Cdc42 expression resulted in embryonic lethality with severe edema. Whole-mount immunofluorescence staining of both knockout embryos showed that the deletion of Cdc42 in ECs impaired lymphatic vessel branching and that the lymphatic lumen size significantly increased. Moreover, we found that the inactivation of Cdc42 compromised mesenteric collecting lymphatic vessel maturation and prevented valve formation. We go on to show that Cdc42 can be activated by vascular endothelial growth factor c (VEGFc) in cultured human dermal lymphatic ECs (HDLECs), and that knocking down Cdc42 expression in these cells using siRNA decreased VEGFc-induced focal adhesion kinase (FAK) phosphorylation. These findings, when taken together with the fact that inactivating FAK plus one allele of Cdc42 in ECs was sufficient to recapitulate the phenotypes of the Cdc42 EC knockout embryos, suggests that Cdc42 and FAK interact genetically during lymphatic development. In addition, Cdc42 and FAK regulated signal transduction is essential for blood and lymphatic vessel separation. Taken together, our data highlights the important role played by Cdc42 in the development of the lymphatic system.

developmental biology↗