Abstract
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.
Highlights
Epithelial Ovarian cancer (EOC) accounts for over 4000 deaths in the UK every year [1]
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
Ethics committee approval was obtained from Hammersmith and Queen Charlotte’s and Chelsea Research Ethics Committee (REC reference: 05/Q0406/178), and tissue samples were provided by the Imperial College Healthcare NHS Trust Tissue Bank (ICHTB)
Summary
Epithelial Ovarian cancer (EOC) accounts for over 4000 deaths in the UK every year [1]. The collapse of intra-tumoural LVs is due to some combination of the high interstitial pressure observed in multiple types of tumours, a lack of lymphatic valves, or induced mechanical pressure of growing tumour cells [6]. In both mice and humans, functional peri-tumoural lymphatics remain [6]. LVs can facilitate metastases both passively and through active changes in lymphatic endothelial cell (LEC) expression that aid cancer-cell infiltration, allowing subsequent drainage to LNs [8]. Tumour cells can arrest within the draining LVs and form in-transit metastases, and in some cases escape the LVs, contributing to loco-regional metastasis, potentially aided by altered LV barrier integrity [8]
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