Annexin A2 is regulated by ovarian cancer-peritoneal cell interactions and promotes metastasis

Abstract

Our recent research identified the protein annexin A2 to be regulated by ovarian cancer-peritoneal cell interactions. This study investigated the role of annexin A2 in ovarian cancer metastasis and its potential utility as a novel therapeutic target, using in vitro and in vivo ovarian cancer models. Annexin A2 expression was examined by qRT-PCR and western blotting in ovarian cancer cell lines and immunohistochemistry in serous ovarian carcinoma tissues. Annexin A2 siRNAs were used to evaluate the effects of annexin A2 suppression on ovarian cancer cell adhesion, motility, and invasion. Furthermore, annexin A2 neutralizing antibodies were used to examine the role of annexin A2 in tumor invasion and metastasis in vivo using a chick chorioallantoic membrane assay and an intraperitoneal xenograft mouse model. Strong annexin A2 immunostaining was observed in 90% (38/42) of the serous ovarian cancer cells and was significantly increased in the cancer-associated stroma compared to non-malignant ovarian tissues. Annexin A2 siRNA significantly inhibited the motility and invasion of serous ovarian cancer cells and adhesion to the peritoneal cells. Annexin A2 neutralizing antibodies significantly inhibited OV-90 cell motility and invasion in vitro and in vivo using the chick chorioallantoic membrane assay. The growth of SKOV-3 cells and their peritoneal dissemination in nude mice was significantly inhibited by annexin A2 neutralizing antibodies. Annexin A2 plays a critical role in ovarian cancer metastasis and is therefore a potential novel therapeutic target against ovarian cancer.

WOMEN IN CANCER PROFILE: My pathway to understanding the role of the tumour microenvironment in cancer progression

“…These in vitro observations concur with a recent study highlighting that acquired chemotherapy resistance in ovarian cancer patients is associated with 23:11 the increased expression of the ABC transporter, ABCB1 (Patch et al 2015). Importantly, we have demonstrated that serum HA levels are increased in ovarian cancer patients following chemotherapy and at recurrence, and can predict prognosis (Ricciardelli et al 2013). Reducing HA production is, therefore, a promising strategy to improve ovarian cancer survival in patients with chemoresistant disease and a focus of ongoing research.…”

“…These studies have led to the identification of several proteins that are mechanistically involved in the peritoneal spread of ovarian cancer and may serve as novel ovarian cancer biomarkers and/or therapeutic targets. Studies with Ph.D. students Noor Lokman and Miranda Ween identified a key link between the annexin A2 signalling pathway and activation of the plasminogen-plasmin system (Ween et al 2011b, Lokman et al 2013, Ricciardelli et al 2015. Our findings, together with published literature, support the notion that ECM processing via the plasminogenplasmin pathway promotes the colonisation and attachment of ovarian cancer cells to the peritoneum and actively contributes to the early stages of ovarian cancer metastasis.…”

“…Recent studies focussing on the tumour microenvironment have identified that the ECM molecule HA, plays an important role in both ovarian cancer invasion and the development of chemotherapy resistance (Ween et al 2011a, Ricciardelli et al 2013. Our studies have confirmed that HA plays an important role in promoting attachment of cancer cells to peritoneal cells via interactions with the HA receptor, CD44 (Ween et al 2011a).…”

“…Our studies have confirmed that HA plays an important role in promoting attachment of cancer cells to peritoneal cells via interactions with the HA receptor, CD44 (Ween et al 2011a). We have also shown that HA can induce resistance to the chemotherapeutic drug carboplatin and increase the expression of ABC transporters that function as drug efflux pumps in ovarian cancer cell lines (Ricciardelli et al 2013). These in vitro observations concur with a recent study highlighting that acquired chemotherapy resistance in ovarian cancer patients is associated with 23:11 the increased expression of the ABC transporter, ABCB1 (Patch et al 2015).…”

“…Our findings, together with published literature, support the notion that ECM processing via the plasminogenplasmin pathway promotes the colonisation and attachment of ovarian cancer cells to the peritoneum and actively contributes to the early stages of ovarian cancer metastasis. Targeting the annexin A2 signalling pathway with annexin A2 neutralising antibodies (Lokman et al 2013) or the plasminogen-plasmin system with plasmin inhibitors are both promising strategies to inhibit ovarian cancer metastasis.…”