Abstract
Notch signaling is frequently activated in ovarian cancer (OC) and contributes to the proliferation and survival of cultured OC cells as well as to tumor formation and angiogenesis in xenograft models. Several studies demonstrate that Notch3 expression renders cancer cells more resistant to carboplatin, contributing to chemoresistance and poor survival of OC-bearing patients. This suggests that Notch3 can represent both a biomarker and a target for therapeutic interventions in OC patients. Although it is still unclear how chemoresistance arises, different lines of evidence support a critical role of cancer stem cells (CSCs), suggesting that CSC targeting by innovative therapeutic approaches might represent a promising tool to efficiently reduce OC recurrence. To date, CSC-directed therapies in OC tumors are mainly targeted to the inhibition of CSC-related signaling pathways, including Notch. As it is increasingly evident the involvement of Notch signaling, and in particular of Notch3, in regulating stem-like cell maintenance and expansion in several tumors, here we provide an overview of the current knowledge of Notch3 role in CSC-mediated OC chemoresistance, finally exploring the potential design of innovative Notch3 inhibition-based therapies for OC treatment, aimed at eradicating tumor through the suppression of CSCs.
Highlights
Ovarian cancer (OC) is relatively rare but it represents the most lethal gynecologic malignancy worldwide, being the fifth principal cause of cancer mortality in women [1]
About 200,000 new OC cases are estimated worldwide every year, with 150,000 deaths [2]. This high mortality-to-incidence ratio is essentially due to the absence of OC-specific symptoms and the lack of effective screening strategies that lead many women to be diagnosed at an advanced stage of the disease, when cancer metastases are already present in the abdominal cavity [3]
Besides the high number of genes related to drug efflux and DNA damage repair, which contribute to cancer stem cells (CSCs) resistance to conventional chemotherapy, the specific role of Notch signaling pathway, mainly of Notch3, has been well established in the regulation of CSC behavior and platinum chemoresistance [6]
Summary
Ovarian cancer (OC) is relatively rare (nearly 3% of all female tumors) but it represents the most lethal gynecologic malignancy worldwide, being the fifth principal cause of cancer mortality in women [1]. The general prognosis in OC patients remains poor, with a 5-year survival rate of about 50% [1] In this scenario, the high percentage of therapeutic failure is mainly due to the occurrence of drug resistance, which is directly correlated with the presence of cancer stem cells (CSCs) [5,6,7]. Besides the high number of genes related to drug efflux and DNA damage repair, which contribute to CSC resistance to conventional chemotherapy, the specific role of Notch signaling pathway, mainly of Notch, has been well established in the regulation of CSC behavior and platinum chemoresistance [6]. We draw a picture on the current knowledge about the role of Notch in ovarian CSC behavior regulation, in order to suggest potential Notch inhibition-based cancer treatments aimed at improving the prognosis of OC patients
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