Paclitaxel-Induced Src Activation Is Inhibited by Dasatinib Treatment, Independently of Cancer Stem Cell Properties, in a Mouse Model of Ovarian Cancer.

Elif Kadife,George Kannourakis,Nuzhat Ahmed,Jock Findlay,Rodney Luwor,Emily Chan

doi:10.3390/cancers11020243

Abstract

Approximately seventy percent of ovarian cancer patients succumb to the disease within the first 5 years of diagnosis, even after successful surgery and effective chemotherapy treatment. A small subset of chemotherapy resistant cancer stem cells (CSCs) cause relapse of ovarian cancers. This study investigated the association between paclitaxel-mediated Src activation (p-Src) and CSC populations in driving ovarian cancer progression. We demonstrate that patients with high-stage serous ovarian carcinomas have significantly elevated levels of p-Src, compared to patient with low-stage and benign ovarian tumours. Additionally, p-Src was significantly enhanced in ascites-derived tumour cells obtained from recurrent patients, compared to chemonaïve patients. Paclitaxel treatment increased Src activation in ovarian cancer cells, causing enrichment of CSC marker expression in the surviving cells in vitro and in xenografts of nude mice. Dasatinib in combination with paclitaxel significantly suppressed p-Src in ovarian cancer cell lines and xenografts but had no effect on the expression of CSC markers. However, combination of paclitaxel and Dasatinib showed lower trend in invasion in liver and pancreas, compared to paclitaxel-only treatment. The tumours treated with combination therapy also had significantly lower infiltration of mononuclear cells. Robust recurrent tumour growth was observed in all mice groups after termination of treatments. The above results suggest that Dasatinib-mediated inhibition of p-Src may not be crucial for paclitaxel-induced CSC-mediated recurrence in ovarian cancer.

Highlights

Every twelve hours one woman dies of ovarian cancer worldwide
We demonstrate that ascites-derived tumour cells, isolated from chemotherapy-treated recurrent ovarian cancer patients, have significantly high expression of activated Src compared to ascites-derived tumour cells of chemonaïve patients
Phosphorylated Src is upregulated in response to chemotherapy treatment in ascites-derived patient’s tumour cells and in vitro ovarian cancer cells

Summary

Introduction

Every twelve hours one woman dies of ovarian cancer worldwide. The high mortality rate in ovarian cancer patients results from the diagnosis of the disease at an advanced-stage when the cancer has already spread into the peritoneal cavity [1]. The management of ovarian cancer patients after debulking surgery involves systemic administration of platinum (cisplatin/carboplatin) and taxane-based (paclitaxel) drugs [2]. This treatment regimen results in a significant reduction of tumour burden due to substantial cancer cell death. A five-year survival period of ovarian cancer patients has remained unchanged and as low as ~30–40% for the last forty years [3]. There is an urgent need to identify and target mechanisms, which allow surviving residual cancer cells to overcome the cytotoxic effects of the chemotherapy and propagate within the changed tumour microenvironment

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