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Cancers (Basel). 2019 Feb 19;11(2). pii: E243. doi: 10.3390/cancers11020243.

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

Author information

1
Fiona Elsey Cancer Research Institute, Ballarat, VIC 3350, Australia. Elif@fecri.org.au.
2
Department of Obstetrics and Gynaecology, University of Melbourne, Melbourne, VIC 3052, Australia. emily.ern@gmail.com.
3
Department of Surgery, Royal Melbourne Hospital, University of Melbourne, Melbourne, VIC 3052, Australia. rluwor@unimelb.edu.au.
4
Fiona Elsey Cancer Research Institute, Ballarat, VIC 3350, Australia. George@fecri.org.au.
5
School of Health and Life Science, Federation University Australia, Ballarat, VIC 3010, Australia. George@fecri.org.au.
6
Department of Obstetrics and Gynaecology, University of Melbourne, Melbourne, VIC 3052, Australia. jock.findlay@hudson.org.au.
7
Centre for Reproductive Health, The Hudson Institute of Medical Research, Clayton, VIC 3168, Australia. jock.findlay@hudson.org.au.
8
Fiona Elsey Cancer Research Institute, Ballarat, VIC 3350, Australia. nuzhata@unimelb.edu.au.
9
Department of Obstetrics and Gynaecology, University of Melbourne, Melbourne, VIC 3052, Australia. nuzhata@unimelb.edu.au.
10
School of Health and Life Science, Federation University Australia, Ballarat, VIC 3010, Australia. nuzhata@unimelb.edu.au.
11
Centre for Reproductive Health, The Hudson Institute of Medical Research, Clayton, VIC 3168, Australia. nuzhata@unimelb.edu.au.

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.

KEYWORDS:

Dasatinib; ascites; cancer stem cells; chemoresistance; chemotherapy; ovarian carcinoma; paclitaxel

PMID:
30791462
DOI:
10.3390/cancers11020243
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