Open AccessPhenotypic modifications in ovarian cancer stem cells following Paclitaxel treatment
Author(s) -
Craveiro Vinicius,
YangHartwich Yang,
Holmberg Jennie C.,
Sumi Natalia J.,
Pizzonia John,
Griffin Brian,
Gill Sabrina K.,
Silasi DanArin,
Azodi Masoud,
Rutherford Thomas,
Alvero Ayesha B.,
Mor Gil
Publication year - 2013
Publication title -
cancer medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.403
H-Index - 53
ISSN - 2045-7634
DOI - 10.1002/cam4.115
Subject(s) - cd44 , cancer stem cell , stem cell , cancer research , ovarian cancer , biology , in vivo , paclitaxel , cancer , in vitro , microbiology and biotechnology , genetics
Epithelial ovarian cancer ( EOC ) is the most lethal gynecologic malignancy. Despite initial responsiveness, 80% of EOC patients recur and present with chemoresistant and a more aggressive disease. This suggests an underlying biology that results in a modified recurrent disease, which is distinct from the primary tumor. Unfortunately, the management of recurrent EOC is similar to primary disease and does not parallel the molecular changes that may have occurred during the process of rebuilding the tumor. We describe the characterization of unique in vitro and in vivo ovarian cancer models to study the process of recurrence. The in vitro model consists of GFP +/ CD 44+/MyD88+ EOC stem cells and mCherry+/ CD 44−/MyD88− EOC cells. The in vivo model consists of mCherry+/ CD 44+/MyD88+ EOC cells injected intraperitoneally. Animals received four doses of Paclitaxel and response to treatment was monitored by in vivo imaging. Phenotype of primary and recurrent disease was characterized by quantitative polymerase chain reaction ( qPCR ) and Western blot analysis. Using the in vivo and in vitro models, we confirmed that chemotherapy enriched for CD 44+/MyD88+ EOC stem cells. However, we observed that the surviving CD 44+/MyD88+ EOC stem cells acquire a more aggressive phenotype characterized by chemoresistance and migratory potential. Our results highlight the mechanisms that may explain the phenotypic heterogeneity of recurrent EOC and emphasize the significant plasticity of ovarian cancer stem cells. The significance of our findings is the possibility of developing new venues to target the surviving CD 44+/MyD88+ EOC stem cells as part of maintenance therapy and therefore preventing recurrence and metastasis, which are the main causes of mortality in patients with ovarian cancer.