ReviewOvarian cancer stem cells: Molecular concepts and relevance as therapeutic targets
Introduction
Ovarian cancer is the most lethal of all gynaecological malignancies and the fifth leading cause of cancer death among women worldwide (Aletti et al., 2007, Jemal et al., 2009). In the majority of the cases, it presents as an advanced metastatic disease where the clinical condition of the patients is compromised by wide spread of cancer to the surrounding abdominal organs (colon, intestine, liver, pancreas, lungs) and accumulation of ascites (tumor fluid) in the peritoneal cavity (Lengyel, 2010, Kipps et al., 2013). Ascites contain single and aggregated clusters of tumor cells as well as a heterogenous population of stromal, red blood and different subsets of immune cells (Latifi et al., 2012). Advanced-stage ovarian cancer patients are treated with primary debulking surgery followed by platinum and taxane-based chemotherapy resulting in a median progression-free survival period of 16–22 months but a subsequent 5-year survival rate of only 27% (Kipps et al., 2013). The latest clinical trials of targeted therapies (bezicumab, imatinib, etc.) as well as the use of combination drugs have failed to improve the outcome of ovarian cancer patients significantly (Matei et al., 2008, Ozols, 2006, Schilder et al., 2008). This is mainly due to a lack of understanding the biology of heterogeneous chemoresistant and recurrent ovarian tumors, thus compromising the efforts to develop treatment modalities for this lethal disease.
Ovarian cancer represents a diverse group of tumors displaying a wide range of morphological features, and genetic-epigenetic alterations each with distinct tumor behaviour (Auersperg et al., 2001, Conic et al., 2011). The heterogeneous nature of ovarian tumors has led to efforts to elucidate the genomic and epigenomic nature of epithelial ovarian cancer (EOC) in particular (Vaughan et al., 2011, Tothill et al., 2008). Of late, the Cancer Genome Atlas (TCGA), using high throughput technologies such as mRNA and microRNA analyses, promoter methylation, DNA copy number changes, and DNA exon sequencing on 489 high-grade serous carcinomas (HGS) published an integrated analyses which provided a comprehensive understanding of the genomic and epigenomic alterations that can affect the clinical outcome of HGS patients (2011). However, the data from the TCGA was derived from primary HGS and does not provide information on the chemoresistant and recurrent EOC. As such, the mechanisms underlying the chemoresistant and recurrent phenotype of ovarian cancer remain relatively unknown resulting in a major hindrance in the development of improved treatments of advanced-stage EOC patients who currently do not have effective treatment options.
One of the emerging concepts in tumor biology is that of ‘cancer stem cell (CSC)’ (Medema, 2013). The CSC theory dictates that the progression and recurrence of cancers are governed by a small subpopulation of CSCs within a tumor which drive tumor progression and relapse due to a recurrent disease (Vermeulen et al., 2008, Vermeulen et al., 2012). Ovarian cancer has been postulated to imitate the CSC model (Aguilar-Gallardo et al., 2012, Curley et al., 2011, Ahmed et al., 2013). The concept that ovarian cancer progression and recurrence is driven by the proliferative and regenerative capacity of CSC has tremendous implications for therapy of ovarian cancer.
This review summarizes the current literature on the existence of normal and cancerous ovarian stem cells and also addresses the cancer stem cell concept in relation to ovarian cancer. We also describe recent data on ovarian CSCs and their interaction with tumor microenvironment in response to therapeutic stress. Considering that the CSC phenotype is influenced by the therapeutic stress-induced ‘CSC niche’ understanding the crosstalk between chemotherapy-treated residual ovarian tumors and their associated microenvironment may help in the development of pre-emptive strategies designed to disrupting the specific ‘pro-stemness’ support required for recurrence. We also provide proof of concept of the ‘ovarian CSC recurrence model’. This supports the ‘Ovarian CSC concept’ and demonstrates that the CSC signature endowed by tumor cells in response to chemotherapy treatment is preserved at relapse in recurrent tumors, emphasising again on the need for the development of CSC-based therapeutic strategies for better management of ovarian cancer patients.
Section snippets
Adult stem cells of the ovaries
Normal tissues constantly undergo turnover as a result of cell death due to age, injury or shedding, and are replaced by new healthy cells. Homeostasis in adult tissues is maintained by a subpopulation of potent tissue-specific stem cells (Berardi et al., 1995, Barker et al., 2007). Despite the fact that the female reproductive tract constantly undergoes tissue remodelling during the reproductive years of a woman (Auersperg et al., 2001), adult stem cells in the ovaries have been understudied.
Development of ovarian cancer
The origin of ovarian cancer stem cells has been hypothesised to result from the wounding and DNA damaging effects of ovulation affecting the slow proliferating stem or progenitor cells residing in the ovarian surface epithelium or its adjacent populations (Auersperg et al., 2001, Flesken-Nikitin et al., 2013). A recent study has demonstrated the presence of common genes that are activated on the ovarian surface epithelium during ovulation and are also over expressed in ovarian cancer in an
Cancer stem cell model and ovarian cancer
The two models of ovarian cancer development described above suggest that the development of ovarian cancer follows the ‘clonal evolution’ theory (Nowell, 1976), in which cancer cells attain genetic mutations that results in the selection of a sub-clonal population of cells with differential phenotypes and malignant potential resulting in a heterogeneous tumor (Alderton, 2013). However, the CSC-model postulates that the initiation and progression of tumors are driven by a small of population of
Chemotherapy and implication for CSCs in ovarian cancer
Systemic administration of platinum and taxane-based drugs is the standard treatment for ovarian cancer patients after debulking surgery. This results in the eradication of majority of tumor burden by eliciting mass cancer cell death via well established DNA and cytoskeletal damage response signalling pathways. Chemotherapy treatment has been shown to be extremely efficient in removing the bulk of the tumor mass, while leaving behind a core of CSC-like cells which are not only very invasive but
Chemotherapeutic treatment results in the generation of ovarian CSCs in vitro and in vivo: a proof of concept experimental model
We have recently demonstrated that the human ovarian HEY cell line treated with cisplatin for five days or paclitaxel for 3 days resulted in surviving residual cells which displayed enhanced expression of ERCC1 and β-tubulin in response to the respective drug treatments. This is consistent with a chemoresistance phenotype of these residual cells induced by the drug treatment (Abubaker et al., 2013). We have also shown chemotherapy-treated residual cells displayed a CSC phenotype as evidenced by
CSC-based targeting of ovarian cancer
Recent searches for therapeutic agents specifically targeted at CSCs in ovarian cancer has been classified into three main classes based on their mode of action: (i) agents that specifically target CSCs with defined expression of markers; (ii) agents that specifically target CSC-mediated pathways; and (iii) high throughput screening of drugs that will specifically target CSC-enriched populations (Kwon and Shin, 2013). These strategies have been discussed in detail in comprehensive reviews on
Conclusions
After the first description of stem cells in ovarian tumors nearly seven years ago (Bapat et al., 2005), significant advances have been made in identifying, characterizing and understanding CSC markers and their biology in ovarian cancer. However, the major challenge still persists in determining the relationship between the identified CSC markers and whether these markers are universal for ovarian cancer as a whole or relate to specific subtypes or grades of ovarian tumors. If we assume that
Acknowledgements
The authors wish to thank Women’s Cancer Foundation for supporting this work. KA is a recipient of an Australian Postgraduate Award. The authors wish to acknowledge and thank Ms François Dobill for her ELISA data and Dr Rod Luwor for his help with the animal experiments.
References (140)
- et al.
Current management strategies for ovarian cancer
Mayo Clin. Proc.
(2007) - et al.
Localization of the stem cell markers LGR5 and Nanog in the normal and the cancerous human ovary and their inter-relationship
Acta Histochem.
(2013) - et al.
Angiogenesis: a promising therapeutic target for ovarian cancer
Crit. Rev. Oncol. Hematol.
(2012) - et al.
Epithelial stem cells: turning over new leaves
Cell
(2007) - et al.
Daoy medulloblastoma cells that express CD133 are radioresistant relative to CD133- cells, and the CD133+ sector is enlarged by hypoxia
Int. J. Radiat. Oncol. Biol. Phys.
(2007) - et al.
Hyaluronan-CD44 interaction activates stem cell marker Nanog, Stat-3-mediated MDR1 gene expression, and ankyrin-regulated multidrug efflux in breast and ovarian tumor cells
J. Biol. Chem.
(2008) EMT and MET in metastasis: where are the cancer stem cells?
Cancer Cell
(2012)- et al.
Ovarian cancer stem cell markers: prognostic and therapeutic implications
Cancer Lett.
(2012) - et al.
A perivascular niche for brain tumor stem cells
Cancer Cell
(2007) - et al.
Multicellular resistance: a paradigm for clinical resistance?
Crit. Rev. Oncol. Hematol.
(2000)
The cell of origin of ovarian epithelial tumours
Lancet Oncol.
Epidemiologic correlates of ovarian cortical inclusion cysts (CICs) support a dual precursor pathway to pelvic epithelial cancer
Gynecol. Oncol.
Systemic presence and tumor-growth promoting effect of ovarian carcinoma released exosomes
Cancer Lett.
Ovarian cancer development and metastasis
Am. J. Pathol.
Metastatic colonization requires the repression of the epithelial-mesenchymal transition inducer Prrx1
Cancer Cell
Intratumoral heterogeneity in the self-renewal and tumorigenic differentiation of ovarian cancer
Stem Cells
Short-term single treatment of chemotherapy results in the enrichment of ovarian cancer stem cell-like cells leading to an increased tumor burden
Mol. Cancer
Overcoming challenges of ovarian cancer stem cells: novel therapeutic approaches
Stem Cell Rev.
Molecular pathways regulating EGF-induced epithelio-mesenchymal transition in human ovarian surface epithelium
Am. J. Physiol. Cell Physiol.
Epithelial-mesenchymal interconversions in normal ovarian surface epithelium and ovarian carcinomas: an exception to the norm
J. Cell Physiol.
Epithelial mesenchymal transition and cancer stem cell-like phenotypes facilitate chemoresistance in recurrent ovarian cancer
Curr. Cancer Drug Targets
Cancerous ovarian stem cells: obscure targets for therapy but relevant to chemoresistance
J. Cell Biochem.
Tumour heterogeneity: the rise of the minority
Nat. Rev. Cancer
Prospective identification of tumorigenic breast cancer cells
Proc. Nat. Acad. Sci. USA
Molecular phenotyping of human ovarian cancer stem cells unravels the mechanisms for repair and chemoresistance
Cell Cycle
Stem-like ovarian cancer cells can serve as tumor vascular progenitors
Stem Cells
Characterization of cultured human ovarian surface epithelial cells: phenotypic plasticity and premalignant changes
Lab Invest.
Ovarian surface epithelium: biology, endocrinology, and pathology
Endocr. Rev.
Stem and progenitor-like cells contribute to the aggressive behavior of human epithelial ovarian cancer
Cancer Res.
Microenvironmental regulation of ovarian cancer metastasis
Cancer Treat Res.
Identification of stem cells in small intestine and colon by marker gene Lgr5
Nature
Origins and molecular pathology of ovarian cancer
Mod. Pathol.
Functional isolation and characterization of human hematopoietic stem cells
Science
Stem cell interaction with somatic niche may hold the key to fertility restoration in cancer patients
Obstet. Gynecol. Int.
Cancer stem cell niche: the place to be
Cancer Res.
Gene expression profiling supports the hypothesis that human ovarian surface epithelia are multipotent and capable of serving as ovarian cancer initiating cells
BMC Med. Genomics
Ovarian carcinoma spheroids disaggregate on type I collagen and invade live human mesothelial cell monolayers
Clin. Exp. Metastasis
Disaggregation and invasion of ovarian carcinoma ascites spheroids
J. Transl. Med.
The cancer stem cell niche–there goes the neighborhood?
Int. J. Cancer
Fibroblasts in omentum activated by tumor cells promote ovarian cancer growth, adhesion and invasiveness
Carcinogenesis
Tissue transglutaminase links TGF-beta, epithelial to mesenchymal transition and a stem cell phenotype in ovarian cancer
Oncogene
Germline cells in ovarian surface epithelium of mammalians: a promising notion
Reprod. Biol. Endocrinol.
C-Kit mediates chemoresistance and tumor-initiating capacity of ovarian cancer cells through activation of Wnt/beta-catenin-ATP-binding cassette G2 signaling
Oncogene
A restricted cell population propagates glioblastoma growth after chemotherapy
Nature
MicroRNA-199a targets CD44 to suppress the tumorigenicity and multidrug resistance of ovarian cancer-initiating cells
FEBS J
Ovarian epithelial cancer stem cells
Sci. World J.
Evidence for cancer stem cells contributing to the pathogenesis of ovarian cancer
Front Biosci
Defining the mode of tumour growth by clonal analysis
Nature
Signal transducers and activators of transcription 3 pathway activation in drug-resistant ovarian cancer
Clin. Cancer Res.
Sustained induction of epithelial to mesenchymal transition activates DNA methylation of genes silenced in basal-like breast cancers
Proc. Nat. Acad. Sci. USA
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2021, Seminars in Cancer BiologyCitation Excerpt :Ovarian cancer stem cells were first found in multicellular spheroids isolated from malignant ascites in patients with advanced ovarian cancer [33]; soon afterward, their presence was verified in an ovarian cancer mouse model by using a side population phenotype [46]. To date, various specific cell surface and functional markers, including CD44, CD117, CD133, CD24, epithelial cell adhesion molecule (EpCAM), and aldehyde dehydrogenase (ALDH) have been utilized to identify and investigate ovarian cancer stem cells [7,34,35,47] (Fig. 1, Table 1). CD44 is an integral membrane glycoprotein that acts as a cell surface receptor for several extracellular matrix (ECM) components, including hyaluronate and osteopontin [48,49].
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2020, Translational OncologyCitation Excerpt :Regimens to treat recurrent EOC are normally informed by responses to first-line therapies and vary significantly; therefore, choice of which agent to use is usually based on toxicity profile, the previous toxicities experienced by the patient, and patient preference (3). Additionally, the aggressiveness of recurrent EOC is mostly attributed to the presence of ovarian cancer stem cells (CSCs), which are chemo-resistant and responsible for the recurrence of cancer [42–45]. Individual patient responses to standardized treatments greatly vary and unfortunately, toxicity profiles are extensive for most chemotherapy drugs with no guarantee of success at the patient level.
Bioengineered adipose-derived stem cells for targeted enzyme-prodrug therapy of ovarian cancer intraperitoneal metastasis
2019, Journal of Controlled ReleaseCitation Excerpt :From our data and similar observations by other groups [35,36], it appears that donor's (patient) treatment with chemotherapeutics may have led to enrichment in CSC populations. While cancer cells develop resistance against anticancer drugs through a variety of different mechanisms [37], overall it appears that the presence of high percentages of ALDH+ cells, CSCs, and MDR-1/ABCG2 positive cells are among the main factors contributing to OVASC-1 cell drug resistance. As a next step, we characterized OVASC-1 cells as tumorspheres because almost all ovarian cancer patients have ascites at recurrence with leaked cancer cells into the peritoneum and existing as spheroids (tumorspheres).
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2019, Journal of Controlled ReleaseCitation Excerpt :Ovarian cancer (OC) is the fifth leading cause of cancer-related deaths among women in the United States and one of the most common gynecological malignancies throughout the world [1].