The purpose of this Thesis is to present a Bayesian analysis of oncological data sets with particular focus on cervical carcinomas and ovarian cancers. Bayesian methods of data analysis have a very long history, and have been used with great success in many disciplines, from Physics to Econometrics. Nonetheless, they remain very controversial among statisticians who belong to the orthodox - i.e, frequentist school, and are not well known by the medical community. To help in that direction, we reviewed in the introductory chapter the basic philosophical and practical differences between the two schools, and in the second chapter, we briefly reviewed the history of Bayesian methodology, from the early efforts of Thomas Bayes and of Pierre Simon de Laplace to the modern contributions of Harold Jeffreys, Richard Cox, and Edwin Jaynes. In many aspects of medical research, we deal with experimental data from which a certain proposition or hypothesis is validated. Unlike in physics, where we have strong and solid foundations such as Newton's law of motion, Snell's optical laws, Kirchoff's laws, Einstein's relativity theory, and many more, we do not have such privileges in medical research. Hence, many hypotheses are constantly tested as new evidence becomes available. One of the actively-researched medical areas is cancer research about which our understanding is still in its infancy. Numerous experiments (both in vivo and in vitro) and clinical trials have been conducted to further our knowledge; thus, Bayesian methodology finds its place to aid us in obtaining scientific inferences about certain propositions or hypotheses from available data and resources. In this work, we use data given to us by our medical collaborators at the Princess Margaret Hospital (PMH) in Toronto to carry out two main projects: Firstly, to make an inference about the oxygenation status (oxygen partial pressure, pO$_2$) within human cervical carcinomas and secondly, an inference about the effectiveness of various molecularly-targeted agents (MTAs) in phase II clinical trials of relapsed ovarian cancer patients. In the first problem, we address the challenges of tumor hypoxia - a state of oxygen deprivation in tumors. Currently, there are two methods to obtain tumor oxygen status, namely the direct Eppendorf needle electrode and the indirect immunohistochemical assay of a protein marker, Carbonic Anhydrase IX (CAIX). In this project, we introduce Bayesian probability theory to obtain inferences about tumor oxygenation from each technique and the concordance between the two techniques. From this study, we conclude that under certain conditions, two biopsies are sufficient to infer the tumor oxygenation level based on the immunohistochemical assays of CAIX. Additionally, there is a fair concordance between the direct and the indirect measurements of tumor oxygenation. In the latter problem, ovarian cancer is the topic of study. Ovarian cancer has the highest mortality rate among gynecological cancers and one that is known to relapse. CA-125 is still the most inexpensive biomarker for monitoring ovarian cancers. From the phase II clinical trial data, we demonstrate the survival advantage of CA-125 responsive group of patients by means of a non-parametric Kaplan-Meier statistic.

The purpose of this Thesis is to present a Bayesian analysis of oncological data sets with particular focus on cervical carcinomas and ovarian cancers. Bayesian methods of data analysis have a very long history, and have been used with great success in many disciplines, from Physics to Econometrics. Nonetheless, they remain very controversial among statisticians who belong to the orthodox - i.e, frequentist school, and are not well known by the medical community. To help in that direction, we reviewed in the introductory chapter the basic philosophical and practical differences between the two schools, and in the second chapter, we briefly reviewed the history of Bayesian methodology, from the early efforts of Thomas Bayes and of Pierre Simon de Laplace to the modern contributions of Harold Jeffreys, Richard Cox, and Edwin Jaynes. In many aspects of medical research, we deal with experimental data from which a certain proposition or hypothesis is validated. Unlike in physics, where we have strong and solid foundations such as Newton's law of motion, Snell's optical laws, Kirchoff's laws, Einstein's relativity theory, and many more, we do not have such privileges in medical research. Hence, many hypotheses are constantly tested as new evidence becomes available. One of the actively-researched medical areas is cancer research about which our understanding is still in its infancy. Numerous experiments (both in vivo and in vitro) and clinical trials have been conducted to further our knowledge; thus, Bayesian methodology finds its place to aid us in obtaining scientific inferences about certain propositions or hypotheses from available data and resources. In this work, we use data given to us by our medical collaborators at the Princess Margaret Hospital (PMH) in Toronto to carry out two main projects: Firstly, to make an inference about the oxygenation status (oxygen partial pressure, pO$_2$) within human cervical carcinomas and secondly, an inference about the effectiveness of various molecularly-targeted agents (MTAs) in phase II clinical trials of relapsed ovarian cancer patients. In the first problem, we address the challenges of tumor hypoxia - a state of oxygen deprivation in tumors. Currently, there are two methods to obtain tumor oxygen status, namely the direct Eppendorf needle electrode and the indirect immunohistochemical assay of a protein marker, Carbonic Anhydrase IX (CAIX). In this project, we introduce Bayesian probability theory to obtain inferences about tumor oxygenation from each technique and the concordance between the two techniques. From this study, we conclude that under certain conditions, two biopsies are sufficient to infer the tumor oxygenation level based on the immunohistochemical assays of CAIX. Additionally, there is a fair concordance between the direct and the indirect measurements of tumor oxygenation. In the latter problem, ovarian cancer is the topic of study. Ovarian cancer has the highest mortality rate among gynecological cancers and one that is known to relapse. CA-125 is still the most inexpensive biomarker for monitoring ovarian cancers. From the phase II clinical trial data, we demonstrate the survival advantage of CA-125 responsive group of patients by means of a non-parametric Kaplan-Meier statistic.

Background: Chlamydia trachomatis in women is a risk factor for tubal factor infertility and extra uterine pregnancies, but the impact of a C. trachomatis infection on male fertility is unclear. It is also hypothesized that persistent infection with C. trachomatis, or other microorganisms, might initiate/promote ovarian tumor development. The aims of the thesis were to study whether C. trachomatis serum antibodies in women and men had an impact on infertility diagnoses, semen characteristics, pregnancy rates and pregnancy outcomes; furthermore, to explore associations of C. trachomatis, and Mycoplasma genitalium, plasma antibodies with epithelial ovarian cancer and borderline ovarian tumors, as well as the presence of C. trachomatis bacteria, and other microorganisms, in ovarian tissues. Materials and methods: Papers I and II: 244/226 infertile couples were tested for serum C. trachomatis IgG, IgA, IgM and chlamydial Heat Shock Protein 60 (cHSP60) IgG antibodies. C. trachomatis IgG positive couples were also tested for C. trachomatis DNA in a urine sample. The follow-up period was 14-54 months. 244 spontaneously pregnant women were also tested for serum C. trachomatis IgG antibodies. Papers III and IV: Plasma samples from 291 women with epithelial ovarian cancer, borderline ovarian tumors and benign conditions, and plasma samples from 271 healthy controls, were analyzed for C. trachomatis IgG, IgA and cHSP60-1 IgG and M. genitalium IgG antibodies. Ovarian tissues from 186 women with benign ovaries, borderline ovarian tumors and epithelial ovarian cancer, as well as tissues from the contra lateral ovary in 126 women, were analyzed for the presence of C. trachomatis, M. genitalium, Neisseria gonorrhoeae, HPV and the polyoma viruses BKV and JCV with nucleic acid amplification tests. Results: Papers I and II: The prevalence of C. trachomatis IgG antibodies was higher among infertile than fertile women, and there were 9 couples with ongoing C. trachomatis infections. In men, C. trachomatis IgG and IgA antibodies were associated with a reduced likelihood to achieve pregnancy for the couple, as well as lower sperm concentration, reduced sperm motility and vitality, increased teratozoospermia index and the occurrence of leukocytes. C. trachomatis IgG and cHSP60 IgG antibodies in infertile women were associated with tubal factor infertility, but not with reduced pregnancy rates or outcomes. Paper III: cHSP60-1 IgG antibodies were associated with ovarian cancer belonging to the postulated type II pathogenetic pathway when plasma samples obtained more than one year prior to diagnosis were analyzed. M. genitalium IgG antibodies were associated with borderline ovarian tumors; however a statistical type 1 error cannot be excluded. Paper IV: None of the microorganisms studied were found in the ovarian tissue samples. Conclusions: C. trachomatis IgG and IgA antibodies in the man substantially decreases the chances of the infertile couple to achieve pregnancy, and are associated with subtle negative changes in semen characteristics. C. trachomatis IgG and cHSP60 IgG antibodies in the woman are risk factors for tubal factor infertility. Prospective plasma cHSP60-1 IgG antibodies are associated with type II ovarian carcinomas, but C. trachomatis bacteria, or the other microorganisms studied, could not be detected in benign, borderline or malignant ovarian tissues.

<p>OVARIAN cancer research focuses on answering important questions related to the disease, determining whether new approaches are feasible to contribute towards improving current treatments or discovering new ones. This study focused on the transcriptional regulation of genes that have been implicated in ovarian cancer, based on the occurrences of single nucleotide polymorphisms (SNPs) within transcription factor binding sites (TFBSs). Through the application of several in silico tools, databases and custom programs, this research aimed to contribute toward the identification of potentially bio-medically important genes or SNPs for pre-diagnosis and subsequent treatment planning of ovarian cancer. A total of 379 candidate genes that have been experimentally associated with ovarian cancer were analyzed. This led to the identification of 121 SNPs that were found to coincide with putative TFBSs potentially influencing a total of 57 transcription factors that would normally bind to these TFBSs. These SNPs with potential phenotypic effect were then evaluated among several population groups, defined by the International HapMap consortium resulting in the identification of three SNPs present in five or more of the eleven population groups that have been sampled.</p>

Formål: Formålet med studiet var at opnå en fordybet forståelse af, hvordan kvinder med nyopdaget kræft i æggestokkene oplever egen mestring og hvordan mening og identitet konstrueres i den første periode efter diagnosen er stillet. Metode: Der er anvendt en kvalitativ metode med narrative interviews af seks kvinder, som har fået diagnosticeret kræft i æggestokkene indenfor et halvt år. Til analyse af data anvendtes en narrativ analysemetode ”The Holistic Content Perspective” for at få et helhedsbillede af informanternes selv, som det blev præsenteret i deres fortællinger.  Resultater: Studiet viser tre forskellige udviklingsveje, som må ses i sammenhæng med kvindernes alder, livsperiode samt sygdommens udbredelse. En udviklingsvej anvendtes af de yngre kvinder, som oplever sygdommen så truende for identiteten, at de forsvarer sig ved at fornægte sygdommens alvorlighed og på ingen måde identificerer sig med denne. De vælger at leve livet uændret som før de blev syge og oplevelsen af mening forsøges fastholdt ved hjælp af fornægtelse af sygdommens alvorlighed. En anden udviklingsvej viste sig hos de ældre kvinder, som forstår sygdommen som en del af livet og som hurtigt begynder en proces af meningsdannelse og tilpasning af identiteten, hvor de forholder sig til sygdommen og dens mulige konsekvenser som tab af livet. Disse kvinder lærer at leve med sygdommen, som en del af deres identitet. En tredje udviklingsvej viste sig hos de kvinder, hvor sygdommen var i et fremskredet stadie og hvor fysiske og sociale lidelser bliver dominerende. Disse kvinder har svært ved at opretholde eller finde mening, i stedet præges de af meningsløshed samtidig med, at identiteten er svær at opretholde, idet selvbilledet og selvforståelsen forsvinder, da de ikke længere kan kende sig selv. Konklusion. Konstruering af mening og identitet som en del af det at mestre livet med nyopdaget kræft i æggestokkene er vigtig for kvinderne, men processerne omkring, hvordan kvinderne mestrer, er forskellige afhængig af alder, livsperiode og sygdommens udbredelse. Sundhedsfremmende indsatser for at forbedre mestringsprocesserne hos disse kvinder må derfor tilpasses de forskellige udviklingsveje for at sikre størst mulig sundhed. / Purpose: The purpose of the study was to obtain an increased understanding of how women with newly diagnosed ovarian cancer are experiencing their own coping and how meaning and identity constructed in the first period after the diagnosis Method: Used a qualitative approach with narrative interviews with six women who have been diagnosed with ovarian cancer within six months. Data analysis used a narrative analysis method "The Holistic Content Perspective" to get an overall picture of the informants' themselves, as it was presented in their stories Result: The study shows three different development paths that must be considered in conjunction with women's age, life period, and the spread of disease. A development path used by younger women who experience the disease as threatening to the identity that they defend themselves by denying the seriousness of the disease and in no way identify with this. They choose to live life the same as before they became ill and the experience of meaningful attempts maintained through denial of the seriousness of the disease. Another path of development emerged in the elderly women who understand the disease as a part of life and quickly begin a providing of meaningful and maintenance of identity, how they relate to disease and its potential consequences such as loss of life. These women learn to live with the disease as part of their identity. A third path of development was found in women where the disease was in an advanced stage and the physical and social suffering becomes dominant. These women struggle to retain or find meaning, instead characterized by meaninglessness, while identity is difficult to maintain, with self image and self-understanding recover from, because they can no longer know themselves Conclusion: The construction of meaning and identity as a part of it to cope with newly discovered cancer of the ovary are important for women, but the processes around how women cope, is different depending on age, life duration and spread of the disease. Health promotion interventions to improve coping processes among these women must keep pace with these different development paths to ensure maximum health. / <p>ISBN 978-91-86739-05-8</p>

In general population 1 of 72 women develop ovarian cancer and to 1 of 95 women this disease is lethal. A great number of clinical trials have shown that the course of the disease is not dependent only on the classical prognostic indicators such as histological tumor type, tumor differentiation, stage of the disease or treatment modalities. More than two decades ago the first publications on heredity factors indicated similarity among the patients diagnosed ovarian malignancies and their first degree relatives. The first genetic autosomal dominant inheritance was determined in the high-risk cancer tumor suppressor BRCA1/2 genes. In spite of the abundant number of trials studying the BRCA1/2 genes role in breast and ovarian carcinogenesis still it is not sufficiently clear the influence of these genes for the disease prognosis. The aim of our conducted trial was to determine the BRCA1/2 genes prognostic significance for progression-free and overall survival in the event of advanced ovarian cancer. In case of advanced ovarian cancer the BRCA1/2 mutation frequency was 51,4 %. Among all determined BRCA1/2 gene mutations BRCA1 4035delA or founder mutation was most frequent. It amounted to 63.6%. Non-optimal cytoreduction (p<0,0001 ) , patients’ older age (p=0,005) and absence of BRCA1/2 mutations (p=0,049) are closely connected with a shorter PFS and OS. Only non-optimal cytoreduction was related to a shorter OS (p=0,010). / Bendrojoje populiacijoje 1 iš 72 moterų suserga kiaušidžių vėžiu ir 1 iš 95 moterų miršta nuo šios ligos. Tyrimų duomenys rodo, kad ligos eiga nėra priklausoma vien tik nuo klasikinių prognozinių rodiklių, tokių kaip histologinis naviko tipas, naviko diferenciacija, ligos stadija, taikytas gydymas.Prognozinių veiksnių paieška krypstą link genetinių veiksnių galinčių įtakoti ligos eigą. Literatūros duomenys apie klinikinę BRCA1/2 genų reikšmę yra kontroversiški – nuo visiškai bereikšmio iki ženkliai teigiamo poveikio ligos eigai prognoziniu požiūriu.. Mūsų tyrėjų grupės atlikto tyrimo tikslas buvo nustatyti BRCA1/2 genų mutacijų dažnį ir jų įvairovę tarp pacienčių, sergančių išplitusiu kiaušidžių vėžiu, ir įvertinti šių mutacijų įtaką berecidyviam ir bendrajam išgyvenamumui. Mes nustatėme , kad tarp pacienčių sergančių išplitusių epiteliniu kiaušidžių vėžiu buvo net 51,4 proc. BRCA 1/2 mutacijų genuose turinčių pacienčių. 98,2 proc. šių pacienčių sirgo serozine papiline adenokarcinoma. Šios histologinės formos kiaušidžių vėžio buvo ženkliai daugiau mutuotų BRCA1/2 genų pacienčių grupėje nei tarp pacienčių be mutacijų (p-0,029). Tyrimo metu nustatėme dažniausiai sutinkamą arba bendro protėvio BRCA 1 4035 delA mutaciją bei taip kad statistiškai reikšmingos įtakos sergančiųjų išplitusiu kiaušidžių vėžiu berecidyviam išgyvenamumui turi pacienčių amžius (p=0,005), BRCA1/2 genų mutacijos(p=0,049) bei operacijos apimtis (p<0,0001), o bendrajam išgyvenamumui – tik operacijos... [toliau žr. visą tekstą]

Bendrojoje populiacijoje 1 iš 72 moterų suserga kiaušidžių vėžiu ir 1 iš 95 moterų miršta nuo šios ligos. Tyrimų duomenys rodo, kad ligos eiga nėra priklausoma vien tik nuo klasikinių prognozinių rodiklių, tokių kaip histologinis naviko tipas, naviko diferenciacija, ligos stadija, taikytas gydymas.Prognozinių veiksnių paieška krypstą link genetinių veiksnių galinčių įtakoti ligos eigą. Literatūros duomenys apie klinikinę BRCA1/2 genų reikšmę yra kontroversiški – nuo visiškai bereikšmio iki ženkliai teigiamo poveikio ligos eigai prognoziniu požiūriu.. Mūsų tyrėjų grupės atlikto tyrimo tikslas buvo nustatyti BRCA1/2 genų mutacijų dažnį ir jų įvairovę tarp pacienčių, sergančių išplitusiu kiaušidžių vėžiu, ir įvertinti šių mutacijų įtaką berecidyviam ir bendrajam išgyvenamumui. Mes nustatėme , kad tarp pacienčių sergančių išplitusių epiteliniu kiaušidžių vėžiu buvo net 51,4 proc. BRCA 1/2 mutacijų genuose turinčių pacienčių. 98,2 proc. šių pacienčių sirgo serozine papiline adenokarcinoma. Šios histologinės formos kiaušidžių vėžio buvo ženkliai daugiau mutuotų BRCA1/2 genų pacienčių grupėje nei tarp pacienčių be mutacijų (p-0,029). Tyrimo metu nustatėme dažniausiai sutinkamą arba bendro protėvio BRCA 1 4035 delA mutaciją bei taip kad statistiškai reikšmingos įtakos sergančiųjų išplitusiu kiaušidžių vėžiu berecidyviam išgyvenamumui turi pacienčių amžius (p=0,005), BRCA1/2 genų mutacijos(p=0,049) bei operacijos apimtis (p<0,0001), o bendrajam išgyvenamumui – tik operacijos... [toliau žr. visą tekstą] / In general population 1 of 72 women develop ovarian cancer and to 1 of 95 women this disease is lethal. A great number of clinical trials have shown that the course of the disease is not dependent only on the classical prognostic indicators such as histological tumor type, tumor differentiation, stage of the disease or treatment modalities. More than two decades ago the first publications on heredity factors indicated similarity among the patients diagnosed ovarian malignancies and their first degree relatives. The first genetic autosomal dominant inheritance was determined in the high-risk cancer tumor suppressor BRCA1/2 genes. In spite of the abundant number of trials studying the BRCA1/2 genes role in breast and ovarian carcinogenesis still it is not sufficiently clear the influence of these genes for the disease prognosis. The aim of our conducted trial was to determine the BRCA1/2 genes prognostic significance for progression-free and overall survival in the event of advanced ovarian cancer. In case of advanced ovarian cancer the BRCA1/2 mutation frequency was 51,4 %. Among all determined BRCA1/2 gene mutations BRCA1 4035delA or founder mutation was most frequent. It amounted to 63.6%. Non-optimal cytoreduction (p<0,0001 ) , patients’ older age (p=0,005) and absence of BRCA1/2 mutations (p=0,049) are closely connected with a shorter PFS and OS. Only non-optimal cytoreduction was related to a shorter OS (p=0,010).

Ovarian cancer is thought to be derived from the ovarian surface epithelium (OSE), but it is often diagnosed during the late stages and therefore the events that contribute to the initiation and progression of ovarian cancer are poorly defined. Epidemiological studies have indicated an association between the female reproductive hormones and ovarian cancer etiology, but the direct effects of 17β-estradiol (E2), progesterone (P4), luteinizing hormone (LH) and follicle stimulating hormone (FSH) on disease pathophysiology are not well understood. A novel transgenic mouse model of ovarian cancer was generated that utilized the Cre/loxP system to inducibly express the oncogene SV40 large and small T-Antigen in the OSE. The tgCAG-LS-TAg mice developed poorly differentiated ovarian tumours with metastasis and ascites throughout the peritoneal space. Although P4 had no effect; E2 significantly accelerated disease progression in tgCAG-LS-TAg mice. The early onset of ovarian cancer was likely mediated by E2’s ability to increase the areas of putative preneoplastic lesions in the OSE. E2 also significantly decreased survival time in ovarian cancer cell xenografts. Microarray analysis of the tumours revealed that E2 mainly affects genes involved in angiogenesis and cellular differentiation, proliferation, and migration. These results suggest that E2 acts on the tumour microenvironment in addition to its direct effects on OSE and ovarian cancer cells. In order to examine the role of the gonadotropins in ovarian cancer progression, the tgCAG-LS-TAg mice were treated with 4-vinylcyclohexene-diepoxide (VCD) to induce menopause. Menopause slowed the progression of ovarian cancer due to a change in the histological subtype from poorly differentiated tumours to Sertoli tumours. Using a transgenic mouse model, it was shown that E2 accelerated ovarian cancer progression, while P4 had little effect on the disease. Menopause (elevated levels of LH and FSH) altered the histological subtype of the ovarian tumours in the tgCAG-LS-TAg mouse model. These results emphasize the importance of generating animal models to accurately recapitulate human disease and utilizing these models to develop novel prevention and treatment strategies for women with ovarian cancer.

Resistance to cisplatin (CDDP)-based therapy is a major hurdle to the successful treatment of human ovarian cancer (OVCA) and the chemoresistant phenotype in OVCA cells is associated with Akt-attenuated, p53-mediated apoptosis. Pro-apoptotic functions of p53 involve both transcription-dependent and -independent signaling pathways and dysfunctional localization and/or inactivation of p53 contribute to the development of chemoresistance. PARC is a cytoplasmic protein regulating p53 subcellular localization and subsequent function. Little is known about the molecular mechanisms regulating PARC. Although PARC contains putative caspase-3 cleavage sites, and CDDP is known to induce the activation of caspases and calpains and induce proteasomal degradation of anti-apoptotic proteins, if and how PARC is regulated by CDDP in OVCA is unknown. Here we present evidence that CDDP promotes calpain-mediated PARC down-regulation, mitochondrial and nuclear p53 accumulation and apoptosis in chemosensitive but not resistant OVCA cells. Inhibition of Akt is required to sensitize chemoresistant cells to CDDP in a p53-dependent manner, an effect enhanced by PARC down-regulation. CDDP-induced PARC down-regulation is reversible by inhibitor of calpain but not of caspase-3 or the 26S proteasome. Furthermore, in vitro experiments confirm the ability of calpain in mediating Ca2+-dependent PARC down-regulation. The role of Ca2+ in PARC down-regulation was further confirmed as ionomycin induced PARC down-regulation in both chemosensitive and chemoresistant ovarian cancer cells. The data presented here implicates the regulation of p53 subcellular localization and apoptosis by PARC as a contributing factor in CDDP resistance in OVCA cells and Ca2+/calpain in PARC post-translational processing and chemosensitivity.

Τα stem κύτταρα είναι ένας υποπληθυσμός κυττάρων με δύο κύριες ιδιότητες: αυτοανανέωση και διαφοροποίηση. Τα stem κύτταρα διαμένουν σε ένα εξειδικευμένο μικροπεριβάλλον, την φωλεά, η οποία παίζει σημαντικό ρόλο στη διατήρηση της ισορροπίας μεταξύ της αυτοανανέωσης και της διαφοροποίησης. Τελευταία δεδομένα εισηγούνται ότι ο καρκίνος αναπτύσσεται από ένα υποσύνολο κυττάρων με ιδιότητες ανάλογες αυτών των φυσιολογικών stem κυττάρων. Τα κύτταρα αυτά αποκαλούνται καρκινικά stem κύτταρα. Η θεωρία των καρκίνικών stem κυττάρων υποστηρίζει ότι τα καρκινικά stem κύτταρα εγκαινιάζουν και συντηρούν την ανάπτυξη και εξέλιξη του όγκου, ευθύνονται για την κυτταρική ετερογένεια των καρκίνικών κυττάρων του όγκου, είναι υπεύθυνα για τις μεταστάσεις και παραμένουν στους ασθενείς παρά τη χρήση των συμβατικών χημειοθεραπευτικών παραγόντων. Πρόσφατα δεδομένα πιστοποιούν την ύπαρξη καρκινικών stem κυττάρων στην ωοθήκη. / Stem cells are a subpopulation of cells with two key properties: self-renewal and differentiation. Stem cells reside in a specialized microenvironment, i.e. niche, which plays an important role in the balance between self-renewal and differentiation. Recent data suggest that cancer develops from a subset of cells with properties similar to those of normal stem cells. These cells are called cancer stem cells. Cancer stem cell hypothesis suggest that cancer stem cells initiate and preserve the growth of tumor, they are responsible for cellular heterogeneity and metastasis of tumor and they are, finally, drug-resistant.Latest data suggest the presence of cancer stem cells in the ovary.