Recent Technological Advances in Using Mouse Models to Study Ovarian Cancer

Serous epithelial ovarian cancer (SEOC) is the most lethal gynecological cancer in the United States with disease recurrence being the major cause of morbidity and mortality. Despite recent advances in our understanding of the molecular mechanisms responsible for the development of SEOC, the survival rate for women with this disease has remained relatively unchanged in the last two decades. Preclinical mouse models of ovarian cancer, including xenograft, syngeneic, and genetically engineered mice, have been developed to provide a mechanism for studying the development and progression of SEOC. Such models strive to increase our understanding of the etiology and dissemination of ovarian cancer in order to overcome barriers to early detection and resistance to standard chemotherapy. Although there is not a single model that is most suitable for studying ovarian cancer, improvements have led to current models that more closely mimic human disease in their genotype and phenotype. Other advances in the field, such as live animal imaging techniques, allow effective monitoring of the microenvironment and therapeutic efficacy. New and improved preclinical mouse models, combined with technological advances to study such models, will undoubtedly render success of future human clinical trials for patients with SEOC.

[1]  Raphael Kopan,et al.  Real-Time Imaging of Notch Activation with a Luciferase Complementation-Based Reporter , 2011, Science Signaling.

[2]  G. Freeman,et al.  Therapeutic PD-1 pathway blockade augments with other modalities of immunotherapy T-cell function to prevent immune decline in ovarian cancer. , 2013, Cancer research.

[3]  A. Skubitz,et al.  Targeting CD133 in an in vivo ovarian cancer model reduces ovarian cancer progression. , 2013, Gynecologic oncology.

[4]  G. Enikolopov,et al.  Ovarian surface epithelium at the junction area contains cancer-prone stem cell niche , 2013, Nature.

[5]  G. Luker,et al.  Imaging CXCL12-CXCR4 Signaling in Ovarian Cancer Therapy , 2013, PloS one.

[6]  D. Levine,et al.  Successful Eradication of Established Peritoneal Ovarian Tumors in SCID-Beige Mice following Adoptive Transfer of T Cells Genetically Targeted to the MUC16 Antigen , 2010, Clinical Cancer Research.

[7]  R. Drapkin,et al.  Modeling High-Grade Serous Carcinoma: How Converging Insights into Pathogenesis and Genetics are Driving Better Experimental Platforms , 2013, Front. Oncol..

[8]  J. Schorge,et al.  Evidence for cancer stem cells contributing to the pathogenesis of ovarian cancer. , 2011, Frontiers in bioscience.

[9]  N. Dubrawsky Cancer statistics , 1989, CA: a cancer journal for clinicians.

[10]  X. Ye,et al.  Vaccination with embryonic stem cells generates effective antitumor immunity against ovarian cancer. , 2013, International journal of molecular medicine.

[11]  G. Luker,et al.  Noninvasive imaging reveals inhibition of ovarian cancer by targeting CXCL12-CXCR4. , 2011, Neoplasia.

[12]  M. Broggini,et al.  Revisiting ovarian cancer preclinical models: implications for a better management of the disease. , 2013, Cancer treatment reviews.

[13]  Tao Zhang,et al.  Identification of potential biomarkers for ovarian cancer by urinary metabolomic profiling. , 2013, Journal of proteome research.

[14]  D. Matei,et al.  Epithelial ovarian cancer experimental models , 2014, Oncogene.

[15]  K. Garber From human to mouse and back: 'tumorgraft' models surge in popularity. , 2009, Journal of the National Cancer Institute.

[16]  K. Sugamura,et al.  Generation of a syngeneic mouse model to study the intraperitoneal dissemination of ovarian cancer with in vivo luciferase imaging. , 2009, Luminescence : the journal of biological and chemical luminescence.

[17]  I. Dick,et al.  Synergistic Effect of CTLA-4 Blockade and Cancer Chemotherapy in the Induction of Anti-Tumor Immunity , 2013, PloS one.

[18]  Robert M Hoffman,et al.  The challenges posed by cancer heterogeneity , 2012, Nature Biotechnology.

[19]  Andrew J. Wilson,et al.  Tracking NF-κB activity in tumor cells during ovarian cancer progression in a syngeneic mouse model , 2013, Journal of Ovarian Research.

[20]  P. Bitterman,et al.  Detection of Tumor‐Associated Neoangiogenesis by Doppler Ultrasonography During Early‐Stage Ovarian Cancer in Laying Hens , 2010, Journal of ultrasound in medicine : official journal of the American Institute of Ultrasound in Medicine.

[21]  J. Plowman,et al.  In vitro and in vivo evaluation of US-NCI compounds in human tumor xenografts. , 1990, Cancer treatment reviews.

[22]  H. Varmus,et al.  Induction of ovarian cancer by defined multiple genetic changes in a mouse model system. , 2002, Cancer cell.

[23]  L. D. White,et al.  Molecular and Functional Characteristics of Ovarian Surface Epithelial Cells Transformed by KrasG12D and loss of Pten in a Mouse Model in vivo , 2011, Oncogene.

[24]  D. Xing,et al.  A mouse model for the molecular characterization of brca1-associated ovarian carcinoma. , 2006, Cancer research.

[25]  M. Neeman,et al.  Ovarian carcinoma: quantitative biexponential MR imaging relaxometry reveals the dynamic recruitment of ferritin-expressing fibroblasts to the angiogenic rim of tumors. , 2013, Radiology.

[26]  M. Sehested,et al.  [18F]FLT PET for Non-Invasive Assessment of Tumor Sensitivity to Chemotherapy: Studies with Experimental Chemotherapy TP202377 in Human Cancer Xenografts in Mice , 2012, PloS one.

[27]  Gerd Ritter,et al.  Intraepithelial CD8+ tumor-infiltrating lymphocytes and a high CD8+/regulatory T cell ratio are associated with favorable prognosis in ovarian cancer. , 2005, Proceedings of the National Academy of Sciences of the United States of America.

[28]  T. Hagemann,et al.  Ovarian cancer cell–derived migration inhibitory factor enhances tumor growth, progression, and angiogenesis , 2007, Molecular Cancer Therapeutics.

[29]  Y. Bignon,et al.  Major oncogenes and tumor suppressor genes involved in epithelial ovarian cancer (review). , 2000, International journal of oncology.

[30]  C. Molthoff,et al.  Human ovarian cancer xenografts in nude mice: Characterization and analysis of antigen expression , 1991, International journal of cancer.

[31]  G. Vassaux,et al.  Early Treg suppression by a listeriolysin-O-expressing E. coli vaccine in heterologous prime-boost vaccination against cancer. , 2011, Vaccine.

[32]  Jay A. Berzofsky,et al.  NKT cell–mediated repression of tumor immunosurveillance by IL-13 and the IL-4R–STAT6 pathway , 2000, Nature Immunology.

[33]  David A. Tuveson,et al.  The Use of Targeted Mouse Models for Preclinical Testing of Novel Cancer Therapeutics , 2006, Clinical Cancer Research.

[34]  A. Flesken-Nikitin,et al.  Induction of carcinogenesis by concurrent inactivation of p53 and Rb1 in the mouse ovarian surface epithelium. , 2003, Cancer research.

[35]  Annie Y. Liu,et al.  An orthotopic model of platinum-sensitive high grade serous fallopian tube carcinoma. , 2012, International journal of clinical and experimental pathology.

[36]  R. Hoffman,et al.  Human ovarian carcinoma metastatic models constructed in nude mice by orthotopic transplantation of histologically-intact patient specimens. , 1993, Anticancer research.

[37]  J. Tanyi,et al.  Dendritic cell-based tumor vaccinations in epithelial ovarian cancer: a systematic review. , 2012, Immunotherapy.

[38]  R. Brentjens,et al.  Adoptive T cell immunotherapy strategies for the treatment of patients with ovarian cancer. , 2010, Discovery medicine.

[39]  G. Coukos,et al.  Prognostic significance of tumor-infiltrating T cells in ovarian cancer: a meta-analysis. , 2012, Gynecologic oncology.

[40]  Evaluation of characteristics of CD44+CD117+ ovarian cancer stem cells in three dimensional basement membrane extract scaffold versus two dimensional monocultures , 2013, BMC Cell Biology.

[41]  R. Buckanovich,et al.  Metformin targets ovarian cancer stem cells in vitro and in vivo. , 2012, Gynecologic oncology.

[42]  O. Fiehn,et al.  Mass spectrometry-based metabolic profiling reveals different metabolite patterns in invasive ovarian carcinomas and ovarian borderline tumors. , 2006, Cancer research.

[43]  D. Howells,et al.  Can Animal Models of Disease Reliably Inform Human Studies? , 2010, PLoS medicine.

[44]  M. Banerjee,et al.  Expression of aldehyde dehydrogenase and CD133 defines ovarian cancer stem cells , 2012, International journal of cancer.

[45]  P. Shaw,et al.  Epithelial-stromal interaction increases cell proliferation, survival and tumorigenicity in a mouse model of human epithelial ovarian cancer. , 2008, Gynecologic oncology.

[46]  R. Hruban,et al.  An In vivo Platform for Translational Drug Development in Pancreatic Cancer , 2006, Clinical Cancer Research.

[47]  G. Freeman,et al.  Dual blockade of PD-1 and CTLA-4 combined with tumor vaccine effectively restores T-cell rejection function in tumors. , 2013, Cancer research.

[48]  Stephen J. Williams,et al.  Magnetic resonance imaging for detection and determination of tumor volume in a genetically engineered mouse model of ovarian cancer , 2007, Cancer biology & therapy.

[49]  M. Anderson,et al.  Tolerization of Tumor-Specific T Cells Despite Efficient Initial Priming in a Primary Murine Model of Prostate Cancer1 , 2007, The Journal of Immunology.

[50]  C. Peterson,et al.  Characterization and evaluation of pre-clinical suitability of a syngeneic orthotopic mouse ovarian cancer model. , 2013, Anticancer research.

[51]  H. Piwnica-Worms,et al.  Kinetics of regulated protein-protein interactions revealed with firefly luciferase complementation imaging in cells and living animals. , 2004, Proceedings of the National Academy of Sciences of the United States of America.

[52]  J. Haselden,et al.  Metabolic Profiling as a Tool for Understanding Mechanisms of Toxicity , 2008, Toxicologic pathology.

[53]  A. Jemal,et al.  Cancer statistics, 2012 , 2012, CA: a cancer journal for clinicians.

[54]  Jean-François Ethier,et al.  Reproductive Biology and Endocrinology Open Access Animal Models of Ovarian Cancer , 2022 .

[55]  D. Redelmeier,et al.  Translation of research evidence from animals to humans. , 2006, JAMA.

[56]  M. Pisanu,et al.  Characterisation of in vivo ovarian cancer models by quantitative 1H magnetic resonance spectroscopy and diffusion‐weighted imaging , 2012, NMR in biomedicine.

[57]  B. Teicher Tumor Models in Cancer Research , 2001, Cancer Drug Discovery and Development.

[58]  T. Orfeo,et al.  One hundred and twenty-seven cultured human tumor cell lines producing tumors in nude mice. , 1977, Journal of the National Cancer Institute.

[59]  Mark T. W. Ebbert,et al.  Tumor grafts derived from women with breast cancer authentically reflect tumor pathology, growth, metastasis and disease outcomes , 2011, Nature Medicine.

[60]  Colleen A Crane,et al.  Characterization of intraperitoneal, orthotopic, and metastatic xenograft models of human ovarian cancer. , 2004, Molecular therapy : the journal of the American Society of Gene Therapy.

[61]  R. Puri,et al.  IL‐13 regulates cancer invasion and metastasis through IL‐13Rα2 via ERK/AP‐1 pathway in mouse model of human ovarian cancer , 2012, International journal of cancer.

[62]  D. Huntsman,et al.  Differences in Tumor Type in Low-stage Versus High-stage Ovarian Carcinomas , 2010, International journal of gynecological pathology : official journal of the International Society of Gynecological Pathologists.

[63]  M. Yi,et al.  Perturbation of Rb, p53, and Brca1 or Brca2 cooperate in inducing metastatic serous epithelial ovarian cancer. , 2012, Cancer research.

[64]  I. Shih,et al.  Ovarian tumorigenesis: a proposed model based on morphological and molecular genetic analysis. , 2004, The American journal of pathology.

[65]  R. Buckanovich,et al.  Ovarian cancer stem cells: working towards the root of stemness. , 2013, Cancer letters.

[66]  A. Godwin,et al.  Hereditary ovarian carcinoma: Heterogeneity, molecular genetics, pathology, and management , 2009, Molecular oncology.

[67]  N. Yang,et al.  Animal Model Generation of a Syngeneic Mouse Model to Study the Effects of Vascular Endothelial Growth Factor in Ovarian Carcinoma , 2002 .

[68]  S. Litwin,et al.  Combined in vivo molecular and anatomic imaging for detection of ovarian carcinoma-associated protease activity and integrin expression in mice. , 2012, Neoplasia.

[69]  A. Godwin,et al.  Genetics and ovarian carcinoma. , 1998, Seminars in oncology.

[70]  A. Gibson,et al.  Conjunctive therapy of cisplatin with the OCT2 inhibitor cimetidine: influence on antitumor efficacy and systemic clearance , 2013, Clinical pharmacology and therapeutics.

[71]  A. Welm,et al.  Overview of Human Primary Tumorgraft Models: Comparisons with Traditional Oncology Preclinical Models and the Clinical Relevance and Utility of Primary Tumorgrafts in Basic and Translational Oncology Research , 2012, Current protocols in pharmacology.

[72]  M. Piver,et al.  Characterization of human ovarian carcinomas in a SCID mouse model. , 1999, Gynecologic oncology.

[73]  L. Seymour,et al.  Clinical predictive value of the in vitro cell line, human xenograft, and mouse allograft preclinical cancer models. , 2003, Clinical cancer research : an official journal of the American Association for Cancer Research.

[74]  D. Huntsman,et al.  Establishment of subrenal capsule xenografts of primary human ovarian tumors in SCID mice: potential models. , 2005, Gynecologic oncology.

[75]  R. Schreiber,et al.  IFNγ and lymphocytes prevent primary tumour development and shape tumour immunogenicity , 2001, Nature.

[76]  E. Mohammadi,et al.  Barriers and facilitators related to the implementation of a physiological track and trigger system: A systematic review of the qualitative evidence , 2017, International journal for quality in health care : journal of the International Society for Quality in Health Care.

[77]  Yasuyoshi Watanabe,et al.  [Molecular imaging for drug development]. , 2007, Brain and nerve = Shinkei kenkyu no shinpo.

[78]  J L Pace,et al.  Development of a syngeneic mouse model for events related to ovarian cancer. , 2000, Carcinogenesis.

[79]  Rodney J Hicks,et al.  In Vivo Activity of Combined PI3K/mTOR and MEK Inhibition in a KrasG12D;Pten Deletion Mouse Model of Ovarian Cancer , 2011, Molecular Cancer Therapeutics.

[80]  M. Hendrix,et al.  A Model of Cancer Stem Cells Derived from Mouse Induced Pluripotent Stem Cells , 2012, PloS one.

[81]  R. Chen,et al.  Molecular phenotyping of human ovarian cancer stem cells unravels the mechanisms for repair and chemoresistance , 2009, Cell cycle.

[82]  M. Dimopoulos,et al.  Immune Response in Ovarian Cancer: How Is the Immune System Involved in Prognosis and Therapy: Potential for Treatment Utilization , 2011, Clinical & developmental immunology.

[83]  R. Kurman,et al.  Noninvasive and Invasive Micropapillary (Low-Grade) Serous Carcinoma of the Ovary: A Clinicopathologic Analysis of 135 Cases , 2003, The American journal of surgical pathology.

[84]  X. Hua,et al.  Development of a syngeneic mouse model of epithelial ovarian cancer , 2010, Journal of ovarian research.

[85]  S. Gambhir,et al.  Non-Invasive Imaging of Phosphoinositide-3-Kinase-Catalytic-Subunit-Alpha (PIK3CA) Promoter Modulation in Small Animal Models , 2013, PloS one.

[86]  Kathleen R. Cho,et al.  Mouse model of human ovarian endometrioid adenocarcinoma based on somatic defects in the Wnt/beta-catenin and PI3K/Pten signaling pathways. , 2007, Cancer cell.

[87]  F. Schmidt Meta-Analysis , 2008 .

[88]  Denise G. Lanza,et al.  Characterization of mammary cancer stem cells in the MMTV-PyMT mouse model , 2012, Tumor Biology.

[89]  Sham S. Kakar,et al.  Identification of Metabolites in the Normal Ovary and Their Transformation in Primary and Metastatic Ovarian Cancer , 2011, PloS one.

[90]  R. L. Baldwin,et al.  A human ovarian carcinoma murine xenograft model useful for preclinical trials. , 2002, Gynecologic oncology.