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Emerging and Evolving Ovarian Cancer Animal Models.

Bobbs AS, Cole JM, Cowden Dahl KD - Cancer Growth Metastasis (2015)

Bottom Line: By the time a woman is diagnosed with OC, the tumor has usually metastasized.Patient-derived xenografts (PDXs) can accurately reflect metastasis, response to therapy, and diverse genetics found in patients.As no single model perfectly copies the human disease, we can use a variety of OC animal models in hypothesis testing that will lead to novel treatment options.

View Article: PubMed Central - PubMed

Affiliation: Department of Biochemistry and Molecular Biology, Indiana University School of Medicine-South Bend, South Bend, IN, USA. ; Harper Cancer Research Institute, South Bend, IN, USA.

ABSTRACT
Ovarian cancer (OC) is the leading cause of death from a gynecological malignancy in the United States. By the time a woman is diagnosed with OC, the tumor has usually metastasized. Mouse models that are used to recapitulate different aspects of human OC have been evolving for nearly 40 years. Xenograft studies in immunocompromised and immunocompetent mice have enhanced our knowledge of metastasis and immune cell involvement in cancer. Patient-derived xenografts (PDXs) can accurately reflect metastasis, response to therapy, and diverse genetics found in patients. Additionally, multiple genetically engineered mouse models have increased our understanding of possible tissues of origin for OC and what role individual mutations play in establishing ovarian tumors. Many of these models are used to test novel therapeutics. As no single model perfectly copies the human disease, we can use a variety of OC animal models in hypothesis testing that will lead to novel treatment options. The goal of this review is to provide an overview of the utility of different mouse models in the study of OC and their suitability for cancer research.

No MeSH data available.


Related in: MedlinePlus

Two-photon microscopy image of SKOV3IP tumor expressing green fluorescent protein (GFP). SKOV3IP labeled with GFP were injected SC into nude mice. After one week, two-photon microscopy was conducted to image tumor cells (green), collagen (blue), and vasculature (red). Therefore, imaging subcutaneous tumor can provide information about how genetic variation affects tumor microenvironment.
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f1-cgm-suppl.1-2015-029: Two-photon microscopy image of SKOV3IP tumor expressing green fluorescent protein (GFP). SKOV3IP labeled with GFP were injected SC into nude mice. After one week, two-photon microscopy was conducted to image tumor cells (green), collagen (blue), and vasculature (red). Therefore, imaging subcutaneous tumor can provide information about how genetic variation affects tumor microenvironment.

Mentions: The use of xenograft models enables researchers to test factors that influence tumor growth, spread, and drug response in a live animal. These elements cannot be entirely recapitulated in tissue culture. To study tumor growth in mice, murine or human OC cells are injected into mice. Cells from different genetic backgrounds are injected into immunocompromised mice such as Nude (Foxn1, Nu/Nu), SCID, NOD/SCID, or NOD-scid IL2Rc (NSG) to enable the cells to engraft without being eliminated by the immune system. Cells are injected SC, intraperitoneally (IP), or intrabursally [(IB) into the bursa that surrounds the mouse ovary]. The SC model is not well suited for ovarian metastasis studies as the tumors do not typically metastasize, and the tumor is not positioned in the right anatomic location or microenvironment. One advantage of the SC model is that it is well suited for investigation with imaging modalities such as two-photon microscopy (Fig. 1). In two-photon microscopy, tumor vasculature (with fluorescent dextrans), collagens (with second harmonic imaging), and fluorescently labeled tumor cells can be measured simultaneously in a live animal. This cannot be done with IP or IB injections because of the depth of the tumors. However, IP and IB tumors can be imaged in live animals with optical imaging approaches using fluorescence or luminescence. In contrast to SC tumors, IP and IB injections of tumor cells into mice can mimic aspects of tumor metastasis, particularly metastatic dissemination. While IP injection cannot mimic the initial steps in metastasis, IP-injected tumor cells such as SKOV3 metastasize to the ovary, peritoneal wall, diaphragm, and form ascites fluid similar to human disease.13 The SKOV3IP cell line is derived from ascites cells that developed in a mouse IP cavity injected with SKOV3 cells.13 Compared to the parental SKOV3 cells, the SKOV3IP cells grow faster, disseminate more, and exhibit overexpressed ERBB2.13 Many cells (including the SKOV3 lines) are frequently transfected or transduced with fluorescence or luminescence-expressing vectors to monitor tumor growth in vivo.14 Similarly, OVCAR3 cells metastasize to the GI tract, omentum, pancreas, kidney, and liver (unpublished data) when injected IP. In some ways, the IB injection mimics the initial steps in metastasis, as the tumor cells exit the bursa to spread throughout the peritoneal cavity. Many cell lines metastasize following IB injection, including A2780, SKOV3, and HEY cells.15,16 Sites of metastasis include diaphragm, mesentery, bowel, and liver.16 In particular, the A2780 cells have been used to study not only metastasis but also chemoresistance. A2780 that are sensitive to cisplatin and a subline of A2780 cells that are resistant to cisplatin cells are also commonly used in xenograft studies of chemoresistance in vivo.17 Many other cell lines not discussed also demonstrate growth in xenograft models.18


Emerging and Evolving Ovarian Cancer Animal Models.

Bobbs AS, Cole JM, Cowden Dahl KD - Cancer Growth Metastasis (2015)

Two-photon microscopy image of SKOV3IP tumor expressing green fluorescent protein (GFP). SKOV3IP labeled with GFP were injected SC into nude mice. After one week, two-photon microscopy was conducted to image tumor cells (green), collagen (blue), and vasculature (red). Therefore, imaging subcutaneous tumor can provide information about how genetic variation affects tumor microenvironment.
© Copyright Policy - open-access
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC4558890&req=5

f1-cgm-suppl.1-2015-029: Two-photon microscopy image of SKOV3IP tumor expressing green fluorescent protein (GFP). SKOV3IP labeled with GFP were injected SC into nude mice. After one week, two-photon microscopy was conducted to image tumor cells (green), collagen (blue), and vasculature (red). Therefore, imaging subcutaneous tumor can provide information about how genetic variation affects tumor microenvironment.
Mentions: The use of xenograft models enables researchers to test factors that influence tumor growth, spread, and drug response in a live animal. These elements cannot be entirely recapitulated in tissue culture. To study tumor growth in mice, murine or human OC cells are injected into mice. Cells from different genetic backgrounds are injected into immunocompromised mice such as Nude (Foxn1, Nu/Nu), SCID, NOD/SCID, or NOD-scid IL2Rc (NSG) to enable the cells to engraft without being eliminated by the immune system. Cells are injected SC, intraperitoneally (IP), or intrabursally [(IB) into the bursa that surrounds the mouse ovary]. The SC model is not well suited for ovarian metastasis studies as the tumors do not typically metastasize, and the tumor is not positioned in the right anatomic location or microenvironment. One advantage of the SC model is that it is well suited for investigation with imaging modalities such as two-photon microscopy (Fig. 1). In two-photon microscopy, tumor vasculature (with fluorescent dextrans), collagens (with second harmonic imaging), and fluorescently labeled tumor cells can be measured simultaneously in a live animal. This cannot be done with IP or IB injections because of the depth of the tumors. However, IP and IB tumors can be imaged in live animals with optical imaging approaches using fluorescence or luminescence. In contrast to SC tumors, IP and IB injections of tumor cells into mice can mimic aspects of tumor metastasis, particularly metastatic dissemination. While IP injection cannot mimic the initial steps in metastasis, IP-injected tumor cells such as SKOV3 metastasize to the ovary, peritoneal wall, diaphragm, and form ascites fluid similar to human disease.13 The SKOV3IP cell line is derived from ascites cells that developed in a mouse IP cavity injected with SKOV3 cells.13 Compared to the parental SKOV3 cells, the SKOV3IP cells grow faster, disseminate more, and exhibit overexpressed ERBB2.13 Many cells (including the SKOV3 lines) are frequently transfected or transduced with fluorescence or luminescence-expressing vectors to monitor tumor growth in vivo.14 Similarly, OVCAR3 cells metastasize to the GI tract, omentum, pancreas, kidney, and liver (unpublished data) when injected IP. In some ways, the IB injection mimics the initial steps in metastasis, as the tumor cells exit the bursa to spread throughout the peritoneal cavity. Many cell lines metastasize following IB injection, including A2780, SKOV3, and HEY cells.15,16 Sites of metastasis include diaphragm, mesentery, bowel, and liver.16 In particular, the A2780 cells have been used to study not only metastasis but also chemoresistance. A2780 that are sensitive to cisplatin and a subline of A2780 cells that are resistant to cisplatin cells are also commonly used in xenograft studies of chemoresistance in vivo.17 Many other cell lines not discussed also demonstrate growth in xenograft models.18

Bottom Line: By the time a woman is diagnosed with OC, the tumor has usually metastasized.Patient-derived xenografts (PDXs) can accurately reflect metastasis, response to therapy, and diverse genetics found in patients.As no single model perfectly copies the human disease, we can use a variety of OC animal models in hypothesis testing that will lead to novel treatment options.

View Article: PubMed Central - PubMed

Affiliation: Department of Biochemistry and Molecular Biology, Indiana University School of Medicine-South Bend, South Bend, IN, USA. ; Harper Cancer Research Institute, South Bend, IN, USA.

ABSTRACT
Ovarian cancer (OC) is the leading cause of death from a gynecological malignancy in the United States. By the time a woman is diagnosed with OC, the tumor has usually metastasized. Mouse models that are used to recapitulate different aspects of human OC have been evolving for nearly 40 years. Xenograft studies in immunocompromised and immunocompetent mice have enhanced our knowledge of metastasis and immune cell involvement in cancer. Patient-derived xenografts (PDXs) can accurately reflect metastasis, response to therapy, and diverse genetics found in patients. Additionally, multiple genetically engineered mouse models have increased our understanding of possible tissues of origin for OC and what role individual mutations play in establishing ovarian tumors. Many of these models are used to test novel therapeutics. As no single model perfectly copies the human disease, we can use a variety of OC animal models in hypothesis testing that will lead to novel treatment options. The goal of this review is to provide an overview of the utility of different mouse models in the study of OC and their suitability for cancer research.

No MeSH data available.


Related in: MedlinePlus