Modeling and Integral X-Ray, Optical, and MRI Visualization of Multiorgan Metastases of Orthotopic 4T1 Breast Carcinoma in BALB/c Mice

Baklaushev, V. P.; Grinenko, N. F.; Yusubalieva, Gaukhar M.; Abakumov, Maxim; Gubskii, I L; Cherepanov, S. A.; Kashparov, I. A.; Burenkov, M. S.; Rabinovich, E.; Ivanova, Natalia V.; Antonova, O. M.; Chekhonin, V. P.

doi:10.1007/s10517-015-2810-3

Cited by 16 publications

(13 citation statements)

References 9 publications

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“…The starting point was to characterize the growth rate and level of reporter expression of luciferase (Luc) expressing 4T1luc2D6 16 and commercially available 4T1luc2 clone (ref. 17 Perkin Elmer) as compared to the parental 4T1 cells.…”

Section: Resultsmentioning

confidence: 99%

“…One of the most frequently used and best studied bioluminescent reporters is the firefly luciferase (Luc). Here, we have characterized the capacity of two Luc-labelled subclones of the murine mammary gland adenocarcinoma 4T1 cells, 4T1luc2D6 16 and 4T1luc2 (Perkin Elmer), to generate tumors and metastases in the immunocompetent mice in comparison with the parental 4T1 cells. In lines with the earlier findings, we found that expression of the luciferase has no effect on either the in vitro proliferation of 4T1 cells, or on their ability to form tumors after the orthotopic transplantation 7 , 9 , 12 , 18 , 28 .…”

Section: Discussionmentioning

confidence: 99%

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Luciferase Expression Allows Bioluminescence Imaging But Imposes Limitations on the Orthotopic Mouse (4T1) Model of Breast Cancer

Baklaushev

Kilpeläinen

Petkov

et al. 2017

Sci Rep

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Implantation of reporter-labeled tumor cells in an immunocompetent host involves a risk of their immune elimination. We have studied this effect in a mouse model of breast cancer after the orthotopic implantation of mammary gland adenocarcinoma 4T1 cells genetically labelled with luciferase (Luc). Mice were implanted with 4T1 cells and two derivative Luc-expressing clones 4T1luc2 and 4T1luc2D6 exhibiting equal in vitro growth rates. In vivo, the daughter 4T1luc2 clone exhibited nearly the same, and 4T1luc2D6, a lower growth rate than the parental cells. The metastatic potential of 4T1 variants was assessed by magnetic resonance, bioluminescent imaging, micro-computed tomography, and densitometry which detected 100-μm metastases in multiple organs and bones at the early stage of their development. After 3–4 weeks, 4T1 generated 11.4 ± 2.1, 4T1luc2D6, 4.5 ± 0.6; and 4T1luc2, <1 metastases per mouse, locations restricted to lungs and regional lymph nodes. Mice bearing Luc-expressing tumors developed IFN-γ response to the dominant CTL epitope of Luc. Induced by intradermal DNA-immunization, such response protected mice from the establishment of 4T1luc2-tumors. Our data show that natural or induced cellular response against the reporter restricts growth and metastatic activity of the reporter-labelled tumor cells. Such cells represent a powerful instrument for improving immunization technique for cancer vaccine applications.

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Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Luciferase Expression Allows Bioluminescence Imaging But Imposes Limitations on the Orthotopic Mouse (4T1) Model of Breast Cancer

Baklaushev

Kilpeläinen

Petkov

et al. 2017

Sci Rep

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“…The characteristics of propagations and metastases of the 4T1 tumor in Balb/c mice is very similar to that of human mammary cancer [12]. In this study, we transduced 4T1 mouse breast cancer cells with firefly luciferase (Fluc) and an inducible, bidirectional tetracycline (Bi-Tet) promoter driving VEGF165 and renilla luciferase (Rluc).…”

Section: Introductionmentioning

confidence: 99%

Molecular Imaging of Inducible VEGF Expression and Tumor Progression in a Breast Cancer Model

Liang

Yue

et al. 2017

Cell Physiol Biochem

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Background: Tumor derived vascular endothelial growth factor (VEGF) can stimulate proliferation and migration of endothelial cells and recruit endothelial progenitor cells into tumors for vascular formation via a paracrine manner. Now increasing evidence suggests that VEGF also serves as an autocrine factor promoting cell survival and tumor angiogenesis. Real time visualization of VEGF activity in the early stages of tumor formation using molecular imaging will provide unprecedented insight into the biological processes of cancer. Methods: The mouse breast cancer cell line 4T1 was transfected with an inducible, bidirectional tetracycline (Bi-Tet) promoter driving VEGF and renilla luciferase (Rluc). This was used to quantitatively image conditional switching of VEGF by bioluminescence imaging (BLI) under the control of systemic administration of doxycycline. Simultaneously, 4T1 cells were labelled with the double fusion reporter gene (Fluc-eGFP) to establish a breast cancer model. Results: We found that inducible VEGF could promote proliferation and attenuate apoptosis due to oxidative stress in an autocrine manner in vitro. In vivo studies revealed that induction of VEGF expression during early tumor development not only dramatically enhanced tumor growth but also increased tumor angiogenesis as visualized by BLI. Finally, immunohistochemistry staining confirmed that inducing VEGF expression promoted cell survival and tumor neovascularization. Conclusion: Together the inducible bidirectional tetracycline (Bi-Tet) co-expression system combined with the dual bioluminescence imaging (BLI) system provides a platform to investigate a target gene’s role in the pathologic process of cancer and facilitates noninvasive monitoring of biological responses in real time.

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“…It has been demonstrated that HAAH is expressed in primitive neuroectodermal tumors but not in normal brain. 19 The authors would posit that as the 4T1 is a highly invasive and metastatic tumor, which is well established to metastasize to the brain 20,21 -the uptake in the head might be due to the metastases in the skull. It is unclear whether this observation is significant or not and thus warrants further investigation.…”

Section: Discussionmentioning

confidence: 99%

A Radiolabeled Fully Human Antibody to Human Aspartyl (Asparaginyl)β-Hydroxylase Is a Promising Agent for Imaging and Therapy of Metastatic Breast Cancer

Revskaya

Jiang

Morgenstern

et al. 2017

Cancer Biotherapy and Radiopharmaceuticals

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There is a need for novel effective and safe therapies for metastatic breast cancer based on targeting tumor-specific molecular markers of cancer. Human aspartyl (asparaginyl) b-hydroxylase (HAAH) is a highly conserved enzyme that hydroxylates epidermal growth factor-like domains in transformation-associated proteins and is overexpressed in a variety of cancers, including breast cancer. A fully human monoclonal antibody (mAb) PAN-622 has been developed to HAAH. In this study, they describe the development of PAN-622 mAb as an agent for imaging and radioimmunotherapy of metastatic breast cancer. PAN-622 was conjugated to several ligands such as DOTA, CHXA †, and DTPA to enable subsequent radiolabeling and its immunoreactivity was evaluated by an HAAHspecific enzyme-linked immunosorbent assay and binding to the HAAH-positive cells. As a result, DTPA-PAN-622 was chosen to investigate biodistribution in healthy CD-1 female mice and 4T1 mammary tumor-bearing BALB/c mice. The 111 In-DTPA-pan622 mAb concentrated in the primary tumors and to some degree in lung metastases as shown by SPECT/CT and Cherenkov imaging. A pilot therapy study with 213 Bi-DTPA-PAN-622 demonstrated a significant effect on the primary tumor. The authors concluded that human mAb PAN-622 to HAAH is a promising reagent for development of imaging and possible therapeutic agents for the treatment of metastatic breast cancer.

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Modeling and Integral X-Ray, Optical, and MRI Visualization of Multiorgan Metastases of Orthotopic 4T1 Breast Carcinoma in BALB/c Mice

Cited by 16 publications

References 9 publications

Luciferase Expression Allows Bioluminescence Imaging But Imposes Limitations on the Orthotopic Mouse (4T1) Model of Breast Cancer

Luciferase Expression Allows Bioluminescence Imaging But Imposes Limitations on the Orthotopic Mouse (4T1) Model of Breast Cancer

Molecular Imaging of Inducible VEGF Expression and Tumor Progression in a Breast Cancer Model

A Radiolabeled Fully Human Antibody to Human Aspartyl (Asparaginyl)β-Hydroxylase Is a Promising Agent for Imaging and Therapy of Metastatic Breast Cancer

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