Of mice and (wo)men: Mouse models of breast cancer metastasis to bone

Goldstein, Robert H.; Weinberg, Robert A.; Rosenblatt, Michael

doi:10.1002/jbmr.68

Cited by 19 publications

(21 citation statements)

References 65 publications

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“…Impedance of entry into the brain by the BBB may contribute to the apparent extended dormancy period of the metastatic cells present in the brain, in combination with other influencing factors. Overall, the long duration from the time of detection of cancer cells in the organs (by PCR and/or histological staining) to the development of visual macrometastasis in mouse organs was similar to the delay in development of measurable metastasis in breast cancer patients following diagnosis of primary breast tumors [46,47]. The extended latency between the injection of tumorspheres and the development of macroscopic metastatic lesions is a limitation of this model.…”

Section: Discussionmentioning

confidence: 96%

"A novel in vivo model for the study of human breast cancer metastasis using primary breast tumor-initiating cells from patient biopsies"

et al. 2012

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BackgroundThe study of breast cancer metastasis depends on the use of established breast cancer cell lines that do not accurately represent the heterogeneity and complexity of human breast tumors. A tumor model was developed using primary breast tumor-initiating cells isolated from patient core biopsies that would more accurately reflect human breast cancer metastasis.MethodsTumorspheres were isolated under serum-free culture conditions from core biopsies collected from five patients with clinical diagnosis of invasive ductal carcinoma (IDC). Isolated tumorspheres were transplanted into the mammary fat pad of NUDE mice to establish tumorigenicity in vivo. Tumors and metastatic lesions were analyzed by hematoxylin and eosin (H+E) staining and immunohistochemistry (IHC).ResultsTumorspheres were successfully isolated from all patient core biopsies, independent of the estrogen receptor α (ERα)/progesterone receptor (PR)/Her2/neu status or tumor grade. Each tumorsphere was estimated to contain 50-100 cells. Transplantation of 50 tumorspheres (1-5 × 103 cells) in combination with Matrigel into the mammary fat pad of NUDE mice resulted in small, palpable tumors that were sustained up to 12 months post-injection. Tumors were serially transplanted three times by re-isolation of tumorspheres from the tumors and injection into the mammary fat pad of NUDE mice. At 3 months post-injection, micrometastases to the lung, liver, kidneys, brain and femur were detected by measuring content of human chromosome 17. Visible macrometastases were detected in the lung, liver and kidneys by 6 months post-injection. Primary tumors variably expressed cytokeratins, Her2/neu, cytoplasmic E-cadherin, nuclear β catenin and fibronectin but were negative for ERα and vimentin. In lung and liver metastases, variable redistribution of E-cadherin and β catenin to the membrane of tumor cells was observed. ERα was re-expressed in lung metastatic cells in two of five samples.ConclusionsTumorspheres isolated under defined culture conditions from patient core biopsies were tumorigenic when transplanted into the mammary fat pad of NUDE mice, and metastasized to multiple mouse organs. Micrometastases in mouse organs demonstrated a dormancy period prior to outgrowth of macrometastases. The development of macrometastases with organ-specific phenotypic distinctions provides a superior model for the investigation of organ-specific effects on metastatic cancer cell survival and growth.

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Section: Discussionmentioning

confidence: 96%

"A novel in vivo model for the study of human breast cancer metastasis using primary breast tumor-initiating cells from patient biopsies"

et al. 2012

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“…Although in vivo mouse models enable study of the metastatic process within the context of whole body physiology, drawbacks include the prolonged time course and relative inefficiency of metastatic colonization of human breast cancer cells into the murine skeletal system, coupled with the inability to perturb and monitor detailed events at the cellular level within the microenvironment [3-6]. In vitro models based on the co-culture of breast cancer cells with bone marrow-derived stromal cells or osteoblasts facilitate the analysis of specific cell interactions, but exclude many critical components of the bone microenvironment [7-17].…”

Section: Introductionmentioning

confidence: 99%

Monitoring Dynamic Interactions Between Breast Cancer Cells and Human Bone Tissue in a Co-culture Model

Contag

Lie²,

Bammer

et al. 2013

Mol Imaging Biol

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Purpose Bone is a preferential site of breast cancer metastasis and models are needed to study this process at the level of the microenvironment. We have used bioluminescence imaging (BLI) and multiplex biomarker immunoassays to monitor dynamic breast cancer cell behaviors in co-culture with human bone tissue. Procedures Femur tissue fragments harvested from hip replacement surgeries were co-cultured with luciferase-positive MDA-MB-231-fLuc cells. BLI was performed to quantify breast cell division and track migration relative to bone tissue. Breast cell colonization of bone tissues was assessed with immunohistochemistry. Biomarkers in co-culture supernatants were profiled with MILLIPLEX® immunoassays. Results BLI demonstrated increased MDA-MB-231-fLuc proliferation (p<0.001) in the presence vs. absence of bones, and revealed breast cell migration toward bone. Immunohistochemistry illustrated MDA-MB-231-fLuc colonization of bone, and MILLIPLEX® profiles of culture supernatants suggested breast/bone crosstalk. Conclusions Breast cell behaviors that facilitate metastasis occur reproducibly in human bone tissue co-cultures and can be monitored and quantified using BLI and multiplex immunoassays.

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“…In particular, in the case of cancer cell extravasation, in vivo video microscopy of tail-vein injected cancer cells to mouse has been the primary means of investigation [21,44]. Moreover, advanced in vivo models were developed to study metastasis through direct injection of breast cancer cells either intravenously or directly to specific organs [45,46], and intravital video microscopy was used to visualize the interactions of cancer cells in the circulatory system and the metastatic site in a more physiologically relevant manner. However, the main disadvantages of in vivo models are that they make it difficult to perform tightly regulated, parametric studies and quantification is limited [47].…”

Section: In Vivo and In Vitro Cancer Models For Invasion Migration mentioning

confidence: 99%

In vitro models of the metastatic cascade: from local invasion to extravasation

Bersini

Jeon

Moretti

et al. 2014

Drug Discovery Today

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A crucial event in the metastatic cascade is the extravasation of circulating cancer cells from blood capillaries to the surrounding tissues. The past 5 years have been characterized by a significant evolution in the development of in vitro extravasation models, which moved from traditional transmigration chambers to more sophisticated microfluidic devices, enabling the study of complex cell–cell and cell–matrix interactions in multicellular, controlled environments. These advanced assays could be applied to screen easily and rapidly a broad spectrum of molecules inhibiting cancer cell endothelial adhesion and extravasation, thus contributing to the design of more focused in vivo tests.

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Of mice and (wo)men: Mouse models of breast cancer metastasis to bone

Cited by 19 publications

References 65 publications

"A novel in vivo model for the study of human breast cancer metastasis using primary breast tumor-initiating cells from patient biopsies"

"A novel in vivo model for the study of human breast cancer metastasis using primary breast tumor-initiating cells from patient biopsies"

Monitoring Dynamic Interactions Between Breast Cancer Cells and Human Bone Tissue in a Co-culture Model

In vitro models of the metastatic cascade: from local invasion to extravasation

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