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Quantitative assessment of breast cancer liver metastasis expansion with patient-derived xenografts

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Abstract

Advanced breast cancer often spreads to the bone, brain, liver, and lungs. The survival time of a patient with breast cancer liver metastasis is often less than 9 months without treatment. Experimental model systems often focus on the lung as a site of metastatic relapse, and therefore, there is less of an understanding of the biological processes that occur during expansive liver metastasis growth. In these studies, 14 genetically distinct breast cancer patient-derived xenografts (PDXs) were characterized for growth in the liver after portal vein injection of cancer cells. Growth in the liver occurred in 12 of 14 models, and the relative growth rate across the PDXs was overall similar to growth in the mammary gland. Pathological and immunohistochemical analyses revealed that the proliferation rates of metastases were relatively similar as the metastases expanded until the tumors became necrotic, and then slightly lower proliferation rates were observed. There were influxes of macrophages and neutrophils as the metastases increased in size, suggesting these innate immune cells may result in differential responses to therapeutics in micrometastases compared to macrometastases. The development and characterization of these models is important as future studies can utilize this information to determine if targeted therapies can slow the progression of metastatic disease at different stages in the liver.

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Acknowledgements

Paraffin embedding services in support of the research project were provided by the Cancer Mouse Models Shared Resource Core supported, in part, with funding from NIH-NCI Cancer Center Support Grant P30 CA016059.

Funding

This work was supported by funds to JCH by METAvivor and the VCU Massey Cancer Center, and to THT from a NCI F30 grant (1F30CA228393-01A1).

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Author notes

  1. Mohammad A. Alzubi and Sahib S. Sohal contributed equally to the work.

Authors and Affiliations

  1. Department of Pathology, Virginia Commonwealth University, 1101 E. Marshall Street, Richmond, VA, 23298, USA

    Mohammad A. Alzubi, Sahib S. Sohal, Madhumitha Sriram, Tia H. Turner, Patricija Zot, Michael Idowu & J. Chuck Harrell

  2. Integrative Life Sciences Program, Virginia Commonwealth University, Richmond, VA, USA

    Mohammad A. Alzubi & J. Chuck Harrell

  3. C. Kenneth and Dianne Wright Center for Clinical and Translational Research, Virginia Commonwealth University, Richmond, VA, USA

    Tia H. Turner & J. Chuck Harrell

  4. Massey Cancer Center, Virginia Commonwealth University, Richmond, VA, USA

    J. Chuck Harrell

Authors
  1. Mohammad A. Alzubi
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  2. Sahib S. Sohal
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  3. Madhumitha Sriram
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  4. Tia H. Turner
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  5. Patricija Zot
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  6. Michael Idowu
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  7. J. Chuck Harrell
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Contributions

Designed experiments; MAA, JCH. Performed animal experiments; MAA. Performed tumor cell preparations; MAA, THT. Performed immunohistochemical experiments and analyzed data; SSS, MAA, MS. Pathological review PZ, MOI. Wrote the manuscript; SSS, JCH. Supervised the study; JCH. All authors reviewed and edited the manuscript.

Corresponding author

Correspondence to J. Chuck Harrell.

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The authors declare no potential conflicts of interest.

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All applicable international, national, and/or institutional guidelines for the care and use of animals were followed and approved by the Virginia Commonwealth University Institutional Animal Care and Use Committees.

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Alzubi, M.A., Sohal, S.S., Sriram, M. et al. Quantitative assessment of breast cancer liver metastasis expansion with patient-derived xenografts. Clin Exp Metastasis 36, 257–269 (2019). https://doi.org/10.1007/s10585-019-09968-z

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  • DOI: https://doi.org/10.1007/s10585-019-09968-z

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