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Ottewell et al. J Cancer Metastasis Treat 2021;7:11 https://dx.doi.org/10.20517/2394-4722.2021.14 Page 17 of 20

human bone implants; these models allow the investigation of the growth of heterogeneous patient samples
from different tumour subtypes and their ability to metastasise and interact with a human bone
environment in a mouse with a semi-competent human immune system [23,52,54] . These models, however, are
far from perfect and are expensive and difficult to run. It is unclear how active the human B cells are in this
model and whether any other human immune cell subsets are present; further work is required to establish
this. A mouse model of human breast cancer to human bone metastasis with a fully competent immune
system would be a highly relevant tool. Extensive work has been carried out by various research groups to
make mouse models with a human-specific immune system for research purposes. In these models, NSG
mice are irradiated prior to injection of human haematopoietic stem cells; the resulting mice have been
successfully used to show effects of immunotherapies in various cancer types including breast cancer [69-71] . It
would be interesting to see if the same process could be used to produce a mouse model of human breast
cancer metastasis to human bone with a competent human immune system and whether this would be
possible given the difficulties of obtaining all three samples (bone, primary tumour and haematopoietic
stem cells) from the same donor to avoid auto immunity.

In conclusion, there is a large array of mouse model systems available to researchers for investigating
various parameters associated with breast cancer bone metastasis. When used in combination, these model
systems cover most aspects associated with the metastatic process including growth at the primary site,
spontaneous spread to bone, homing to the metastatic niche, dormancy and metastatic outgrowth. Models
are also available to investigate the effects of immune cells on these processes. However, to date, there is not
one model system that covers all of the processes, and there are no systems which reliably model
spontaneous development of the primary tumour followed by bone metastasis. Researchers must therefore
select the most appropriate model system(s) for their research question and interpret their data accordingly,
giving special consideration to the need for experiments to be performed either with multiple cell lines or in
multiple systems before reliable conclusions can be made.

DECLARATIONS
Authors’ contributions
Wrote the manuscript and provided data for Figures 1-3: Ottewell PD
Edited the manuscript and provided text and data for Figure 4: Lawson MA

Availability of data and materials
Not applicable.

Financial support and sponsorship
None.

Conflicts of interest
All authors declared that there are no conflicts of interest.

Ethical approval and consent to participate
Not applicable.

Consent for publication
Not applicable.