Mimicking breast cancer-induced bone metastasis in vivo: current transplantation models and advanced humanized strategies

Abstract

Bone metastasis is a complication that occurs in 80 % of women with advanced breast cancer. Despite the prevalence of bone metastatic disease, the avenues for its clinical management are still restricted to palliative treatment options. In fact, the underlying mechanisms of breast cancer osteotropism have not yet been fully elucidated due to a lack of suitable in vivo models that are able to recapitulate the human disease. In this work, we review the current transplantation-based models to investigate breast cancer-induced bone metastasis and delineate the strengths and limitations of the use of different grafting techniques, tissue sources, and hosts. We further show that humanized xenograft models incorporating human cells or tissue grafts at the primary tumor site or the metastatic site mimic more closely the human disease. Tissue-engineered constructs are emerging as a reproducible alternative to recapitulate functional humanized tissues in these murine models. The development of advanced humanized animal models may provide better platforms to investigate the mutual interactions between human cancer cells and their microenvironment and ultimately improve the translation of preclinical drug trials to the clinic.

Lessons from patient-derived xenografts for better in vitro modeling of human cancer

“…While traditional in vivo studies often make use of human cancers transplanted into immunocompromised rodents, the incompatibilities between tumor and host often result in disruptions of critical native processes requiring species-specific interactions [26]. Efforts have therefore been made to incorporate additional human components into host animals to mitigate these differences and to better mimic the human disease, either through genetic engineering approaches to introduce human versions of certain genes [27], the seeding of human immune cells or stromal components [28,29], or through implantation of human organoids [30][31][32].…”

Biomechanical forces in the skeleton and their relevance to bone metastasis: Biology and engineering considerations

“…However, to develop effective therapeutic strategies based on these principles, much more sophisticated experimental and computational strategies will be needed. For example, ‘humanized mice’ can overcome challenges associated with studying human cells in a murine organism, and additionally may recapitulate the full range of (human) primary tumor development and metastatic cascade to the skeleton [243]. In addition, human bone fragments or tissue-engineered bone substitutes provide attractive alternatives for studies of human bone metastasis [244, 245].…”

Biomimetic strategies to recapitulate organ specific microenvironments for studying breast cancer metastasis

“…However, mouse organ microenvironment physiologically differs from humans and this must be considered while evaluating the results from this model. To overcome this drawback, researchers have integrated biomaterial based co‐culture models with in vivo models . We refer to them as hybrid in vivo models (Table ).…”

“…To overcome this drawback, researchers have integrated biomaterial based co-culture models with in vivo models. 57 We refer to them as hybrid in vivo models (Table 1). In a general sense, a human bone mimicking microenvironment is created by culturing BMSCs on a biomaterial scaffold, which is subcutaneously implanted in mice creating a biomimetic metastatic site.…”