Trends in Bone Metastasis Modeling

Abstract

Bone is one of the most common sites for cancer metastasis. Bone tissue is composed by different kinds of cells that coexist in a coordinated balance. Due to the complexity of bone, it is impossible to capture the intricate interactions between cells under either physiological or pathological conditions. Hence, a variety of in vivo and in vitro approaches have been developed. Various models of tumor–bone diseases are routinely used to provide valuable information on the relationship between metastatic cancer cells and the bone tissue. Ideally, when modeling the metastasis of human cancers to bone, models would replicate the intra-tumor heterogeneity, as well as the genetic and phenotypic changes that occur with human cancers; such models would be scalable and reproducible to allow high-throughput investigation. Despite the continuous progress, there is still a lack of solid, amenable, and affordable models that are able to fully recapitulate the biological processes happening in vivo, permitting a correct interpretation of results. In the last decades, researchers have demonstrated that three-dimensional (3D) methods could be an innovative approach that lies between bi-dimensional (2D) models and animal models. Scientific evidence supports that the tumor microenvironment can be better reproduced in a 3D system than a 2D cell culture, and the 3D systems can be scaled up for drug screening in the same way as the 2D systems thanks to the current technologies developed. However, 3D models cannot completely recapitulate the inter- and intra-tumor heterogeneity found in patients. In contrast, ex vivo cultures of fragments of bone preserve key cell–cell and cell–matrix interactions and allow the study of bone cells in their natural 3D environment. Moreover, ex vivo bone organ cultures could be a better model to resemble the human pathogenic metastasis condition and useful tools to predict in vivo response to therapies. The aim of our review is to provide an overview of the current trends in bone metastasis modeling. By showing the existing in vitro and ex vivo systems, we aspire to contribute to broaden the knowledge on bone metastasis models and make these tools more appealing for further translational studies.

Advancing Treatment of Bone Metastases through Novel Translational Approaches Targeting the Bone Microenvironment

“…Additionally, microfluidic models enable passive pumping or active pumping methods within lumens to investigate both the effects of increased shear stress in the microenvironment, as well as the dynamics of cell extravasation in the context of a growing metastatic bone niche [171,172]. A comprehensive and well-crafted review by Laranga, et al, highlights many of the pros and cons of different BM methods, including the significant advantages microfluidic devices have in generating model systems for investigating a plethora of both biologically and clinically relevant questions [173]. Importantly, the ease of use, customizability, and 3-D coculture capabilities of microfluidics lends to its increased adoption compared to more expensive, and less reproducible scaffold based [174] or bioreactor systems [175] commonly employed for studying metastatic microenvironments.…”

Advances in Engineered Three-Dimensional (3D) Body Articulation Unit Models

“…84 constructs, these synthetic hydrogels have enhanced key cartilage markers, promoting cartilage formation, such as type I collagen and non-collagen. [89][90][91] Moreover, the synthetic hydrogel can be fine-tuned by various chemical modifications that promote cartilage production through augmenting cartilage transforming growth factor-β3 (TGF-β3) and the expression of type II collagen and GAGs. 54,92 Undoubtedly, the choice of scaffolding material leads to a new path in developing the 3D articulation models.…”

Muscle and Bone Defects in Metastatic Disease

“…Animal models of skeletal metastasis are essential for understanding the pathogenesis of cancer bone metastases. There has been an increased interest in generating new threedimensional (3D) in vitro models including patient-derived xenograft models, organoid, and scaffold models that can mimic native bone microenvironment [176][177][178][179][180][181][182][183][184][185]. In addition, numerous new compounds have been evaluated for their effect and therapeutic potential on metastatic bone disease [186,187,[196][197][198][188][189][190][191][192][193][194][195].…”