Engineering 3D approaches to model the dynamic microenvironments of cancer bone metastasis

Abstract

Cancer metastasis to bone is a three-dimensional (3D), multistep, dynamic process that requires the sequential involvement of three microenvironments, namely, the primary tumour microenvironment, the circulation microenvironment and the bone microenvironment. Engineered 3D approaches allow for a vivid recapitulation of in vivo cancerous microenvironments in vitro, in which the biological behaviours of cancer cells can be assessed under different metastatic conditions. Therefore, modelling bone metastasis microenvironments with 3D cultures is imperative for advancing cancer research and anti-cancer treatment strategies. In this review, multicellular tumour spheroids and bioreactors, tissue engineering constructs and scaffolds, microfluidic systems and 3D bioprinting technology are discussed to explore the progression of the 3D engineering approaches used to model the three microenvironments of bone metastasis. We aim to provide new insights into cancer biology and advance the translation of new therapies for bone metastasis.

Prostate Cancer Phenotype Influences Bone Mineralization at Metastasis: A Study Using an In Vitro Prostate Cancer Metastasis Testbed

“…The inability of 2D models to recapitulate entirely the complex nature of the bone–cancer microenvironment, as well as the failure of animal models to reproduce some vital characteristics specific to humans, compels the development of 3D in vitro models for systematically studying the interactions between prostate cancer cells and the bone microenvironment. In fact, several 3D in vitro models have been reported for investigating the interaction between the bone microenvironment and metastasized prostate cancer cells . Recent studies have investigated the interactions between human osteoblasts and prostate cancer cells in 3D tissue‐engineered bone .…”

“…In fact, several 3D in vitro models have been reported for investigating the interaction between the bone microenvironment and metastasized prostate cancer cells. (16)(17)(18) Recent studies have investigated the interactions between human osteoblasts and prostate cancer cells in 3D tissue-engineered bone. (19,20) Researchers have also included the design of collagen-based scaffolds to simulate prostate cancer bone metastases.…”

Hesperetin Prevents Bone Resorption by Inhibiting RANKL-Induced Osteoclastogenesis and Jnk Mediated Irf-3/c-Jun Activation

“…Osteoporosis features diminished bone mineral density (BMD) and increased bone fragility, and has been shown to derive from the unbalanced activities of bone resorption and formation ( Xie et al, 2014 ; Marozik et al, 2018 ). Currently, bisphosphonate (e.g., alendronate, risedronate), selective estrogen receptor modulators (SERMs) and RANKL antibody (denosumab) ( Maximov et al, 2013 ; Pazianas and Abrahamsen, 2016 ; Qiao and Tang, 2018 ) are representative components inhibiting osteoporosis. However, the accompanying inevitable side effects such as fever, hypercalcemia and hypertension, thromboembolism, atypical fractures, severe gastrointestinal disorders, and osteonecrosis of the jaw (ONJ) ( Tian et al, 2014 ) largely restrain their clinical application, which propels the development of novel pharmaceutical remedies to affect osteoclast formation without cytotoxicity.…”

Advances on Bone Substitutes through 3D Bioprinting

“…Besides BTE, 3D bioprinting is strongly relevant in the field of cancer research, where 2D tumor models do not reconstitute the complexity of the dynamic tumor microenvironment [ 186 ]. Conversely, 3D-bioprinted models allow for reproduction of cell–cell and cell–matrix interactions and have the advantage to integrate a vascular system to study tumor angiogenesis [ 187 ]. Hence, the tumor tissue should be placed within a bioprinted vascularized parenchyma to analyze how cancer cells grow and other carcinogenic events, i.e., intravasation and extravasation [ 188 ].…”