Osteosarcoma tumor microenvironment: the key for the successful development of biologically relevant 3D in vitro models

Abstract

Osteosarcoma (OS) is the most common primary bone cancer in children and young adults. This type of cancer is characterized by a high mortality rate, especially for patients with resistant lung metastases. Given its low incidence, high genetic heterogeneity, the lack of effective targets, and poor availability of relevant in vitro and in vivo models to study the tumor progression and the metastatic cascade, the pathophysiology of OS is still poorly understood and the translation of novel drugs into the market has become stagnant. Due to the importance of the tumor microenvironment (TME) in the development of metastases and the growing interest in targeting TME-specific pathways for novel therapeutics in cancer, models that closely represent these interactions are crucial for a better understanding of cancer-related events. In OS research, most studies rely on oversimplified two-dimensional (2D) assays and complex animal models that do not faithfully recapitulate OS development and progression. In turn, three-dimensional (3D) models are able to mimic not only the physical 3D environment in which cancer cells grow but also involve interactions with the TME, including its extracellular matrix, and thus are promising tools for drug screening studies. In this review, the existing and innovative OS in vitro 3D models are highlighted, focusing on how the TME is crucial to develop effective platforms for OS tumor and metastasis modeling in a physiologically relevant context.

Bionic Bilayer Scaffold for Synchronous Hyperthermia Therapy of Orthotopic Osteosarcoma and Osteochondral Regeneration

“…Afterward, the tumor tissue was resected along with bone tissue by surgical operation, followed by implantation of our prepared scaffolds and suturing of muscles and skin incisions (as shown in Figure d). Such an orthotopic osteosarcoma model afforded similarities to clinical realities by simulating growth behavior and treatment strategy of osteosarcoma within the human body . In detail, current studies focused on the osteosarcoma therapy primarily employ subcutaneous bone tumor models to assess their tumor elimination efficacy, while ignoring the repair issue of bone defects caused by osteosarcoma resection.…”

“…53 To sum up, it was reasonable to make a conclusion that the bionic bilayer CR780-PEG@ alginate−PLLA/HA composite scaffold had an improved osteogenesis functionality in addition to excellent chondro- genesis ability in vitro by upregulating expressions of all genes mentioned-above. 54…”

Multifunctional 3D-printed bioceramic scaffolds: Recent strategies for osteosarcoma treatment

“…Bone homeostasis and the replacement of the old bone matrix depend on the proper interaction of these cells with one another and their microenvironment. 34 When genetic mutations (TP53, RB1, RECQL4) occur in BMSCs or BMSC-derived pro-osteoblasts, these mutations accumulate to a subpopulation of cancer stem cells (CSCs) that may lead to incompletely differentiated osteoblasts or osteoclasts. 35 , 36 Through interactions with the tumor microenvironment (TME), CSCs can self-renew and maintain osteosarcoma progression.…”

Proteasome Inhibitors and Their Potential Applicability in Osteosarcoma Treatment

“…In OS research, most studies rely on oversimplified two-dimensional (2D) assessments that do not fully recapitulate the changes in signaling that promote OS progression. These models fail to acknowledge the dynamic environment in which cancer cells grow, including proper cell–cell and cell–extracellular matrix interactions that influence cancer progression [ 155 ]. Therefore, incorporating three-dimensional (3D) culture models that mimic better the physical microenvironment of OS cells, in the design of experiments for PI testing, may provide a more realistic picture of their anti-tumor effects.…”