Three-dimensional in vitro tumor models for cancer research and drug evaluation

Abstract

Cancer occurs when cells acquire genomic instability and inflammation, produce abnormal levels of epigenetic factors/proteins and tumor suppressors, reprogram the energy metabolism and evade immune destruction, leading to the disruption of cell cycle/normal growth. An early event in carcinogenesis is loss of polarity and detachment from the natural basement membrane, allowing cells to form distinct three-dimensional (3D) structures that interact with each other and with the surrounding microenvironment. Although valuable information has been accumulated from traditional in vitro studies in which cells are grown on flat and hard plastic surfaces (2D culture), this culture condition does not reflect the essential features of tumor tissues. Further, fundamental understanding of cancer metastasis cannot be obtained readily from 2D studies because they lack the complex and dynamic cell-cell communications and cell-matrix interactions that occur during cancer metastasis. These shortcomings, along with lack of spatial depth and cell connectivity, limit the applicability of 2D cultures to accurate testing of pharmacologically active compounds, free or sequestered in nanoparticles. To recapitulate features of native tumor microenvironments, various biomimetic 3D tumor models have been developed to incorporate cancer and stromal cells, relevant matrix components, and biochemical and biophysical cues, into one spatially and temporally integrated system. In this article, we review recent advances in creating 3D tumor models employing tissue engineering principles. We then evaluate the utilities of these novel models for the testing of anticancer drugs and their delivery systems. We highlight the profound differences in responses from 3D in vitro tumors and conventional monolayer cultures. Overall, strategic integration of biological principles and engineering approaches will both improve understanding of tumor progression and invasion and support discovery of more personalized first line treatments for cancer patients.

Review Article

“…The mimicry of 3D environment in organoid cultures is its major virtue, and proves it to be more closely representative of its primary tumor. Furthermore, researchers are also trying to optimize tumor microenvironment in organoid cultures by adding stromal cells and blood vessel-mimicking modules by architectural engineering of culture devices [17,18]. However, these methods are still at its infant stage and cannot replace in vivo models up to date.…”

Methods for Culturing Human Femur Tissue Explants to Study Breast Cancer Cell Colonization of the Metastatic Niche

“…Although 2-dimensional cell culture models have formed the mainstay of in vitro approaches for cancer research, it has long been recognized that cell behavior is fundamentally altered in monolayer culture systems 18,36,37 . This has led to the development of engineered microenvironments that mimic the complexity of 3-dimensional living tissues, including matrix-and scaffold-based models composed of natural materials such as collagen, or synthetic polymers seeded with specific cell types to create tissue-like microenvironments [36][37][38][39][40][41] . Engineered approaches have also included the use of bioreactor platforms to control and study the hormonal milieu of the microenvironment 18,19,[41][42][43] .…”

“…This has led to the development of engineered microenvironments that mimic the complexity of 3-dimensional living tissues, including matrix-and scaffold-based models composed of natural materials such as collagen, or synthetic polymers seeded with specific cell types to create tissue-like microenvironments [36][37][38][39][40][41] . Engineered approaches have also included the use of bioreactor platforms to control and study the hormonal milieu of the microenvironment 18,19,[41][42][43] . Although biomimetic models and bioreactors provide many elements of a complex tissue microenvironment in a controlled setting, and have been successfully applied to advance the study of breast cancer metastasis to bone .…”

Biomimetic Model of Tumor Microenvironment on Microfluidic Platform

“…[6,7] This complexity has largely prevented a comprehensive understanding of TME in conventional in vitro models, which have been too simple to recapitulate the intricate interactions ( Figure 1A). [8,9] During recent decades, microfabrication technologies have been shown to be valu able tools in the exploration of tumor pro gression. Recently, several studies using microfluidic platform have been reported that recreate the 3D context of each aspect of the TME and metastasis in vitro.…”