Microengineered cancer-on-a-chip platforms to study the metastatic microenvironment

Abstract

More than 90% of cancer-related deaths can be attributed to the occurrence of metastatic diseases. Recent studies have highlighted the importance of the multicellular, biochemical and biophysical stimuli from the tumor microenvironment during carcinogenesis, treatment failure, and metastasis. Therefore, there is a need for experimental platforms that are able to recapitulate the complex pathophysiological features of the metastatic microenvironment. Recent advancements in biomaterials, microfluidics, and tissue engineering have led to the development of living multicellular microculture systems, which are maintained in controllable microenvironments and function with organ level complexity. The applications of these "on-chip" technologies for detection, separation, characterization and three dimensional (3D) propagation of cancer cells have been extensively reviewed in previous works. In this contribution, we focus on integrative microengineered platforms that allow the study of multiple aspects of the metastatic microenvironment, including the physicochemical cues from the tumor associated stroma, the heterocellular interactions that drive trans-endothelial migration and angiogenesis, the environmental stresses that metastatic cancer cells encounter during migration, and the physicochemical gradients that direct cell motility and invasion. We discuss the application of these systems as in vitro assays to elucidate fundamental mechanisms of cancer metastasis, as well as their use as human relevant platforms for drug screening in biomimetic microenvironments. We then conclude with our commentaries on current progress and future perspectives of microengineered systems for fundamental and translational cancer research.

Synergistic anti-hepatoma effect of bufalin combined with sorafenib via mediating the tumor vascular microenvironment by targeting mTOR/VEGF signaling

“…There have been numerous studies on tumor angiogenesis in previous years. For example, studies have revealed that the major cytokines responsible for tumor angiogenesis are secreted via the intricate interaction between tumor cells and stromal cells (5,6). Among these factors, vascular endothelial growth factor (VEGF) is pivotal as the primary molecular driver in vasculogenesis (7).…”

Tumour-on-a-chip: microfluidic models of tumour morphology, growth and microenvironment

“…Examples of first-generation tumour-on-achip systems include a chip in which lung cancer spheroids were embedded in micro-patterned three-dimensional matrices immediately contiguous to a microchannel lined with endothelial cells (figure 1c) [4], and a breast tumour-on-a-chip model comprised the upper and lower cell culture chambers separated by an ECM-derived membrane that mimics a basement membrane in vivo (figure 1d) [13]. Previous reviews in the literature on tumour-on-a-chip technology include the construction of three-dimensional tumour models [14][15][16][17], its applications to specific cancer studies such as metastasis [18,19], and its utilities in drug discovery [20,21].…”

Microfluidic applications on circulating tumor cell isolation and biomimicking of cancer metastasis

“…The tumor microenvironment plays an important role in cancer initiation, progression, metastasis, and drug resistance [97]. The tumor microenvironment is the actual physiological environment supporting and regulates the development of tumor cells.…”

“…MET also plays an important role as it enables CTCs with EMT to reverse and restore the epithelial phenotype, regain the adhesion ability to form the secondary tumor [15]. In this process, tumor cells will lose cell polarity, rearrange cell–cell junction, undergo elongation, and thereby be able to migrate to distant tissues [97]. Microfluidic systems used for monitoring EMT process have been studied in many papers [107].…”