Advanced biomaterials and microengineering technologies to recapitulate the stepwise process of cancer metastasis

Abstract

Cancer is one of the leading causes of death globally according to the World Health Organization. Although improved treatments and early diagnoses have reduced cancer related mortalities, metastatic disease remains a major clinical challenge. The local tumor microenvironment plays a significant role in cancer metastasis, where tumor cells respond and adapt to a plethora of biochemical and biophysical signals from stromal cells and extracellular matrix (ECM) proteins. Due to these complexities, there is a critical need to understand molecular mechanisms underlying cancer metastasis to facilitate the discovery of more effective therapies. In the past few years, the integration of advanced biomaterials and microengineering approaches has initiated the development of innovative platform technologies for cancer research. These technologies enable the creation of biomimetic in vitro models with physiologically relevant (i.e. in vivo-like) characteristics to conduct studies ranging from fundamental cancer biology to high-throughput drug screening. In this review article, we discuss the biological significance of each step of the metastatic cascade and provide a broad overview on recent progress to recapitulate these stages using advanced biomaterials and microengineered technologies. In each section, we will highlight the advantages and shortcomings of each approach and provide our perspectives on future directions.

Tumor microenvironment complexity and therapeutic implications at a glance

“…The cornerstone of the current review compared to the previous ones is its comprehensiveness. Previous reviews in this area are focused, for example, on recapitulating the gradual process of cancer metastasis by discussing advanced biomaterials and microtechnologies [19]. Also, they may highlight the mechanics of tumor metastasis [20].…”

Vascularized microfluidic platforms to mimic the tumor microenvironment

“…Groups have utilized subtractive and additive tissue engineering processes to form microfluidic collagen scaffolds (Bettinger, Borenstein, & Tao, ; Bhatia & Ingber, ; Peela et al, ; Tien, ). Scaffolds with complex microfluidic networks have also been formed using additive methods of combining layers of natural materials formed with lithographic techniques and have been used to investigate various behaviors such as cell‐cell interactions during angiogenesis or metastasis, extravasation of breast cancer cells and interactions with the endothelium (Bhatia & Ingber, ; Bischel, Young, Mader, & Beebe, ; Farahat et al, ; Ghousifam et al, ; Jeon et al, ; Lee et al, ; Mi et al, ; Nagaraju et al, ; Peela et al, ; Price et al, ; Soleimani et al, ; Song et al, ; Y. Ma et al, ; Zheng et al, ). While these microfluidic devices have provided insight into tumor behavior, the in vitro platforms consist of small number of cells limiting the use of biological assays such as polymerase chain reaction or enzyme‐linked immunosorbent assay, or they lack a continuous endothelium failing to recapitulate the in vivo tumor microenvironment.…”

“…However, using a non-protein based scaffold material limits physiological cell-matrix interactions, which affects proliferation and representative cell response (Antoine, Vlachos, & Rylander, 2014. Groups have utilized subtractive and additive tissue engineering processes to form microfluidic collagen scaffolds (Bettinger, Borenstein, & Tao, 2012;Bhatia & Ingber, 2014;Peela et al, 2017;Tien, 2014). Scaffolds with complex microfluidic networks have also been formed using additive methods of combining layers of natural materials formed with lithographic techniques and have been used to investigate various behaviors such as cell-cell interactions during angiogenesis or metastasis, extravasation of breast cancer cells and interactions with the endothelium (Bhatia & Ingber, 2014;Bischel, Young, Mader, & Beebe, 2013;Farahat et al, 2012;Ghousifam et al, 2017;Jeon et al, 2015;Lee et al, 2014;Mi et al, 2016;Nagaraju et al, 2018;Peela et al, 2017;Price et al, 2008;Soleimani et al, 2018;Song et al, 2009;Y.…”

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].…”