Biomimetic Model of Tumor Microenvironment on Microfluidic Platform

Abstract

COMMUNICATION (1 of 7)© 2017 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim Biomimetic Model of Tumor Microenvironment on Microfluidic PlatformMinhwan Chung, Jungho Ahn, Kyungmin Son, Sudong Kim, and Noo Li Jeon* DOI: 10.1002/adhm.201700196 "cure." [4,5] The TME is a complex, inter acting system including the tumor itself, other noncancerous cell types such as immune, stromal and endothelial cells, and the extracellular matrix surrounding these cells. [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. [10][11][12][13] However, to our knowledge, no versatile in vitro experimental model that reconstitutes direct interplay between constituents of the TME during tumorigenesis has yet been reported. Here we describe a biomimetic TME model to mimic the complex inter actions of the tumor, stromal, and endothe lial cells, all of which are essential components of the TME that hinder the effective treatment of cancers. [14][15][16] We used a micro fluidic platform from our previous studies. [17,18] Various effects of extracellular matrix (ECM) and the stroma on the physiology of tumor cells and angiogenesis were tested. Finally, we could mimic simultaneous angiogenesis and lymphangiogenesis in the TME with interactions between the tumor cells.Although the cancer stroma is well known for its many roles in multiple cancer stages, direct interactions between cancer and stromal cells have remained largely unknown. [19] Addition ally, cancer cell interaction with the ECM is another TME factor that regulates the behavior of the cancer cells and their resist ance to drugs. [20] Recently, in vitro activation of tumor stoma and corresponding ECM remodeling have been reported using a microfluidic platform. [21] However, single cell responses of the cancer cells in response to the stroma coculture and ECM composition has not yet been described. To examine cancer stromal cell interaction with a 3D ECM, we used a micro fluidic 3D cell culture platform previously reported from our group. [17,18] The array of microposts in the platform enabled straightforward micropatterning of the hydrogel which allowed flexible experimental configurations. We first cocultured cancer and stromal cells within fibrin gel in different microchannels, which still allowed the cells to interact with each other in a par acrine manner ( Figure 1B). Twice as many fibroblasts as cancer cells were patterned to exclude an autocrine or indirect effectThe "Tumor microenvironment" (TME) is a complex, interacting system of the tumor and its surrounding environment. The TME has drawn more attention recently in attempts to overcome current drug...

Application of microscale culture technologies for studying lymphatic vessel biology

“…In a separate study, Chung et al created a biomimetic TME model that allowed for simultaneous observation of angiogenesis and lymphangiogenesis while co‐cultured with cancer cells and fibroblasts. Choi et al used a cylindrical 3‐D vessel assay that demonstrated that LSS (2 dyn/cm 2 ) selectively suppresses Notch activation in LECs but not BECs, resulting in an increase in lymphatic sprouting.…”

Vascularized microfluidic platforms to mimic the tumor microenvironment

“…Other proteins such as fibrin have also been used as a scaffold material. Groups have utilized fibrin by itself or as a blend with different collagen percentages for various applications including cardiac, wound healing and cancer invasion studies (Chung, Ahn, Son, Kim, & Jeon, ; Lee, Park, Ryu, & Jeon, ; Mol et al, ; Nagaraju, Truong, Mouneimne, & Nikkhah, ; Purtscher, Rothbauer, Holnthoner, Redl, & Ertl, ). However, low ultimate tensile strength of this material suggests it is not well suited for tissues of high stiffness such as breast tumor microenvironments, making collagen a more desirable scaffold material (Cummings, Gawlitta, Nerem, & Stegemann, ).…”

“…Groups have utilized fibrin by itself or as a blend with different collagen percentages for various applications including cardiac, wound healing and cancer invasion studies (Chung, Ahn, Son, Kim, & Jeon, 2017;Lee, Park, Ryu, & Jeon, 2014;Mol et al, 2005;Nagaraju, Truong, Mouneimne, & Nikkhah, 2018;Purtscher, Rothbauer, Holnthoner, Redl, & Ertl, 2015).…”

Ex Vivo Tumor‐on‐a‐Chip Platforms to Study Intercellular Interactions within the Tumor Microenvironment

“…Several studies have shown the critical role of CAFs in cancer progression, although the mechanisms by which they promote disease progression have yet to be unraveled . Given that fibroblasts are one of the key cell populations in the stroma, a number of studies have examined tumor–fibroblast interactions on chip . Integration of microfabrication along with biomaterial‐assisted cell encapsulation can be used to compartmentalize different cell populations .…”