Abstract
In this study, to model 3D chemotactic tumor-stroma invasion in vitro, we developed an innovative microfluidic chip allowing side-by-side positioning of 3D hydrogel-based matrices. We were able to (1) create a dual matrix architecture that extended in a continuous manner, thus allowing invasion from one 3D matrix to another, and (2) establish distinct regions of tumor and stroma cell/ECM compositions, with a clearly demarcated tumor invasion front, thus allowing us to quantitatively analyze progression of cancer cells into the stroma at a tissue or single-cell level. We showed significantly enhanced cancer cell invasion in response to a transient gradient of epidermal growth factor (EGF). 3D tracking at the single-cell level displayed increased migration speed and persistence. Subsequently, we analyzed changes in expression of EGF receptors, cell aspect ratio, and protrusive activity. These findings show the unique ability of our model to quantitatively analyze 3D chemotactic invasion, both globally by tracking the progression of the invasion front, and at the single-cell level by examining changes in cellular behavior and morphology using high-resolution imaging. Taken together, we have shown a novel model recapitulating 3D tumor-stroma interactions for studies of real-time cell invasion and morphological changes within a single platform.
Highlights
Breast cancer is the one of leading causes of cancer-related death among women in the United States[1]
Motivated by the need to simulate the invasion of cancer cells from the primary ‘tumor’ into the enclosing stroma, a microfluidic platform was designed to organize the cancer cells into a central tumor region surrounded by a stroma entity[39,40]
Our findings suggest that the migratory phenotype of breast cancer cells, is linked to the activation of EGF receptors (EGFRs) and further demonstrates successful delivery of epidermal growth factor (EGF) to the cells within the 3D microfluidic device
Summary
Breast cancer is the one of leading causes of cancer-related death among women in the United States[1]. Despite significant advances in therapeutic regimens, anti-cancer drugs often fail due to lack of comprehensive preclinical studies utilizing models incorporating the complexities of the native tumor-stroma microenvironment[7,8,9,10,11] In this regard, the interactions that arise from a variety of biochemical and biophysical gradients, and cellular components should not be overlooked when developing in vitro tumor microenvironment models[12]. Cancer cells in vivo have been shown to migrate toward one specific areas of vascularization It was unclear whether the cancer cell’s response was due to the sole role of biochemical (i.e. chemoattractants) or biophysical (i.e. interstitial flow or collagen stiffness) gradients[21]. The lack of encapsulated cells within 3D ECM-based matrices, which are representative of cancer invasion within the stroma, could influence the biological findings[27]
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