Migration through extra-cellular matrix (ECM) and intravasation across a cellular barrier comprise the initial, rate-limiting steps of cancer metastasis. Physiologically relevant and well-controlled models that mimic the in vivo tumor microenvironment will enable better understanding of the initial steps of metastasis and evaluation of potential therapy efficacy. In vivo models have physiological relevancy, yet inherently lack a high level of control. In vitro cancer migration models have high levels of control, yet lack critical components of the tumor microenvironment. We propose a new technology, a microfluidic migration and intravasation assay (?MIA). The ?MIA replicates essential components of the in vivo tumor microenvironment, including a 3D ECM and a vasculature, while providing tight control of biochemical and biophysical parameters. To further establish the ?MIA, we propose to use it to investigate a specific biophysical factor - interstitial flow - which has not previously been studied in the context of metastatic disease. The objective of the proposed work is to evaluate the metastatic potential of cancerous cells by developing the ?MIA and identifying novel extent of invasion metrics (Specific Aim 1), and applying them to study the influence of interstitial flow on cancer cell metastasis (Specific Aim 2). The ?MIA will have an input channel for the cancer cells, a 3D collagen gel to simulate native ECM, and an endothelial cell (EC) layer adherent to the gel in a second channel. The configuration will permit migration of cancer cells either from the input channel or within the gel towards the second channel. Optimized gel parameters will present appropriate chemotactic gradients and physical parameters simulating a tumor microenvironment and inducing cancer cell migration. The EC layer will mimic the in vivo vascular barrier allowing observation of cancer cell intravasation. Optical access from two vantage points will permit real time observation of cancer cell migration and intravasation. The optical access combined with image processing techniques will quantify cancer cell morphological and migratory parameters, leading to identification of novel extent of invasion metrics that will quantify the metastatic potential of cancer cells. Finally, we will leverage the microfluidic capability of the ?MIA to induce interstitial flow across the gel, and quantify the effects of this biophysical parameter on cancer cell invasion. Taken together, the two aims establish the ?MIA as an excellent platform for quantitative research of molecular mechanisms governing cancer cell invasion. For example, therapies capitalizing on altered vascular morphology near tumors would clearly benefit from using the ?MIA as a development platform, as the system provides a characterized EC layer in conjunction with a well-controlled system. Future development will enable the ?MIA to serve as a cancer cell diagnostic device and a high throughput drug development tool. Cancer spreads and invades through a process called metastasis, often resulting in patient death. The metastasis process is not well understood, since there is a shortage of well-controlled models that realistically represent the tumor microenvironment and its blood supply. This application seeks to develop a well-controlled and realistic tumor environment model to aid cancer metastasis research and eventually provide a platform to more efficiently develop and evaluate cancer therapies.
Cancer spreads and invades through a process called metastasis, often resulting in patient death. The metastasis process is not well understood, since there is a shortage of well-controlled models that realistically represent the tumor microenvironment and its blood supply. This proposal seeks to develop a well-controlled and realistic tumor environment model to aid cancer metastasis research and eventually provide a platform to more efficiently develop and evaluate cancer therapies.
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|Polacheck, William J; Zervantonakis, Ioannis K; Kamm, Roger D (2013) Tumor cell migration in complex microenvironments. Cell Mol Life Sci 70:1335-56|
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