Tumor Engineering

Project 1: Shear stress-mediated cross talk between endothelial cells and breast cancer cells and its effect on the angiogenic response and metastatic potential of breast tumors
Graduate Student Researcher: Cara Buchanan

The proximity of endothelial cells to cancer cells within the tumor microenvironment suggests reciprocal growth factor exchange and cross-talk could directly stimulate tumor growth and metastasis, however, the role of the tumor vascular niche in regulating expression of pro-angiogenic growth factors is not well understood. It is hypothesized that endothelial cells directly influence the angiogenic response and metastatic potential of breast cancer cells through regulation and stimulation of tumorigenic growth factors. The expression profiles of these factors, such as vascular endothelial growth factor, the angiopoietins and matrix metalloproteinases are a critical determinant of the angiogenic response and metastatic potential, and should be well understood to overcome tumor resistance to anti-angiogenic therapies.

By integrating tissue engineering strategies with cancer biology, micro-scale fluid mechanics, and optical flow diagnostics, we will create a novel 3D in vitro tumor vascular model in which the interaction between tumor and endothelial cells under physiologically relevant fluid shear conditions can be monitored (Fig. 1). We are currently developing and validating a first-of-its kind in vitro breast tumor vascular model in which the co-culture of breast cancer cells and endothelial cells can be conducted under physiologically accurate conditions. Utilizing a tissue engineering approach of novel scaffolds within a bioreactor, this model will serve as a tool to investigate bidirectional cross-talk between breast cancer cells and endothelial cells, as well as the cellular response to dynamic conditions representative of the physical tumor microenvironment at various stages of development. Our ultimate goal is to understand shear stress-mediated cross talk between endothelial cells and breast cancer cells and its effect on the angiogenic response and metastatic potential of breast tumors. Understanding the role of the vascular niche in supporting the growth and metastasis of tumors may provide insight for the design of new therapeutic strategies to eradiate angiogenesis-dependent tumors. This research strategy can also be used to understand how region-specificity for tumor metastasis is related to different shear stress/flow patterns.

Related Papers
C. S. Szot, C. F. Buchanan, P. Gatenholm, M. N. Rylander, J. W. Freeman, 2011, “Investigation of Cancer Cell Behavior on Nanofibrous Scaffolds,” Materials Science and Engineering C, 31: 37-42.

Funding
Cara is funded through a National Science Foundation Graduate Research Fellowship.

Project 2: Development of a 3D in vitro Vascularized Breast Cancer Model
Graduate Student Researcher: Chris Szot

Despite rising success rates when cancer is diagnosed and treated in its early stages, a tumor that has developed neovascularization and metastasized poses a significantly greater risk of mortality. Current therapeutic options, some of which were developed over a quarter century ago, include surgery, radiation therapy, chemotherapy, hormone therapy, and immunotherapy. Problems with current treatments include recurrent tumors, non-specific targeting, targeting that is too specific, damage to vital organs, aggravation of existing conditions, and infertility. There is a need for innovative cancer therapeutics that are not prone to these problems and which can effectively inhibit tumor development.

The progression of cancer research, and subsequent discovery of permanent treatment options, is limited by the experimental systems available for studying its complex mechanisms. A majority of cancer research is conducted using small animal models; intricate, living systems that can be variable and contain many uncontrollable factors. Current in vitro models of tumorigenesis are restricted by the use of static, 2D cell culture monolayers that lack the structural architecture necessary for proper cell-cell interaction and an in vivo phenotype and 3D cell culture systems that restore the cellular morphology and phenotypes observed in vivo but are too simplistic for studying the pathological mechanisms of angiogenesis, invasion, and metastasis. Tissue engineering, specifically the unique cell culturing techniques provided by the use of 3D scaffolds and bioreactor technology, offers an exciting approach for studying cancer development in vitro.

Similar to normal tissue progression, an emerging tumor requires oxygen and nutrients supplied by the vasculature to maintain cell function, growth, and survival. Tumors experience a transition from an avascular to a vascular state by responding to changes in the tumor microenvironment and initiating an angiogenic response from the host vasculature. Typical stages of tumor development and important markers associated with hypoxia and angiogenesis are shown in the figure below.

Our group is investigating the ability to induce an angiogenic shift in human breast cancer cells in vitro through employing a tissue engineering approach in which cancer cells are subjected to culturing conditions that mimic specific tumor microenvironmental cues. The goal of this project is to construct an environment in which we can adjust each aspect of the tumor microenvironment to synergistically control the angiogenic shift and direct it towards the development of a 3D in vitro vascularized breast cancer model that can be used to better understand the pathological mechanisms of tumorigenesis, angiogenesis, and metastasis. The Figure to the right shows formation of a neovessel in response to culturing of endothelial and cancer cells together in a hydrogel.

Related Papers
C. S. Szot, C. F. Buchanan, P. Gatenholm, M. N. Rylander, J. W. Freeman, 2011, “Investigation of Cancer Cell Behavior on Nanofibrous Scaffolds,” Materials Science and Engineering C, 31: 37-42.