(594d) Hyaluronic Acid-Collagen Blend Hydrogels: 3D ECM Mimics to Investigate Tumor Cell Migration

Our research aims to understand the role of extracellular matrix (ECM) on the migratory potential of brain tumor cells using physiologically relevant 3D in vitro models. In particular, we have developed hyaluronic acid (HA)-collagen blend hydrogels to investigate brain tumor cell migration in vitro. HA was chosen because it makes up ~50% of the normal brain ECM (grey matter (neuropil)) [1]. Also, it has been observed that HA production increases in the tumor microenvironment. Collagen was selected because it is found in the cancer brain microenvironment [2]. As a model tumor system, we are investigating glioblastoma multiforme (GBM), which afflicts more than 20,000 individuals in the United States annually. GBMs are a tumor of astrocytes (a type of glial cell in the central nervous system (CNS)) [3]. GBMs are characterized by their infiltration capacity and high degree of mobility; and median patient survival is poor [3].

Hydrogel blends were created by combining thiolated HA and collagen (pepsin solubilized bovine collagen comprising of ~ 97% collagen type I and ~ 3 % collagen type III) both of which form hydrogels at 37ºC, conditions acceptable for cell encapsulation. We first examined GBM morphology in 2D culture on hydrogel blends and observed that cells undergo a distinct change in morphology (rounded to spread) as the concentration of collagen in the blend was increased. We then investigated cell behavior in 3D by maintaining constant collagen concentration and gradually increasing the concentration of HA. It was observed that cells could migrate at low concentrations of HA; however as the concentration was further increased, cells showed an increasingly rounded morphology and failed to migrate. We are currently measuring the migration rates of GBMs in these composite hydrogels and quantifying cell spreading and circularity index to quantitate cell morphology. We are also examining behavior of normal astrocytes in these hydrogels and comparing it to its tumor counterpart. Ultimately, by using these biomimetic materials and modifying them with several other relevant biomolecules, we hope to gain a better fundamental understanding of the migration mechanisms underlying GBM tumors.

References

[1] C.L. Gladson, J Neuropathol Exp Neurol. 1999. 58 (10); 1029-1040.

[2] A.C. Bellail et al., Int J Biochem Cell Biol. 2004. 36 (6); 1046-1069.

[3] P.Y. Wen et al., N Engl J Med. 2008. 359 (5); 492-507.