Chitosan-Alginate Scaffold Culture System for Hepatocellular Carcinoma Increases Malignancy and Drug Resistance
- 488 Downloads
Hepatocellular carcinoma (HCC) is a prevalent solid malignancy. Critically needed discovery of new therapeutics has been hindered by lack of an in vitro cell culture system that can effectively represent the in vivo tumor microenvironment. To address this need, a 3D in vitro HCC model was developed using a biocompatible, chitosan-alginate (CA) scaffold cultured with human HCC cell lines.
The correlation between the cell function, such as secretion of growth factors and production of ECM in vitro, and the tumor growth and blood vessel recruitment in vivo was investigated.
HCC cells grown on 3D CA scaffolds demonstrated morphological characteristics and increased expression of markers of highly malignant cells. Implantation of CA scaffolds cultured with human HCC cells in mice showed accelerated tumor growth. Histology revealed marked differences in morphology and organization of newly formed blood vessels between tumors produced by different pre-cultured conditions. Resistance to doxorubicin was significantly pronounced in CA scaffold-cultured HCC cells compared to 2D or Matrigel cultured HCC cells.
This 3D model of HCC, with its ability to more closely mimic the in vivo tumor behavior, may serve as an invaluable model for study and application of novel anticancer therapeutics against HCC.
KEY WORDSchitosan drug resistance hepatocellular carcinoma in vitro model scaffolds tumor microenvironment
This work is supported in part by NIH grants (R01EB006043 and R01CA134213). Jim Park and Omid Veiseh would like to acknowledge support through the ASA Foundation Fellowship Research Award and an NIH training grant (T32CA138312), respectively. Additionally, we would like to acknowledge the use of the SEM at the Dept of Materials Science and Engineering and Keck Microscopy Imaging Facility at the University of Washington.
- 9.Tredan O, Galmarini CM, Patel K, Tannock IF. Drug resistance and the solid tumor microenvironment. J Natl Cancer Inst Monogr. 2007;99:1441–54.Google Scholar
- 29.Hodgson E. A textbook of modern toxicology. 3rd ed: Wiley-Interscience; 2004.Google Scholar
- 38.Hirschhaeuser F, Menne H, Dittfeld C, West J, Mueller-Klieser W, Kunz-Schughart LA. Multicellular tumor spheroids: an underestimated tool is catching up again. J. Biotechnol. 2010; In Press, Corrected Proof.Google Scholar
- 40.Patel K, Tannock I. The influence of P-glycoprotein expression and its inhibitors on the distribution of doxorubicin in breast tumors. 2009. p. 356.Google Scholar