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Engineering tumors with 3D scaffolds

Abstract

Microenvironmental conditions control tumorigenesis and biomimetic culture systems that allow for in vitro and in vivo tumor modeling may greatly aid studies of cancer cells' dependency on these conditions. We engineered three-dimensional (3D) human tumor models using carcinoma cells in polymeric scaffolds that recreated microenvironmental characteristics representative of tumors in vivo. Strikingly, the angiogenic characteristics of tumor cells were dramatically altered upon 3D culture within this system, and corresponded much more closely to tumors formed in vivo. Cells in this model were also less sensitive to chemotherapy and yielded tumors with enhanced malignant potential. We assessed the broad relevance of these findings with 3D culture of other tumor cell lines in this same model, comparison with standard 3D Matrigel culture and in vivo experiments. This new biomimetic model may provide a broadly applicable 3D culture system to study the effect of microenvironmental conditions on tumor malignancy in vitro and in vivo.

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Figure 1: Characterization of tumor model.
Figure 2: Angiogenic characteristics.
Figure 3: Tumor growth in vivo from cells precultured in 2D and 3D.
Figure 4: Invasiveness and drug responsiveness.

References

  1. Bissell, M.J. & Radisky, D. Putting tumours in context. Nat. Rev. Cancer 1, 46–54 (2001).

    Article  CAS  Google Scholar 

  2. Hanahan, D. & Weinberg, R.A. The hallmarks of cancer. Cell 100, 57–70 (2000).

    Article  CAS  Google Scholar 

  3. Harris, A.L. Hypoxia–a key regulatory factor in tumour growth. Nat. Rev. Cancer 2, 38–47 (2002).

    Article  CAS  Google Scholar 

  4. Debnath, J. & Brugge, J.S. Modelling glandular epithelial cancers in three-dimensional cultures. Nat. Rev. Cancer 5, 675–688 (2005).

    Article  CAS  Google Scholar 

  5. Sutherland, R.M. et al. Oxygenation and differentiation in multicellular spheroids of human colon carcinoma. Cancer Res. 46, 5320–5329 (1986).

    CAS  PubMed  Google Scholar 

  6. Debnath, J., Muthuswamy, S.K. & Brugge, J.S. Morphogenesis and oncogenesis of MCF-10A mammary epithelial acini grown in three-dimensional basement membrane cultures. Methods 30, 256–268 (2003).

    Article  CAS  Google Scholar 

  7. Lee, G.Y., Kenny, P.A., Lee, E.H. & Bissell, M.J. Three-dimensional culture models of normal and malignant breast epithelial cells. Nat. Methods 4, 359–365 (2007).

    Article  CAS  Google Scholar 

  8. Adam, M.F., Dorie, M.J. & Brown, J.M. Oxygen tension measurements of tumors growing in mice. Int. J. Radiat. Oncol. Biol. Phys. 45, 171–180 (1999).

    Article  CAS  Google Scholar 

  9. Zahir, N. et al. Autocrine laminin-5 ligates {alpha}6{beta}4 integrin and activates RAC and NF{kappa}B to mediate anchorage-independent survival of mammary tumors. J. Cell Biol. 163, 1397–1407 (2003).

    Article  CAS  Google Scholar 

  10. Yuen, H.W. et al. Suppression of laminin-5 expression leads to increased motility, tumorigenicity, and invasion. Exp. Cell Res. 309, 198–210 (2005).

    Article  CAS  Google Scholar 

  11. Sethi, T. et al. Extracellular matrix proteins protect small cell lung cancer cells against apoptosis: a mechanism for small cell lung cancer growth and drug resistance in vivo. Nat. Med. 5, 662–668 (1999).

    Article  CAS  Google Scholar 

  12. Zhang, Y., Lu, H., Dazin, P. & Kapila, Y. Squamous cell carcinoma cell aggregates escape suspension-induced, p53-mediated anoikis: fibronectin and integrin {alpha}v mediate survival signals through focal adhesion kinase. J. Biol. Chem. 279, 48342–48349 (2004).

    Article  CAS  Google Scholar 

  13. Kerbel, R. & Folkman, J. Clinical translation of angiogenesis inhibitors. Nat. Rev. Cancer 2, 727–739 (2002).

    Article  CAS  Google Scholar 

  14. Le, Y.J. & Corry, P.M. Hypoxia-induced bFGF gene expression is mediated through the JNK signal transduction pathway. Mol. Cell. Biochem. 202, 1–8 (1999).

    Article  CAS  Google Scholar 

  15. Xie, K. Interleukin-8 and human cancer biology. Cytokine Growth Factor Rev. 12, 375–391 (2001).

    Article  CAS  Google Scholar 

  16. Mizukami, Y. et al. Induction of interleukin-8 preserves the angiogenic response in HIF-1alpha-deficient colon cancer cells. Nat. Med. 11, 992–997 (2005).

    Article  CAS  Google Scholar 

  17. Li, A. et al. Autocrine role of interleukin-8 in induction of endothelial cell proliferation, survival, migration and MMP-2 production and angiogenesis. Angiogenesis 8, 63–71 (2005).

    Article  CAS  Google Scholar 

  18. Christofori, G. New signals from the invasive front. Nature 441, 444–450 (2006).

    Article  CAS  Google Scholar 

  19. Mueller, M.M. & Fusenig, N.E. Friends or foes - bipolar effects of the tumour stroma in cancer. Nat. Rev. Cancer 4, 839–849 (2004).

    Article  CAS  Google Scholar 

  20. Janes, S.M. & Watt, F.M. New roles for integrins in squamous-cell carcinoma. Nat. Rev. Cancer 6, 175–183 (2006).

    Article  CAS  Google Scholar 

  21. Maschler, S. et al. Tumor cell invasiveness correlates with changes in integrin expression and localization. Oncogene 24, 2032–2041 (2005).

    Article  CAS  Google Scholar 

  22. Qian, F., Zhang, Z.C., Wu, X.F., Li, Y.P. & Xu, Q. Interaction between integrin [alpha]5 and fibronectin is required for metastasis of B16F10 melanoma cells. Biochem. Biophys. Res. Commun. 333, 1269–1275 (2005).

    Article  CAS  Google Scholar 

  23. Islam, S., Carey, T.E., Wolf, G.T., Wheelock, M.J. & Johnson, K.R. Expression of N-cadherin by human squamous carcinoma cells induces a scattered fibroblastic phenotype with disrupted cell-cell adhesion. J. Cell Biol. 135, 1643–1654 (1996).

    Article  CAS  Google Scholar 

  24. Desmouliere, A., Guyot, C. & Gabbiani, G. The stroma reaction myofibroblast: a key player in the control of tumor cell behavior. Int. J. Dev. Biol. 48, 509–517 (2004).

    Article  CAS  Google Scholar 

  25. dit Faute, M.A. et al. Distinctive alterations of invasiveness, drug esistance and cell-cell organization in 3D-cultures of MCF-7, a human breast cancer cell line, and its multidrug resistant variant. Clin. Exp. Metastasis 19, 161–168 (2002).

    Article  Google Scholar 

  26. Kumar, P. et al. Combination treatment significantly enhances the efficacy of antitumor therapy by preferentially targeting angiogenesis. Lab. Invest. 85, 756–767 (2005).

    Article  CAS  Google Scholar 

  27. Ferrara, N., Hillan, K.J. & Novotny, W. Bevacizumab (Avastin), a humanized anti-VEGF monoclonal antibody for cancer therapy. Biochem. Biophys. Res. Commun. 333, 328–335 (2005).

    Article  CAS  Google Scholar 

  28. Alsberg, E., Anderson, K.W., Albeiruti, A., Rowley, J.A. & Mooney, D.J. Engineering growing tissues. Proc. Natl. Acad. Sci. USA 99, 12025–12030 (2002).

    Article  CAS  Google Scholar 

  29. Richardson, T.P., Peters, M.C., Ennett, A.B. & Mooney, D.J. Polymeric system for dual growth factor delivery. Nat. Biotechnol. 19, 1029–1034 (2001).

    Article  CAS  Google Scholar 

  30. Harris, L.D., Kim, B.S. & Mooney, D.J. Open pore biodegradable matrices formed with gas foaming. J. Biomed. Mater. Res. 42, 396–402 (1998).

    Article  CAS  Google Scholar 

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Acknowledgements

We thank K. Polyak (Dana Farber Cancer Institute) for her insightful review of this article, P. Kumar (University of Michigan) for helpful discussions, B. Tilton (Harvard University) for assistance with flow cytometry and Oxford Optronics for support with Oxylite measurements. Financial support was provided by the US National Institutes of Health (RO1 HL069957) and the Deutsche Forschungsgemeinschaft (post-doctoral fellowship to C.F.).

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Correspondence to David J Mooney.

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Fischbach, C., Chen, R., Matsumoto, T. et al. Engineering tumors with 3D scaffolds. Nat Methods 4, 855–860 (2007). https://doi.org/10.1038/nmeth1085

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  • DOI: https://doi.org/10.1038/nmeth1085

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