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Solid stress inhibits the growth of multicellular tumor spheroids

Nature Biotechnology volume 15, pages 778–783 (1997)Cite this article

Abstract

In normal tissues, the processes of growth, remodeling, and morphogenesis are tightly regulated by the stress field; conversely, stress may be generated by these processes. We demonstrate that solid stress inhibits tumor growth in vitro, regardless of host species, tissue of origin, or differentiation state. The inhibiting stress for multicellular tumor spheroid growth in agarose matrices was 45 to 120 mm Hg. This stress, which greatly exceeds blood pressure in tumor vessels, is sufficient to induce the collapse of vascular or lymphatic vessels in tumors in vivo and can explain impaired blood flow, poor lymphatic drainage, and suboptimal drug delivery previously reported in solid tumors. The stress-induced growth inhibition of plateau-phase spheroids was accompanied, at the cellular level, by decreased apoptosis with no significant changes in proliferation. A concomitant increase in the cellular packing density was observed, which may prevent cells from undergoing apoptosis via a cell-volume or cell-shape transduction mechanism. These results suggest that solid stress controls tumor growth at both the macroscopic and cellular levels, and thus influences tumor progression and delivery of therapeutic agents.

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References

  1. Wolff, J. 1870. Über die innere Architektur der Knochen und ihre Bedeutung für die Frage vom Knochenwachsum. Virchow. Arch. 50: 389–453.

    Article  Google Scholar 

  2. Fung, Y.C. 1990. Biomechanical aspects of growth and tissue engineering, pp. 499–546 in Biomechanks, motion, How, stress, and growth. Fung, Y.C. (ed). Springer-verlag, New York.

    Google Scholar 

  3. Fung, Y.C. and Liu, S.Q. 1989. Change of residual strain in arteries due to hypertrophy caused by aortic constriction. Circ. Res. 65: 1340–1349.

    Article  CAS  Google Scholar 

  4. Burton, K. and Taylor, D.L. 1997. Traction forces of cytokinesis measured with optically modified elastfc substrata. Nature 385: 450–454.

    Article  CAS  Google Scholar 

  5. Fung, Y.C. 1991. What are the residual stresses doing in our blood vessels? Ann. Biomed. Eng. 19: 237–249.

    Article  CAS  Google Scholar 

  6. Omens, J.H. and Fung, Y.C. 1990. Residual strain in rat left ventricle. Circ. Res. 66: 37–45.

    Article  CAS  Google Scholar 

  7. Han, H.C. and Fung, Y.C. 1991. Residual strain in porcine and canine trachea. J. Biomech. Eng. 24: 307–315.

    Article  CAS  Google Scholar 

  8. Vaage, J. 1992. Fibrosis in immune control of mammary-tumor growth. Int. J. Cancer 51: 325–328.

    Article  CAS  Google Scholar 

  9. Gartner, M.F.R.M., Fearns, C., Lynette Wilson, E., Campbell, J.A.H. and Dowdle, E.B. 1992. Unusual growth characteristics of human melanoma xenografts in the nude mouse: a model for desmoplasia, dormancy and progression. Br. J. Cancer 65: 487–490.

    Article  CAS  Google Scholar 

  10. Eaves, G. 1973. The invasive growth of malignant tumours as a purely mechanical process. J. Pathol. 109: 233–237.

    Article  CAS  Google Scholar 

  11. Young, J.S. 1959. The invasive growth of malignant tumours: an experimental interpretation based on elastic-jelly models. J. Path. Bact. 77: 321–326.

    Article  CAS  Google Scholar 

  12. Falk, R. 1978. Patterns of vasculature in two pairs of related fibrosarcomas in the rat and their relation to tumour responses to single large doses of radiation. Eur. J. Cancer 14: 237–250.

    Article  CAS  Google Scholar 

  13. Falk, P. 1980. The vascular pattern of the spontaneous C3H mouse mammary carcinoma and its significance in radiation response and in hyperthermia. Eur. J. Cancer 16: 203–217.

    Article  CAS  Google Scholar 

  14. Tozer, G.M., Lewis S., Michalowski, A., and Aber, V. 1990. The relationship between regional variations in blood flow and histology in a transplanted rat fibrosarcoma. Br. J. Cancer 61: 250–257.

    Article  CAS  Google Scholar 

  15. Li, L., Price, J.E., Fan, D., Zhang, R.D., Bucana, C.D., Fidler, I.J. et al. 1989. Correlation of growth capacity of human tumor cells in hard agarose with their in vivo proliferative capacity at specific metastatic sites. J. Natl. Cancer Inst. 81: 1406–1412.

    Article  CAS  Google Scholar 

  16. Jain, R.K. 1988. Determinants of tumor blood flow: a review. Cancer Res. 48: 2641–58.

    CAS  Google Scholar 

  17. Knight, M.M., Lee, D.A. and Bader, D.L. 1996. Distribution of chondrocyte deformation in compressed agarose gel using confocal microscopy. Cell. Eng. 1: 97–102.

    Google Scholar 

  18. Sutherland, R.M. 1988. Cell and environment interactions in tumor microregions: the multicell spheroid model. Science 240: 177–184.

    Article  CAS  Google Scholar 

  19. Freyer, J.P. 1988. Role of necrosis in regulating the growth saturation of multicellular spheroids. Cancer Res. 48: 2432–2439.

    CAS  PubMed  Google Scholar 

  20. Gompertz, B. 1825. On the nature of the function expressive of the law of human mortality, and on a new method of determining the value of life contingencies. Phil. Trans. R. Soc. 116: 513–585.

    Google Scholar 

  21. Gyllenberg, M. and Webb, G.F. 1989. Quiescence as an explanation of Gompertzian tumor growth. Growth Dev. Aging 53: 25–33.

    CAS  PubMed  Google Scholar 

  22. Nicolson, G.L., Lembo, T.M. and Welch, D.R. 1988. Growth of rat mammary adenocarcinoma cells in semisolid clonogenic medium not correlated with spontaneous metastatic behavior: heterogeneity in the metastatic, antigenic, enzymatic, and drug sensitivity properties of cells from different sized colonies. Cancer Res. 48: 399–404.

    CAS  PubMed  Google Scholar 

  23. Johnson, E.M., Berk, D.A., Jain, R.K. and Deen, W.M. 1996. Hindered diffusion in agarose gels: test of effective medium model. Biophys. J. 70: 1017–1026.

    Article  CAS  Google Scholar 

  24. Raff, M.C. 1992. Social controls on cell survival and cell death. Nature 356: 397–400.

    Article  CAS  Google Scholar 

  25. Bates, R.C., Buret, A., van Helden, D.F., Horton, M.A., and Burns, G.F. 1994. Apoptosis induced by inhibition of intercellular contact. J. Cell Biol. 125: 403–415.

    Article  CAS  Google Scholar 

  26. Freyer, J.P. 1994. Ratesof oxygen consumption for proliferating and quiescent cells isolated from multicellular tumor spheroids. Adv. Exp. Med. Biol. 345: 335–342.

    Article  CAS  Google Scholar 

  27. Olive, P.L. and Durand, R.E. 1994. Drugs and radiation resistance in spheroids: cell contact and kinetics. Cancer Metastasis Rev. 13: 121–138.

    Article  CAS  Google Scholar 

  28. Kobayashi, H., Man, S., Graham, C.H., Kapitain, S.J., Teicher, B.A., Kerbel, R.S., et al. 1993. Acquired multicellular-mediated resistance to alkylating agents in cancer. Proc. Natl. Acad. Sci. USA 90: 3294–3298.

    Article  CAS  Google Scholar 

  29. Kerbel, R.S., Rak, J.W., Kobayashi, H., Man, S., St. Croix, B., Graham, C.H. et al. 1994. Multicellular resistance: anew paradigm to explain aspects of acquired drug resistance of solid tumors. Cold Spring Harbor Symp. Quant. Biol. (Molec. Gen. Cancer) 59: 661–672.

    Article  CAS  Google Scholar 

  30. St. Croix, B., Rak, J.W., Kapitain, S.J., Sheehan, C., Graham, C.H., Kerbel, R.S. et al. 1996. Reversal by hyaluronidase of adhesion-dependent multicellular drug resistance in mammary carcinoma cells. J. Natl. Cancer Inst. 88: 1285–1296.

    Article  CAS  Google Scholar 

  31. Rak, J.W. and Kerbel, R.S. 1993. Growth advantage (“clonal dominance”) of metastatically competent tumor cell variants expressed under selective two- or three-dimensional tissue culture conditions. In Vitro Cell. Dev. Biol. 29A: 742–748.

    Article  CAS  Google Scholar 

  32. Holmgren, L., O'Reilly, M.S. and Folkman, J. 1995. Dormancy of micrometastases: balanced proliferation and apoptosis in the presence of angiogenesis suppression. Nature Med. 1: 149–153.

    Article  CAS  Google Scholar 

  33. Freyer, J.P. and Schor, P.L. 1989. Regrowth kinetics of cells from different regions of multicellular spheroids of four cell lines. J. Cell. Physiol. 138: 384–392.

    Article  CAS  Google Scholar 

  34. lozzo, R.V. 1995. Tumor Stroma as a regulator of neoplastic behavior. Agonistic and antagonistic elements embedded in the same connective tissue. Lab. Invest 73: 157–160.

    Google Scholar 

  35. Stetler-Stevenson, W.G. 1996. Dynamics of matrix turnover during pathologic remodeling of the extracellular matrix. Am. J. Pathol. 148: 1345–1350.

    CAS  PubMed  PubMed Central  Google Scholar 

  36. Boucher, Y. and Jain, R.K. 1992. Microvascular pressure is the principal driving force for interstitial hypertension in solid tumors: implications for vascular collapse. Cancer Res. 52: 5110–4.

    CAS  PubMed  Google Scholar 

  37. Boucher, Y., Baxter, L.T. and Jain, R.K. 1990. Interstitial pressure gradients in tissue-isolated and subcutaneous tumors: implications for therapy. Cancer Res. 50: 4478–84.

    CAS  PubMed  Google Scholar 

  38. Boucher, Y., Leunig, M. and Jain, R.K. 1996. Tumor angiogenesis and interstitial hypertension. Cancer Res. 56: 4264–4266.

    CAS  PubMed  Google Scholar 

  39. MacPhee, P.J. and Michel, C.C. 1995. Subatmospheric closing pressures in individual microvessels of rats and frogs. J. Physiol. 484: 183–187.

    Article  CAS  Google Scholar 

  40. Netti, P.A., Roberge, S., Boucher, Y., Baxter, L.T. and Jain, R.K. 1996. Effect of transvascular fluid exchange on pressure - flow relationship in tumors: a proposed mechanism for tumor blood flow heterogeneity. Microvasc. Res. 52: 27–46.

    Article  CAS  Google Scholar 

  41. Tanigawa, N., Kanazawa, T., Satomura, K., Kikasa, Y., Hashida, M., Muranishi, S. et al. 1981. Experimental study on lymphatic vascular changes in the development of cancer. Lymphology 14: 149–154.

    CAS  PubMed  Google Scholar 

  42. lscove, N.N. and Schreier, M.H. 1979. Clonal growth of cells in semisolid or viscous medium, pp. 379–385 in Immunological methods. Academic Press.

    Google Scholar 

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Authors and Affiliations

  1. Department of Radiation Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, MA, 02114

    Gabriel Helmlinger, Paolo A. Netti, Hera C. Lichtenbeld, Robert J. Melder & Rakesh K. Jain

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Correspondence to Rakesh K. Jain.

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Helmlinger, G., Netti, P., Lichtenbeld, H. et al. Solid stress inhibits the growth of multicellular tumor spheroids. Nat Biotechnol 15, 778–783 (1997). https://doi.org/10.1038/nbt0897-778

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