Abstract

Solid stress and tissue stiffness affect tumour growth, invasion, metastasis and treatment. Unlike stiffness, which can be precisely mapped in tumours, the measurement of solid stresses is challenging. Here, we show that 2D spatial maps of the solid stress and the resulting elastic energy in excised or in situ tumours with arbitrary shapes and a wide range of sizes can be obtained via three distinct and quantitative techniques that rely on the measurement of tissue displacement after disruption of the confining structures. Application of these methods in models of primary tumours and metastasis revealed that (i) solid stress depends on both cancer cells and their microenvironments, (ii) solid stress increases with tumour size and (iii) mechanical confinement by the surrounding tissue substantially contributes to intratumoral solid stress. Further study of the genesis and consequences of solid stress, facilitated by the engineering principles presented here, may lead to new discoveries and therapies.

Access optionsAccess options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

References

  1. 1.

    , & . The role of mechanical forces in tumor growth and therapy. Annu. Rev. Biomed. Eng. 16, 321–346 (2014).

  2. 2.

    et al. Extracellular matrix stiffness and composition jointly regulate the induction of malignant phenotypes in mammary epithelium. Nat. Mater. 13, 970–978 (2014).

  3. 3.

    et al. Tissue mechanics modulate microRNA-dependent PTEN expression to regulate malignant progression. Nat. Med. 20, 360–367 (2014).

  4. 4.

    et al. Actomyosin-mediated cellular tension drives increased tissue stiffness and β-catenin activation to induce epidermal hyperplasia and tumor growth. Cancer Cell 19, 776–791 (2011).

  5. 5.

    , & The physics of cancer: the role of physical interactions and mechanical forces in metastasis. Nat. Rev. Cancer 11, 512–522 (2011).

  6. 6.

    et al. Biomechanical remodeling of the microenvironment by stromal caveolin-1 favors tumor invasion and metastasis. Cell 146, 148–163 (2011).

  7. 7.

    et al. Tumor mechanics and metabolic dysfunction. Free Radic. Biol. Med. 79, 269–280 (2015).

  8. 8.

    , , , & Solid stress inhibits the growth of multicellular tumor spheroids. Nat. Biotechnol. 15, 778–783 (1997).

  9. 9.

    et al. Causes, consequences, and remedies for growth-induced solid stress in murine and human tumors. Proc. Natl Acad. Sci. USA 109, 15101–15108 (2012).

  10. 10.

    & Microvascular pressure is the principal driving force for interstitial hypertension in solid tumors: implications for vascular collapse. Cancer Res. 52, 5110–5114 (1992).

  11. 11.

    , , , & Taxane-induced apoptosis decompresses blood vessels and lowers interstitial fluid pressure in solid tumors: clinical implications. Cancer Res. 59, 3776–3782 (1999).

  12. 12.

    et al. Lymphatic metastasis in the absence of functional intratumor lymphatics. Science 296, 1883–1886 (2002).

  13. 13.

    et al. Pathology: cancer cells compress intratumour vessels. Nature 427, 695 (2004).

  14. 14.

    et al. Angiotensin inhibition enhances drug delivery and potentiates chemotherapy by decompressing tumour blood vessels. Nat. Commun. 4, 2516 (2013).

  15. 15.

    Antiangiogenesis strategies revisited: from starving tumors to alleviating hypoxia. Cancer Cell 26, 605–622 (2014).

  16. 16.

    et al. Mechanical induction of the tumorigenic β-catenin pathway by tumour growth pressure. Nature 523, 92–95 (2015).

  17. 17.

    et al. Mechanical compression drives cancer cells toward invasive phenotype. Proc. Natl Acad. Sci. USA 109, 911–916 (2012).

  18. 18.

    et al. Enzymatic targeting of the stroma ablates physical barriers to treatment of pancreatic ductal adenocarcinoma. Cancer Cell 21, 418–429 (2012).

  19. 19.

    et al. Compression of pancreatic tumor blood vessels by hyaluronan is caused by solid stress and not interstitial fluid pressure. Cancer Cell 26, 14–15 (2014).

  20. 20.

    US National Library of Medicine. Proton w/FOLFIRINOX-Losartan for pancreatic cancer. ClinicalTrials.gov (2013).

  21. 21.

    US National Library of Medicine. PEGPH20 plus nab-paclitaxel plus Gemcitabine compared with nab-paclitaxel plus Gemcitabine in subjects with stage IV untreated pancreatic cancer (HALO-109-202). ClinicalTrials.gov (2013).

  22. 22.

    & in Frontiers in Biomechanics (eds Schmid-Schönbein, G. W. et al. ) Ch. 9 (Springer, 1986).

  23. 23.

    & . Stress-modulated growth, residual stress, and vascular heterogeneity. J. Biomech. Eng. 123, 528–535 (2001).

  24. 24.

    et al. Quantifying cell-generated mechanical forces within living embryonic tissues. Nat. Methods 11, 183–189 (2014).

  25. 25.

    et al. Measuring mechanical tension across vinculin reveals regulation of focal adhesion dynamics. Nature 466, 263–266 (2010).

  26. 26.

    & Theory of Elasticity (McGraw-Hill, 1951).

  27. 27.

    et al. The nanomechanical signature of breast cancer. Nat. Nanotech. 7, 757–765 (2012).

  28. 28.

    , , , & In situ force mapping of mammary gland transformation. Integr. Biol. (Camb). 3, 910–921 (2011).

  29. 29.

    et al. Three-dimensional microscopy of the tumor microenvironment in vivo using optical frequency domain imaging. Nat. Med. 15, 1219–1223 (2009).

  30. 30.

    , & Mechanical restrictions on biological responses by adherent cells within collagen gels. J. Mech. Behav. Biomed. Mat. 14, 216–226 (2012).

  31. 31.

    et al. Stromal fibroblasts present in invasive human breast carcinomas promote tumor growth and angiogenesis through elevated SDF-1/CXCL12 secretion. Cell 121, 335–348 (2005).

  32. 32.

    et al. Coevolution of solid stress and interstitial fluid pressure in tumors during progression: implications for vascular collapse. Cancer Res. 73, 3833–3841 (2013).

  33. 33.

    , , , & Role of constitutive behavior and tumor-host mechanical interactions in the state of stress and growth of solid tumors. PLoS ONE 9, e104717 (2014).

  34. 34.

    , , & Obesity and cancer: an angiogenic and inflammatory link. Microcirculation 23, 191–206 (2016).

  35. 35.

    et al. Obesity-induced inflammation and desmoplasia promote pancreatic cancer progression and resistance to chemotherapy. Cancer Discov. 6, 852–869 (2016).

  36. 36.

    et al. The histological growth pattern of colorectal cancer liver metastases has prognostic value. Clin. Exp. Metastasis 29, 541–549 (2012).

  37. 37.

    et al. Growth pattern of colorectal liver metastasis as a marker of recurrence risk. Clin. Exp. Metastasis 32, 369–381 (2015).

  38. 38.

    et al. Aligned collagen is a prognostic signature for survival in human breast carcinoma. Am. J. Pathol. 178, 1221–1232 (2011).

  39. 39.

    et al. Elasticity as a biomarker for prostate cancer: a systematic review. BJU. Int. 113, 523–534 (2014).

  40. 40.

    et al. Predicting prognostic factors of breast cancer using shear wave elastography. Ultrasound Med. Biol. 40, 269–274 (2014).

  41. 41.

    et al. High tumor interstitial fluid pressure identifies cervical cancer patients with improved survival from radiotherapy plus cisplatin versus radiotherapy alone. Int. J. Cancer 135, 1692–1699 (2014).

  42. 42.

    et al. Interstitial hypertension in carcinoma of uterine cervix in patients: possible correlation with tumor oxygenation and radiation response. Cancer Res. 51, 6695–6698 (1991).

  43. 43.

    et al. Long-term performance of interstial fluid pressure and hypoxia as prognostic factors in cervix cancer. Radiother. Oncol. 80, 132–137 (2006).

  44. 44.

    , & Tissue cells feel and respond to the stiffness of their substrate. Science 310, 1139–1143 (2005).

  45. 45.

    , , , & Poroelasticity of cartilage at the nanoscale. Biophys. J. 101, 2304–2313 (2011).

  46. 46.

    Fields, Forces, and Flows in Biological Systems Ch. 4 (Garland Science, 2011).

  47. 47.

    & Calibration of atomic-force microscope tips. Rev. Sci. Instrum. 64, 1868–1873 (1993).

  48. 48.

    et al. Collagen network primarily controls Poisson's ratio of bovine articular cartilage in compression. J. Orthop. Res. 24, 690–699 (2006).

  49. 49.

    et al. Stimulation of aggrecan synthesis in cartilage explants by cyclic loading is localized to regions of high interstitial fluid flow. Arch. Biochem. Biophys. 366, 1–7 (1999).

  50. 50.

    , , , & Role of extracellular matrix assembly in interstitial transport in solid tumors. Cancer Res. 60, 2497–2503 (2000).

  51. 51.

    , , , & Mouse colon carcinoma cells established for high incidence of experimental hepatic metastasis exhibit accelerated and anchorage-independent growth. Clin. Exp. Metastasis 22, 513–521 (2005).

  52. 52.

    et al. Vascular permeability and microcirculation of gliomas and mammary carcinomas transplanted in rat and mouse cranial windows. Cancer Res. 54, 4564–4568 (1994).

  53. 53.

    et al. Dataset for solid stress and elastic energy as measures of tumour mechanopathology. figshare (2016).

Download references

Acknowledgements

We thank S. Roberge, C. Smith, J. Kahn and M. Duquette for technical assistance. We also thank P. Huang, N. Bardeesy and T. Irimura for providing MMTV-M3C, AK4.4 and SL4 cells, respectively. This work was supported in part by funding from the National Cancer Institute (P01-CA080124), an NCI Outstanding Investigator Award (R35-CA197743) and a Department of Defense Breast Cancer Research Innovator award (W81XWH-10-1-0016) to R.K.J., a DP2 OD008780 to T.P.P., a R01 grant (HL128168) to L.L.M., T.P.P. and J.W.B., a Susan G. Komen Foundation Fellowship (PDF14301739) to G.S., a National Institutes of Health award (F31HL126449) to M.D., and an UNCF-Merck Science Initiative Postdoctoral Fellowship, Burroughs Wellcome Fund Postdoctoral Enrichment Program Award and a NCI grant (F32CA183465) to D.J.

Author information

Affiliations

  1. Edwin L. Steele Laboratories, Department of Radiation Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02114, USA

    • Hadi T. Nia
    • , Hao Liu
    • , Giorgio Seano
    • , Meenal Datta
    • , Dennis Jones
    • , Nuh Rahbari
    • , Joao Incio
    • , Vikash P. Chauhan
    • , Keehoon Jung
    • , John D. Martin
    • , Vasileios Askoxylakis
    • , Timothy P. Padera
    • , Dai Fukumura
    • , Yves Boucher
    • , Lance L. Munn
    •  & Rakesh K. Jain
  2. Leder Human Biology and Translational Medicine, Biology and Biomedical Sciences, Harvard Medical School, Boston, Massachusetts 02115, USA

    • Hao Liu
  3. Department of Chemical and Biological Engineering, Tufts University, Medford, Massachusetts 02155, USA

    • Meenal Datta
  4. Department of Internal Medicine, Hospital S. Joao, I3S, Institute for Innovation and Research in Health, and Faculty of Medicine, Porto University, 4200-319 Porto, Portugal

    • Joao Incio
  5. Orthopedic Oncology Service, Center for Sarcoma and Connective Tissue Oncology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts 02114, USA

    • Francis J. Hornicek
  6. Center for Biomedical Engineering, Departments of Mechanical, Electrical and Biological Engineering, Massachusetts Institute of Technology, Cambridge, Massachusetts 02139, USA

    • Alan J. Grodzinsky
  7. Department of Biomedical Engineering, Bucknell University, Lewisburg, Pennsylvania 17837, USA

    • James W. Baish

Authors

  1. Search for Hadi T. Nia in:

  2. Search for Hao Liu in:

  3. Search for Giorgio Seano in:

  4. Search for Meenal Datta in:

  5. Search for Dennis Jones in:

  6. Search for Nuh Rahbari in:

  7. Search for Joao Incio in:

  8. Search for Vikash P. Chauhan in:

  9. Search for Keehoon Jung in:

  10. Search for John D. Martin in:

  11. Search for Vasileios Askoxylakis in:

  12. Search for Timothy P. Padera in:

  13. Search for Dai Fukumura in:

  14. Search for Yves Boucher in:

  15. Search for Francis J. Hornicek in:

  16. Search for Alan J. Grodzinsky in:

  17. Search for James W. Baish in:

  18. Search for Lance L. Munn in:

  19. Search for Rakesh K. Jain in:

Contributions

H.T.N. and R.K.J. designed the study; H.T.N., H.L., G.S., M.D., D.J., N.R., J.I., K.J. performed the research; H.T.N., H.L., G.S., M.D., D.J., N.R., J.I., V.P.C., K.J., J.D.M., V.A., T.P.P., D.F., Y.B., F.J.H., A.J.G., J.W.B., L.L.M. and R.K.J. analysed the data; H.T.N., M.D., G.S., V.P.C., L.L.M. and R.K.J. wrote the manuscript.

Competing interests

R.K.J. received consultant fees from Ophthotech, SPARC, SynDevRx and XTuit. R.K.J. owns equity in Enlight, Ophthotech, SynDevRx and XTuit, and serves on the Board of Directors of XTuit and the Boards of Trustees of Tekla Healthcare Investors, Tekla Life Sciences Investors, the Tekla Healthcare Opportunities Fund and the Tekla World Healthcare Fund. No reagents or funding from these companies were used in these studies.

Corresponding author

Correspondence to Rakesh K. Jain.

Supplementary information

PDF files

  1. 1.

    Supplementary information

    Supplementary Notes, Figures and Tables

Zip files

  1. 1.

    MATLAB scripts

    Custom MATLAB code

About this article

Publication history

Received

Accepted

Published

DOI

https://doi.org/10.1038/s41551-016-0004

Further reading