Solid stress and elastic energy as measures of tumour mechanopathology

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 two-dimensional spatial mappings of solid stress and the resulting elastic energy in excised or in situ tumours with arbitrary shapes and wide size ranges 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 microenvironment; (ii) solid stress increases with tumour size; and (iii) mechanical confinement by the surrounding tissue significantly contributes to intratumoural solid stress. Further study of the genesis and consequences of solid stress, facilitated by the engineering principles presented here, may lead to significant discoveries and new therapies.

[1]  Triantafyllos Stylianopoulos,et al.  The role of mechanical forces in tumor growth and therapy. , 2014, Annual review of biomedical engineering.

[2]  T. Irimura,et al.  Mouse Colon Carcinoma Cells Established for High Incidence of Experimental Hepatic Metastasis Exhibit Accelerated and Anchorage-Independent Growth , 2005, Clinical & Experimental Metastasis.

[3]  J. Bechhoefer,et al.  Calibration of atomic‐force microscope tips , 1993 .

[4]  R. Jain,et al.  Role of extracellular matrix assembly in interstitial transport in solid tumors. , 2000, Cancer research.

[5]  P. Janmey,et al.  Tissue Cells Feel and Respond to the Stiffness of Their Substrate , 2005, Science.

[6]  R. Jain,et al.  Obesity-Induced Inflammation and Desmoplasia Promote Pancreatic Cancer Progression and Resistance to Chemotherapy. , 2016, Cancer discovery.

[7]  V. Weaver,et al.  In situ force mapping of mammary gland transformation. , 2011, Integrative biology : quantitative biosciences from nano to macro.

[8]  Benjamin J Vakoc,et al.  Three-dimensional microscopy of the tumor microenvironment in vivo using optical frequency domain imaging , 2009, Nature Medicine.

[9]  V. Weaver,et al.  Tumor mechanics and metabolic dysfunction. , 2015, Free radical biology & medicine.

[10]  R. DePinho,et al.  Compression of pancreatic tumor blood vessels by hyaluronan is caused by solid stress and not interstitial fluid pressure. , 2014, Cancer cell.

[11]  Donald E Ingber,et al.  Quantifying cell-generated mechanical forces within living embryonic tissues , 2013, Nature Methods.

[12]  Aude Michel,et al.  Mechanical induction of the tumorigenic β-catenin pathway by tumour growth pressure , 2015, Nature.

[13]  Savio Lau-Yuen Woo,et al.  Frontiers in Biomechanics , 1986, Springer New York.

[14]  Alan J. Grodzinsky,et al.  Fields, Forces, and Flows in Biological Systems , 2011 .

[15]  G. G. Van den Eynden,et al.  The histological growth pattern of colorectal cancer liver metastases has prognostic value , 2012, Clinical & Experimental Metastasis.

[16]  Dennis C. Sgroi,et al.  Stromal Fibroblasts Present in Invasive Human Breast Carcinomas Promote Tumor Growth and Angiogenesis through Elevated SDF-1/CXCL12 Secretion , 2005, Cell.

[17]  S. Timoshenko,et al.  Theory of elasticity , 1975 .

[18]  High tumor interstitial fluid pressure identifies cervical cancer patients with improved survival from radiotherapy plus cisplatin versus radiotherapy alone , 2014, International journal of cancer.

[19]  Triantafyllos Stylianopoulos,et al.  Causes, consequences, and remedies for growth-induced solid stress in murine and human tumors , 2012, Proceedings of the National Academy of Sciences.

[20]  J D Humphrey,et al.  Stress-modulated growth, residual stress, and vascular heterogeneity. , 2001, Journal of biomechanical engineering.

[21]  R K Jain,et al.  Microvascular pressure is the principal driving force for interstitial hypertension in solid tumors: implications for vascular collapse. , 1992, Cancer research.

[22]  R K Jain,et al.  Vascular permeability and microcirculation of gliomas and mammary carcinomas transplanted in rat and mouse cranial windows. , 1994, Cancer research.

[23]  Triantafyllos Stylianopoulos,et al.  Role of Constitutive Behavior and Tumor-Host Mechanical Interactions in the State of Stress and Growth of Solid Tumors , 2014, PloS one.

[24]  Hans Clevers,et al.  Actomyosin-Mediated Cellular Tension Drives Increased Tissue Stiffness and β-Catenin Activation to Induce Epidermal Hyperplasia and Tumor Growth. , 2024, Cancer cell.

[25]  C. Horgan,et al.  Mechanical restrictions on biological responses by adherent cells within collagen gels. , 2012, Journal of the mechanical behavior of biomedical materials.

[26]  Taekjip Ha,et al.  Measuring mechanical tension across vinculin reveals regulation of focal adhesion dynamics , 2010, Nature.

[27]  E B Hunziker,et al.  Stimulation of aggrecan synthesis in cartilage explants by cyclic loading is localized to regions of high interstitial fluid flow. , 1999, Archives of biochemistry and biophysics.

[28]  R K Jain,et al.  Interstitial hypertension in carcinoma of uterine cervix in patients: possible correlation with tumor oxygenation and radiation response. , 1991, Cancer research.

[29]  David J Mooney,et al.  Extracellular matrix stiffness and composition jointly regulate the induction of malignant phenotypes in mammary epithelium. , 2014, Nature materials.

[30]  R K Jain,et al.  Taxane-induced apoptosis decompresses blood vessels and lowers interstitial fluid pressure in solid tumors: clinical implications. , 1999, Cancer research.

[31]  R. Jain,et al.  Obesity and Cancer: An Angiogenic and Inflammatory Link , 2016, Microcirculation.

[32]  Paolo A. Netti,et al.  Solid stress inhibits the growth of multicellular tumor spheroids , 1997, Nature Biotechnology.

[33]  Carlos Cuevas,et al.  Enzymatic targeting of the stroma ablates physical barriers to treatment of pancreatic ductal adenocarcinoma. , 2012, Cancer cell.

[34]  R. Jain,et al.  Antiangiogenesis strategies revisited: from starving tumors to alleviating hypoxia. , 2014, Cancer cell.

[35]  Wenmiao Shu,et al.  Elasticity as a biomarker for prostate cancer: a systematic review , 2014, BJU international.

[36]  Matija Snuderl,et al.  Coevolution of solid stress and interstitial fluid pressure in tumors during progression: implications for vascular collapse. , 2013, Cancer research.

[37]  Rakesh K Jain,et al.  Lymphatic Metastasis in the Absence of Functional Intratumor Lymphatics , 2002, Science.

[38]  Clinical Implications. , 2017, Hypertension.

[39]  Rakesh K. Jain,et al.  Angiotensin inhibition enhances drug delivery and potentiates chemotherapy by decompressing tumour blood vessels , 2013, Nature Communications.

[40]  Paolo P. Provenzano,et al.  Aligned Collagen Is a Prognostic Signature for Survival in Human Breast Carcinoma Address Reprint Requests to See Related Commentary on Page 966 , 2022 .

[41]  E. Mohammadi,et al.  Barriers and facilitators related to the implementation of a physiological track and trigger system: A systematic review of the qualitative evidence , 2017, International journal for quality in health care : journal of the International Society for Quality in Health Care.

[42]  Denis Wirtz,et al.  The physics of cancer: the role of physical interactions and mechanical forces in metastasis , 2011, Nature Reviews Cancer.

[43]  A. Fyles,et al.  Long-term performance of interstial fluid pressure and hypoxia as prognostic factors in cervix cancer. , 2006, Radiotherapy and oncology : journal of the European Society for Therapeutic Radiology and Oncology.

[44]  Ricardo Garcia,et al.  Biomechanical Remodeling of the Microenvironment by Stromal Caveolin-1 Favors Tumor Invasion and Metastasis , 2011, Cell.

[45]  I. Christensen,et al.  Growth pattern of colorectal liver metastasis as a marker of recurrence risk , 2015, Clinical & Experimental Metastasis.

[46]  Teodor Gotszalk,et al.  Calibration of atomic force microscope , 2008 .

[47]  Yang Li,et al.  Poroelasticity of cartilage at the nanoscale. , 2011, Biophysical journal.

[48]  Guanqing Ou,et al.  Tissue mechanics modulate microRNA-dependent PTEN expression to regulate malignant progression , 2014, Nature Medicine.

[49]  H. Kim,et al.  Predicting prognostic factors of breast cancer using shear wave elastography. , 2014, Ultrasound in medicine & biology.

[50]  Juha Töyräs,et al.  Collagen network primarily controls Poisson's ratio of bovine articular cartilage in compression , 2006, Journal of orthopaedic research : official publication of the Orthopaedic Research Society.

[51]  Ueli Aebi,et al.  The nanomechanical signature of breast cancer. , 2012, Nature nanotechnology.

[52]  Rakesh K. Jain,et al.  Pathology: Cancer cells compress intratumour vessels , 2004, Nature.

[53]  Rakesh K Jain,et al.  Mechanical compression drives cancer cells toward invasive phenotype , 2011, Proceedings of the National Academy of Sciences.