Abstract
Abstract Introduction: Increased tissue stiffness is a widely accepted and actively studied biomechanical property of desmoplastic tumors, and has been linked to several hallmarks of cancer, such as growth, invasion and metastasis. The abnormal mechanics of tumors, however, are not limited to tissue stiffening. We recently demonstrated that solid stress represents a new mechanopathology that is consistently elevated in mouse and human tumors. The solid stress, transmitted by solid elements of the extracellular matrix, is distinct from interstitial fluid pressure. Therefore, tumors are not only more rigid than many normal tissues, but cancer cells also produce and are exposed to these physical forces. Composed of a combination of tension and compression, these forces are significant in tumors, but negligible in most normal tissues. Methods and Results: We developed the experimental and mathematical frameworks to provide (i) two-dimensional spatial map of solid stress in tumors (planar cut method), (ii) sensitive estimation of solid stress in small tumors with small magnitudes of solid stress, e.g., metastatic lesions (slicing method), and (iii) in situ quantification of solid stress in tumors, which retains the effects of the normal surrounding tissues (needle biopsy method). All three methods are based on the physical concept of releasing the solid stress in a controlled way with defined geometry, and then quantifying the stress-induced deformation by high-resolution ultrasonography or optical microscopy. Given the specific topography of the stress relaxation and the geometric and material properties of the tumour, the solid stress and discharged elastic energy is estimated using mathematical modeling. Applying these novel methods to multiple mouse cancer models in primary and metastatic settings has led to the following novel findings: (i) solid stress and elastic energy may be different between primary vs. metastatic settings, as they depend on both cancer cells and their microenvironment; (ii) tumor with higher elastic energy are not necessarily stiffer, and the stiffer tumors do not necessarily have higher elastic energy; (iii) solid stress increases with tumour size; and (iv) the normal tissue surrounding a tumour significantly contributes to the intratumoral solid stress. Conclusions: We developed three distinct methods to perform in situ and sensitive measurement of solid stress and obtain 2-D spatial map of solid stress in human and mouse tumors. Application of these methods in models of primary tumors and metastasis revealed that: (i) solid stress depends on both cancer cells and their microenvironment; it increases with tumour size; and 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 significant discoveries and new therapies. Citation Format: Hadi Nia, Hao Liu, Giorgio Seano, Meenal Datta, Dennis Jones, Nuh Rahbari, Joao Incio, Vikash Chauhan, Keehoon Jung, John Martin, Vasileios Askoxylakis, Tim Padera, Dai Fukumura, Yves Boucher, Francis Hornicek, Alan Grodzinsky, James Baish, Lance Munn, Rakesh Jain. Solid stress and elastic energy as measures of tumor mechanopathology [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3987. doi:10.1158/1538-7445.AM2017-3987
