Mechanical forces can promote tumor aggression. Mechanical forces can promote tumor aggression. An expanding tumor mass results in increased solid stress. Solid stress refers to the force exerted by the solid structural components of a tissue experiencing growth. This stress, together with the mechanical resistance produced by the ECM and stromal cells, promotes an increase in interstitial pressure. Interstitial pressure relates to the interstitial fluid occupying the space between cells and containing water-soluble components of biological tissues. High hydrostatic pressure will force plasma to exit blood and lymphatic capillaries to enter the interstitial space. Conversely, when hydrostatic pressure in capillaries is decreased, interstitial fluid can enter these vessels. Thus, high solid stress and interstitial pressure can impair lymphatic drainage and drug delivery, and in severe cases can precipitate vessel compression and collapse. Insufficient blood supply generates regions of hypoxia within a tumor, a condition that can induce an epithelial-to-mesenchymal or stem-like transition and treatment-resistant qualities in tumor cells. To counter these mechanical stresses, tumors often develop a desmoplastic response characterized by the recruitment of fibroblasts and immune cells with increased deposition of ECM proteins including collagen, fibronectin, and tenascin C. Fibroblasts can stimulate tumor cell growth through paracrine factors and, together with tumor cells, remodel the ECM through cell-generated tension and elevated production of ECM molecules and cross-linking enzymes. A linearized and stiffened ECM provides tracks for immune infiltration and may facilitate tumor cell invasion and metastasis. Jason J. Northey et al. Cancer Discov 2017;7:1224-1237 ©2017 by American Association for Cancer Research