Abstract LB-348: Evolution of physical forces in the tumor microenvironment and implications for therapeutic resistance.
Authors: Triantafyllos Stylianopoulos, John D. Martin, Saloni Jain, Matija Snuderl, Vikash P. Chauhan, Lance L. Munn, Yves Boucher, Rakesh K. Jain
Journal: Cancer Research (2013)

Abstract In solid tumors a fraction of vessels are compressed or totally collapsed (1). As a consequence, the vascular network in tumors is poorly perfused and insufficient for delivery of oxygen and drugs from the blood. This creates a hypoxic microenvironment and reduces delivery of therapeutics, resulting in resistance to radio-, chemo- and immunotherapy. We hypothesized that physical forces in tumors compress tumor vessels. These forces stem from fluid and solid components of tumors. Interstitial fluid pressure (IFP), the isotropic stress exerted by fluid, increases in tumors because of leaky blood vessels and dysfunctional lymphatic vessels. In previous research, we showed that IFP is uniformly elevated in tumors and drops precipitously in the tumor margin. Moreover, elevated IFP cannot compress leaky vessels and thus, vessel compression must result from forces exerted by the solid components of a tumor (2). Despite important in vitro work on solid stress in avascular tumor spheroids, little work has been performed in vivo for the evolution of solid forces in a growing tumor. To this end, we combined in vivo experiments in mice bearing tumors with a novel mathematical model to analyze the evolution of fluid and solid forces in tumors (3). First, we performed experiments and found that the evolution of solid stress is related to tumor volume. Then, we incorporated this information into our mathematical model and showed that solid stress levels are higher in the tumor interior and lower in the periphery. Elevated compressive stress in the interior of the tumor was found to be sufficient to cause the collapse of blood vessels and result in a lower growth rate of cancer cells compared to the tumor periphery, independently from that caused by the lack of nutrients due to vessel collapse. Furthermore, solid stress levels in the periphery of the tumor can cause blood vessels in the surrounding normal tissue to deform to elliptical shapes but not collapse. We present histological sections of human carcinomas, liposarcomas and pancreatic neuroendocrine tumors that demonstrate such vessel deformations. Contrary to solid stress that is accumulated during progression, model predictions confirmed that IFP levels depend only on the microvascular pressure and the permeability of the tumor vessels. 1. Padera TP, et al. Nature 2004;427(6976):695. 2. Boucher Y, Jain RK. Cancer Res 1992;52(18):5110-4. 3. Stylianopoulos T, Martin JD, Chauhan VP, et al. PNAS 2012;109 (38):15101-8. Citation Format: Triantafyllos Stylianopoulos, John D. Martin, Saloni Jain, Matija Snuderl, Vikash P. Chauhan, Lance L. Munn, Yves Boucher, Rakesh K. Jain. Evolution of physical forces in the tumor microenvironment and implications for therapeutic resistance. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr LB-348. doi:10.1158/1538-7445.AM2013-LB-348