title: Stress-mediated progression of solid tumors: effect of mechanical stress on tissue oxygenation, cancer cell proliferation, and drug delivery.
abstract: Oxygen supply plays a central role in cancer cell proliferation. While vascular density increases at the early stages of carcinogenesis, mechanical solid stresses developed during growth compress tumor blood vessels and, thus, drastically reduce not only the supply of oxygen, but also the delivery of drugs at inner tumor regions. Among other effects, hypoxia and reduced drug delivery compromise the efficacy of radiation and chemo/nanotherapy, respectively. In the present study, we developed a mathematical model of tumor growth to investigate the interconnections among tumor oxygenation that supports cancer cell proliferation, the heterogeneous accumulation of mechanical stresses owing to tumor growth, the non-uniform compression of intratumoral blood vessels due to the mechanical stresses, and the insufficient delivery of oxygen and therapeutic agents because of vessel compression. We found that the high vascular density and increased cancer cell proliferation often observed in the periphery compared to the interior of a tumor can be attributed to heterogeneous solid stress accumulation. Highly vascularized peripheral regions are also associated with greater oxygenation compared with the compressed, less vascularized inner regions. We also modeled the delivery of drugs of two distinct sizes, namely chemotherapy and nanomedicine. Model predictions suggest that drug delivery is affected negatively by vessel compression independently of the size of the therapeutic agent. Finally, we demonstrated the applicability of our model to actual geometries, employing a breast tumor model derived from MR images.
authors.affiliation: Cancer Biophysics Laboratory, Department of Mechanical and Manufacturing Engineering, University of Cyprus, P.O. Box 20537, 1678, Nicosia, Cyprus.
authors.forename: Fotios
authors.initials: F
authors.lastname: Mpekris
authors.affiliation: Cancer Biophysics Laboratory, Department of Mechanical and Manufacturing Engineering, University of Cyprus, P.O. Box 20537, 1678, Nicosia, Cyprus.
authors.forename: Stelios
authors.initials: S
authors.lastname: Angeli
authors.affiliation: Cancer Biophysics Laboratory, Department of Mechanical and Manufacturing Engineering, University of Cyprus, P.O. Box 20537, 1678, Nicosia, Cyprus.
authors.forename: Athanassios P
authors.initials: AP
authors.lastname: Pirentis
authors.affiliation: Cancer Biophysics Laboratory, Department of Mechanical and Manufacturing Engineering, University of Cyprus, P.O. Box 20537, 1678, Nicosia, Cyprus. tstylian@ucy.ac.cy.
authors.forename: Triantafyllos
authors.initials: T
authors.lastname: Stylianopoulos
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000493:pharmacokinetics*; D001943:Breast Neoplasms / Q000188:drug therapy / Q000473:pathology* / Q000503:physiopathology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D003198:Computer Simulation; D018450:Disease Progression; D040542:Mechanotransduction, Cellular; D008657:Metabolic Clearance Rate; D051379:Mice; D008954:Models, Biological; D018384:Oxidative Stress / Q000187:drug effects; D010100:Oxygen / Q000378:metabolism*; D010101:Oxygen Consumption; D013314:Stress, Mechanical
chemical_list: D000970:Antineoplastic Agents; D010100:Oxygen
keywords: Chemotherapy; Hypoxia; Mathematical modeling; Nanomedicine; Tumor perfusion; Vascular density; Vessel collapse