title: Microenvironmental Niches and Sanctuaries: A Route to Acquired Resistance.
abstract: A tumor vasculature that is functionally abnormal results in irregular gradients of metabolites and drugs within the tumor tissue. Recently, significant efforts have been committed to experimentally examine how cellular response to anti-cancer treatments varies based on the environment in which the cells are grown. In vitro studies point to specific conditions in which tumor cells can remain dormant and survive the treatment. In vivo results suggest that cells can escape the effects of drug therapy in tissue regions that are poorly penetrated by the drugs. Better understanding how the tumor microenvironments influence the emergence of drug resistance in both primary and metastatic tumors may improve drug development and the design of more effective therapeutic protocols. This chapter presents a hybrid agent-based model of the growth of tumor micrometastases and explores how microenvironmental factors can contribute to the development of acquired resistance in response to a DNA damaging drug. The specific microenvironments of interest in this work are tumor hypoxic niches and tumor normoxic sanctuaries with poor drug penetration. We aim to quantify how spatial constraints of limited drug transport and quiescent cell survival contribute to the development of drug resistant tumors.
authors.affiliation: Mathematical Modeling of Biological Systems, Centre for Mathematical Science, Technical University of Munich, Garching, Germany. cerit@ma.tum.de.
authors.forename: Judith
authors.initials: J
authors.lastname: Pérez-Velázquez
authors.affiliation: Department of Mathematics and Statistics, The College of New Jersey, Ewing, NJ, USA.
authors.forename: Jana L
authors.initials: JL
authors.lastname: Gevertz
authors.affiliation: Integrated Mathematical Oncology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL, USA.
authors.forename: Aleksandra
authors.initials: A
authors.lastname: Karolak
authors.affiliation: Integrated Mathematical Oncology, H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL, USA.|Department of Oncologic Sciences, College of Medicine, University of South Florida, Tampa, FL, USA.
authors.forename: Katarzyna A
authors.initials: KA
authors.lastname: Rejniak
mesh_terms: D000970:Antineoplastic Agents / Q000493:pharmacokinetics*; D001692:Biological Transport; D004058:Diffusion; D019008:Drug Resistance, Neoplasm; D006801:Humans; D000860:Hypoxia / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D015233:Models, Statistical; D009369:Neoplasms / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D010539:Permeability; D017211:Treatment Failure; D059016:Tumor Microenvironment / Q000187:drug effects
chemical_list: D000970:Antineoplastic Agents
keywords: Agent-based model; Anticancer drug resistance; Drug sanctuary; Hypoxic niche; Tumor microenvironment