Microenvironmental Niches and Sanctuaries: A Route to Acquired Resistance

Adv Exp Med Biol. 2016;936:149-164. doi: 10.1007/978-3-319-42023-3_8.

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.

Keywords: Agent-based model; Anticancer drug resistance; Drug sanctuary; Hypoxic niche; Tumor microenvironment.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Antineoplastic Agents / pharmacokinetics*
  • Biological Transport
  • Diffusion
  • Drug Resistance, Neoplasm*
  • Humans
  • Hypoxia / drug therapy*
  • Hypoxia / metabolism
  • Hypoxia / pathology
  • Models, Statistical*
  • Neoplasms / drug therapy*
  • Neoplasms / metabolism
  • Neoplasms / pathology
  • Permeability
  • Treatment Failure
  • Tumor Microenvironment / drug effects

Substances

  • Antineoplastic Agents