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Stromal Barriers Within the Tumor Microenvironment and Obstacles to Nanomedicine

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Book cover Cancer Drug Delivery Systems Based on the Tumor Microenvironment

Abstract

Nanomedicine has been heralded as the elusive “magic bullet” of cancer chemotherapeutics ever since the description of the Enhanced Permeability and Retention (EPR) effect in 1986. However, decades of research have often shown a great discrepancy between the salient effects seen in preclinical models and the suboptimal effects seen in clinical trials. This indicates that various obstacles exist within human tumors that impede the delivery and penetration of nanomedicine and that the EPR effect itself may be necessary but not sufficient for an efficacious nanomedicine formulation. Furthermore, these obstacles may be absent or much weaker in often used preclinical models, pointing at the importance of developing novel, clinically relevant preclinical models for testing the efficacy of nanomedicine. It is becoming increasingly clear that the various cellular and extracellular matrix components of the tumor stroma that together consist the tumor microenvironment (TME) play an important role in determining the efficiency of nanomedicine penetration into the tumor. We refer to the impediments that these stromal components of the TME pose to nanomedicine as “stromal barriers”. In this chapter, we review the factors affecting nanomedicine delivery with a particular emphasis on the stromal barriers within the TME. We also review the preclinical models available for testing the efficacy of nanomedicine, and how novel models might be developed to further our understanding of the principles governing nanomedicine delivery and penetration into tumors.

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Abbreviations

ABC:

accelerated blood clearance

ADC:

antibody-drug conjugate

CAF:

cancer-associated fibroblast

CAST:

cancer stromal targeting

CDX:

cell-line-derived xenograft

CPP:

cell-penetrating peptide

ECM:

extracellular matrix

EMT:

epithelial-to-mesenchymal transition

EndMT:

endothelial-to-mesenchymal transition

EPR:

enhanced permeability and retention

GEMM:

genetically engineered mouse model

HA:

hyaluronic acid

IFP:

interstitial fluid pressure

LOX:

lysyl oxidase

MSC:

mesenchymal stem cell

PDX:

patient-derived xenograft

PEG:

polyethylene glycol

PFT:

pericyte-to-fibroblast transition

RES:

reticuloendothelial system

TAM:

tumor-associated macrophage

TCGA:

The Cancer Genome Atlas

TEC:

tumor endothelial cell

TEM:

tumor endothelial marker

TGF-β:

transforming growth factor-beta

TME:

tumor microenvironment

VEGF:

vascular endothelial growth factor

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  1. Department of Pharmaceutical Biomedicine, Okayama University Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama, Japan

    Hiroyoshi Y. Tanaka & Mitsunobu R. Kano

  2. Department of Pharmaceutical Biomedicine, Okayama University Graduate School of Interdisciplinary Science and Engineering in Health Systems, Okayama, Japan

    Mitsunobu R. Kano

Authors
  1. Hiroyoshi Y. Tanaka
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  2. Mitsunobu R. Kano
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Correspondence to Mitsunobu R. Kano .

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  1. Division of Developmental Therapeutics, Exploratory Oncology Research & Clinical Trial Center, National Cancer Center, Kashiwa, Japan

    Yasuhiro Matsumura

  2. Moores UCSD Cancer Center and Department of Pathology, University of California San Diego, La Jolla, CA, USA

    David Tarin

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Tanaka, H.Y., Kano, M.R. (2019). Stromal Barriers Within the Tumor Microenvironment and Obstacles to Nanomedicine. In: Matsumura, Y., Tarin, D. (eds) Cancer Drug Delivery Systems Based on the Tumor Microenvironment. Springer, Tokyo. https://doi.org/10.1007/978-4-431-56880-3_4

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