Hypoxic tumor environments exhibit disrupted collagen I fibers and low macromolecular transport

PloS One
Samata M KakkadZaver M Bhujwalla

Abstract

Hypoxic tumor microenvironments result in an aggressive phenotype and resistance to therapy that lead to tumor progression, recurrence, and metastasis. While poor vascularization and the resultant inadequate drug delivery are known to contribute to drug resistance, the effect of hypoxia on molecular transport through the interstitium, and the role of the extracellular matrix (ECM) in mediating this transport are unexplored. The dense mesh of fibers present in the ECM can especially influence the movement of macromolecules. Collagen 1 (Col1) fibers form a key component of the ECM in breast cancers. Here we characterized the influence of hypoxia on macromolecular transport in tumors, and the role of Col1 fibers in mediating this transport using an MDA-MB-231 breast cancer xenograft model engineered to express red fluorescent protein under hypoxia. Magnetic resonance imaging of macromolecular transport was combined with second harmonic generation microscopy of Col1 fibers. Hypoxic tumor regions displayed significantly decreased Col1 fiber density and volume, as well as significantly lower macromolecular draining and pooling rates, than normoxic regions. Regions adjacent to severely hypoxic areas revealed higher deposition of Col1 ...Continue Reading

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Citations

Jan 7, 2015·Cell Biochemistry and Biophysics·Wei WangDong-Sheng Zhou
Mar 7, 2019·Cancer Metastasis Reviews·Samata KakkadZaver M Bhujwalla
Mar 31, 2015·The Cancer Journal·Robert J Gillies, Robert A Gatenby
Feb 26, 2016·Science Translational Medicine·Pedro M Enriquez-NavasRobert A Gatenby
Jan 30, 2019·NMR in Biomedicine·Marie-France PenetZaver M Bhujwalla
Nov 9, 2014·Molecular Cancer Therapeutics·Lisa PollaroChristian Heinis
Nov 2, 2016·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Marie-France PenetZaver M Bhujwalla

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Methods Mentioned

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xenograft

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