title: Hypoxic tumor environments exhibit disrupted collagen I fibers and low macromolecular transport.
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 fibers and increased macromolecular transport. These data suggest that Col1 fibers may facilitate macromolecular transport in tumors, and their reduction in hypoxic regions may reduce this transport. Decreased macromolecular transport in hypoxic regions may also contribute to poor drug delivery and tumor recurrence in hypoxic regions. High Col1 fiber density observed around hypoxic regions may facilitate the escape of aggressive cancer cells from hypoxic regions.
authors.affiliation: JHU ICMIC Program, Division of Cancer Imaging Research, The Russell H. Morgan Department of Radiology and Radiological Science, The Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America ; Universität Bremen, Fachbereich 2, Bremen, Germany.
authors.forename: Samata M
authors.initials: SM
authors.lastname: Kakkad
authors.affiliation: JHU ICMIC Program, Division of Cancer Imaging Research, The Russell H. Morgan Department of Radiology and Radiological Science, The Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America.
authors.forename: Marie-France
authors.initials: MF
authors.lastname: Penet
authors.affiliation: JHU ICMIC Program, Division of Cancer Imaging Research, The Russell H. Morgan Department of Radiology and Radiological Science, The Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America.
authors.forename: Alireza
authors.initials: A
authors.lastname: Akhbardeh
authors.affiliation: JHU ICMIC Program, Division of Cancer Imaging Research, The Russell H. Morgan Department of Radiology and Radiological Science, The Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America ; Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America.
authors.forename: Arvind P
authors.initials: AP
authors.lastname: Pathak
authors.affiliation: JHU ICMIC Program, Division of Cancer Imaging Research, The Russell H. Morgan Department of Radiology and Radiological Science, The Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America.
authors.forename: Meiyappan
authors.initials: M
authors.lastname: Solaiyappan
authors.affiliation: JHU ICMIC Program, Division of Cancer Imaging Research, The Russell H. Morgan Department of Radiology and Radiological Science, The Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America ; Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America.
authors.forename: Venu
authors.initials: V
authors.lastname: Raman
authors.affiliation: Universität Bremen, Fachbereich 2, Bremen, Germany.
authors.forename: Dieter
authors.initials: D
authors.lastname: Leibfritz
authors.affiliation: JHU ICMIC Program, Division of Cancer Imaging Research, The Russell H. Morgan Department of Radiology and Radiological Science, The Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America ; Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America.
authors.forename: Kristine
authors.initials: K
authors.lastname: Glunde
authors.affiliation: JHU ICMIC Program, Division of Cancer Imaging Research, The Russell H. Morgan Department of Radiology and Radiological Science, The Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America ; Sidney Kimmel Comprehensive Cancer Center, The Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America.
authors.forename: Zaver M
authors.initials: ZM
authors.lastname: Bhujwalla
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000378:metabolism / Q000494:pharmacology; D001692:Biological Transport; D001943:Breast Neoplasms / Q000098:blood supply* / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D060846:Cell Engineering; D045744:Cell Line, Tumor; D024042:Collagen Type I / Q000096:biosynthesis / Q000648:ultrastructure*; D005109:Extracellular Matrix / Q000187:drug effects; D005260:Female; D017930:Genes, Reporter; D006801:Humans; D000860:Hypoxia / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D008164:Luminescent Proteins / Q000235:genetics / Q000378:metabolism; D008279:Magnetic Resonance Imaging; D051379:Mice; D016513:Mice, SCID; D008856:Microscopy, Fluorescence; D009368:Neoplasm Transplantation; D009389:Neovascularization, Pathologic; D014183:Transplantation, Heterologous; D059016:Tumor Microenvironment; D000097573:Red Fluorescent Protein
chemical_list: D000970:Antineoplastic Agents; D024042:Collagen Type I; D008164:Luminescent Proteins; D000097573:Red Fluorescent Protein