J Breast Cancer.  2019 Jun;22(2):155-171. 10.4048/jbc.2019.22.e26.

Insights into Hypoxia: Non-invasive Assessment through Imaging Modalities and Its Application in Breast Cancer

• Daimiel I

• KMID: 2450112
• DOI: http://doi.org/10.4048/jbc.2019.22.e26

Abstract

Oxygen is crucial to maintain the homeostasis in aerobic cells. Hypoxia is a condition in which cells are deprived of the oxygen supply necessary for their optimum performance. Whereas oxygen deprivation may occur in normal physiological processes, hypoxia is frequently associated with pathological conditions. It has been identified as a stressor in the tumor microenvironment, acting as a key mediator of cancer development. Numerous pathways are activated in hypoxic cells that affect cell signaling and gene regulation to promote the survival of these cells by stimulating angiogenesis, switching cellular metabolism, slowing their growth rate, and preventing apoptosis. The induction of dysregulated metabolism in cancer cells by hypoxia results in aggressive tumor phenotypes that are characterized by rapid progression, treatment resistance, and poor prognosis. A non-invasive assessment of hypoxia-induced metabolic and architectural changes in tumors is advisable to fully improve breast cancer (BC) patient management, by potentially reducing the need for invasive biopsy procedures and evaluating tumor response to treatment. This review provides a comprehensive overview of the molecular changes in breast tumors secondary to hypoxia and the non-invasive imaging alternatives to evaluate oxygen deprivation, with an emphasis on their application in BC and the advantages and limitations of the currently available techniques.

Keyword

Breast neoplasms; Hypoxia; Molecular imaging

MeSH Terms

Anoxia*
Apoptosis
Biopsy
Breast Neoplasms*
Breast*
Homeostasis
Humans
Metabolism
Molecular Imaging
Oxygen
Phenotype
Physiological Processes
Prognosis
Tumor Microenvironment
Oxygen

Figure

• 

  Figure 1 Diagram of the effects of hypoxia in tumor cells.GLUT = glucose transporter; ROS = teactive oxygen species; Bcl-2 = B-cell lymphoma 2; EPO = erythropoietin; IL = interleukin; PG = prostaglandin; TAMS = tumor-associated macrophages; VEGF = vascular endotelial growth factor; uPAR = urokinase plasminogen activator receptor; HIF = hypoxia-inducible factor; BRCA 1/2 = breast cancer genes; PTEN = phosphatase and tensin homolog; AKT = protein kinase B; MSH 2 = mutS protein homolog 2; MLH 1 = mutL homolog 1.

• 

  Figure 2 PA imaging of placental oxygenation on day 14 of gestation. (A) The placenta in a sagittal plane (obtained by a B-mode ultrasound scan) and parametric images created with the PA oxyhemo mode making possible the evaluation of blood oxygen saturation during variations in the oxygen levels supplied to the mother (5%–100%). PA imaging sequences during hyperoxygenation (B), hypoxia (C) and hyperoxygenation (D). Reprinted with permission from reference 76: Arthuis CJ, Novell A, Raes F, Escoffre JM, Lerondel S, et al. Real-time monitoring of placental oxygenation during maternal hypoxia and hyperoxygenation using photoacoustic imaging. PLoS One 2017;12:e0169850.PA = photoacoustic.

• 

  Figure 3 Imaging of hypoxia within CT26 tumour bearing mice (n = 13), PET-MRI: (A-D) Representative PET-MRI images showing the global co-localisation of FMISO uptake and BOLD MRI signal. Images were acquired 120 minutes post-injection of 10 MBq of 18F FMISO PET. (A) Representative maximum-intensity-projection FMISO PET Image; (B) Transversal slice showing FMISO uptake within the tumour; (C) T2*-weighted MRI and (D) BOLD image derived from T2* mapping. White dashed lines: tumour limits, white arrows: oxygenated tumour area (increased BOLD signal), black circle: hypoxic tumour areas (decreased BOLD signal). CLI: (E) Representative FMISO CLI image of the same mouse as for (A) to (D) acquired just after the PET-MRI scan. (F) Tumour-to-background ratio for PET, MRI and CLI following the injection of FMISO determined by the ratio of the signal from the tumour and a contralateral irrelevant region of interest (muscle). Reprinted with permission from reference 85: Desvaux E, Courteau A, Bellaye P-S, Guillemin M, Drouet C, Walker P, et al. Cherenkov luminescence imaging is a fast and relevant preclinical tool to assess tumour hypoxia in vivo. EJNMMI Res 2018;8:111.PET = positron emission tomography; MRI = magnetic resonance imaging; FMISO = fluoromisoinidazole; BOLD = blood oxygen level dependent; CLI = Cherenkov luminescence imaging.*p < 0.001.

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