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Prevention of hypoxia by myoglobin expression in human tumor cells promotes differentiation and inhibits metastasis
Maria Galluzzo, … , Paolo M. Comoglio, Paolo Michieli
Maria Galluzzo, … , Paolo M. Comoglio, Paolo Michieli
Published March 23, 2009
Citation Information: J Clin Invest. 2009;119(4):865-875. https://doi.org/10.1172/JCI36579.
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Research Article Article has an altmetric score of 7

Prevention of hypoxia by myoglobin expression in human tumor cells promotes differentiation and inhibits metastasis

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Abstract

As a tumor grows, it requires increased amounts of oxygen. However, the tumor blood vessels that form to meet this demand are functionally impaired, leading to regions of hypoxia within the tumor. Such hypoxia is one of the hallmarks of malignancy and is thought to promote a number of tumorigenic properties. Here, we sought to determine how tumors without hypoxia would progress by engineering A549 human lung carcinoma cells to ectopically express myoglobin (Mb), a multifunctional heme protein that specializes in oxygen transport, storage, and buffering. Mb expression prevented the hypoxic response in vitro and delayed tumor engraftment and reduced tumor growth following xenotransplantation into mice. Experimental tumors expressing Mb displayed reduced or no hypoxia, minimal HIF-1α levels, and a homogeneously low vessel density. Mb-mediated tumor oxygenation promoted differentiation of cancer cells and suppressed both local and distal metastatic spreading. These effects were primarily due to reduced tumor hypoxia, because they were not observed using point-mutated forms of myoglobin unable to bind oxygen and they were abrogated by expression of a constitutively active form of HIF-1α. Although limited to xenograft models, these data provide experimental proof of the concept that hypoxia is not just a side effect of deregulated growth but a key factor on which the tumor relies in order to promote its own expansion.

Authors

Maria Galluzzo, Selma Pennacchietti, Stefania Rosano, Paolo M. Comoglio, Paolo Michieli

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Figure 1

Mb expression attenuates the hypoxic response of cancer cells.

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Mb expression attenuates the hypoxic response of cancer cells.
(A) Lenti...
(A) Lentiviral vector–transduced cells were incubated in normoxia (21% O2) or hypoxia (1% O2) for 24 hours, and intracellular ATP levels were determined on total cell lysates. Statistical significance was calculated between each experimental sample and the empty vector (EV) control at 21% O2. *P < 0.05; **P < 0.01. (B) Cells were incubated in normoxia or hypoxia, and lactate concentration was determined in the conditioned medium. (C) Cells were incubated in normoxia or hypoxia and then resuspended in normoxic medium. Oxygen consumption was measured in a sealed chamber using a Clark-type electrode. (D) Cells were incubated at different pO2 values for 3 hours, and HIF-1α levels were determined by Western blotting using anti–HIF-1α antibodies. (E) Cells were subjected to repeated cycles of hypoxia and reoxygenation (1 hour at 21%, 3%, 1%, or 0.1% O2 followed by 30 minutes at 21% O2, repeated 3 times), and HIF-1α levels were determined by Western blotting. Cells incubated at 21% O2 were used as controls.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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