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Cancer Cell. 2018 Oct 8;34(4):659-673.e6. doi: 10.1016/j.ccell.2018.08.016. Epub 2018 Sep 27.

Subversion of Systemic Glucose Metabolism as a Mechanism to Support the Growth of Leukemia Cells.

Author information

1
Division of Hematology, University of Colorado Anschutz Medical Campus, 12700 E 19(th) Avenue, Aurora, CO 80045, USA.
2
Mucosal Inflammation Program, University of Colorado Anschutz Medical Campus, 12700 E 19(th) Avenue, Aurora, CO 80045, USA.
3
Division of Biomedical Informatics and Personalized Medicine, Department of Medicine, University of Colorado Anschutz Medical Campus, 12700 E 19(th) Avenue, Aurora, CO 80045, USA.
4
Center for Cancer and Blood Disorders, Children's Hospital Colorado, 13123 E 16th Avenue, Aurora, CO 80045, USA.
5
Department of Pathology and Laboratory Medicine, University of Rochester, 601 Elmwood Avenue, Rochester, NY 14642, USA.
6
Functional Genomics Center, University of Rochester, 601 Elmwood Avenue, Rochester, NY 14642, USA.
7
Department of Radiology, Animal Imaging Shared Resources, University of Colorado Anschutz Medical Campus, 12700 E 19(th) Avenue, Aurora, CO 80045, USA.
8
Division of Hematology, University of Colorado Anschutz Medical Campus, 12700 E 19(th) Avenue, Aurora, CO 80045, USA. Electronic address: craig.jordan@ucdenver.edu.

Abstract

From an organismal perspective, cancer cell populations can be considered analogous to parasites that compete with the host for essential systemic resources such as glucose. Here, we employed leukemia models and human leukemia samples to document a form of adaptive homeostasis, where malignant cells alter systemic physiology through impairment of both host insulin sensitivity and insulin secretion to provide tumors with increased glucose. Mechanistically, tumor cells induce high-level production of IGFBP1 from adipose tissue to mediate insulin sensitivity. Further, leukemia-induced gut dysbiosis, serotonin loss, and incretin inactivation combine to suppress insulin secretion. Importantly, attenuated disease progression and prolonged survival are achieved through disruption of the leukemia-induced adaptive homeostasis. Our studies provide a paradigm for systemic management of leukemic disease.

KEYWORDS:

IGFBP1; adaptive homeostasis; adipose tissue; insulin resistance; leukemia; microbiota; serotonin; short-chain fatty acids

Comment in

PMID:
30270124
PMCID:
PMC6177322
[Available on 2019-10-08]
DOI:
10.1016/j.ccell.2018.08.016
[Indexed for MEDLINE]

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