Normalizing glucose levels reconfigures the mammary tumor immune and metabolic microenvironment and decreases metastatic seeding.

Autor: Alsheikh HAM; Department of Pathology, University of Alabama at Birmingham, Birmingham, AL, USA., Metge BJ; Department of Pathology, University of Alabama at Birmingham, Birmingham, AL, USA., Ha CM; Department of Pathology, University of Alabama at Birmingham, Birmingham, AL, USA., Hinshaw DC; Department of Pathology, University of Alabama at Birmingham, Birmingham, AL, USA., Mota MSV; Department of Pathology, University of Alabama at Birmingham, Birmingham, AL, USA., Kammerud SC; Department of Pathology, University of Alabama at Birmingham, Birmingham, AL, USA., Lama-Sherpa T; Department of Pathology, University of Alabama at Birmingham, Birmingham, AL, USA., Sharafeldin N; Division of Hematology & Oncology, Dept of Medicine, UAB School of Medicine, UAB, USA; Institute for Cancer Outcomes and Survivorship, School of Medicine, University of Alabama at Birmingham, Birmingham, AL, USA; O'Neal Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, AL, USA., Wende AR; Department of Pathology, University of Alabama at Birmingham, Birmingham, AL, USA., Samant RS; Department of Pathology, University of Alabama at Birmingham, Birmingham, AL, USA; Birmingham Veterans Affairs, Birmingham, AL, USA; O'Neal Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, AL, USA., Shevde LA; Department of Pathology, University of Alabama at Birmingham, Birmingham, AL, USA; O'Neal Comprehensive Cancer Center, University of Alabama at Birmingham, Birmingham, AL, USA. Electronic address: lsamant@uab.edu.
Jazyk: angličtina
Zdroj: Cancer letters [Cancer Lett] 2021 Oct 01; Vol. 517, pp. 24-34. Date of Electronic Publication: 2021 May 28.
DOI: 10.1016/j.canlet.2021.05.022
Abstrakt: Obesity and diabetes cumulatively create a distinct systemic metabolic pathophysiological syndrome that predisposes patients to several diseases including breast cancer. Moreover, diabetic and obese women with breast cancer show a significant increase in mortality compared to non-obese and/or non-diabetic women. We hypothesized that these metabolic conditions incite an aggressive tumor phenotype by way of impacting tumor cell-autonomous and tumor cell non-autonomous events. In this study, we established a type 2 diabetic mouse model of triple-negative mammary carcinoma and investigated the effect of a glucose lowering therapy, metformin, on the overall tumor characteristics and immune/metabolic microenvironment. Diabetic mice exhibited larger mammary tumors that had increased adiposity with high levels of O-GlcNAc protein post-translational modification. These tumors also presented with a distinct stromal profile characterized by altered collagen architecture, increased infiltration by tumor-permissive M2 macrophages, and early metastatic seeding compared to non-diabetic/lean mice. Metformin treatment of the diabetic/obese mice effectively normalized glucose levels, reconfigured the mammary tumor milieu, and decreased metastatic seeding. Our results highlight the impact of two metabolic complications of obesity and diabetes on tumor cell attributes and showcase metformin's ability to revert tumor cell and stromal changes induced by an obese and diabetic host environment.
(Copyright © 2021 Elsevier B.V. All rights reserved.)
Databáze: MEDLINE
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