Adipocyte-released insulin-like growth factor-1 is regulated by glucose and fatty acids and controls breast cancer cell growth in vitro.
OBJECTIVE
Type 2 diabetes and obesity are associated with increased risk of site-specific cancers. We have investigated whether metabolic alterations at the level of adipose-derived differentiating cells may affect specific phenotypes of breast cancer cells.


METHODS
Growth profiles of breast cancer cell lines were evaluated in co-cultures with differentiated adipocytes or their precursor cells and upon treatment with adipocyte conditioned media. Production and release of cytokines and growth factors were assessed by real-time RT-PCR and multiplex-based ELISA assays.


RESULTS
Co-cultures with either differentiated mouse 3T3-L1 or human mammary adipocytes increased viability of MCF-7 cells to a greater extent, when compared with their undifferentiated precursors. Adipocytes cultured in 25 mmol/l glucose were twofold more effective in promoting cell growth, compared with those grown in 5.5 mmol/l glucose, and activated mitogenic pathways in MCF-7 cells. Growth-promoting action was also enhanced when adipocytes were incubated in the presence of palmitate or oleate. Interestingly, 3T3-L1 and human adipocytes released higher amounts of keratinocyte-derived chemokine/IL-8, the protein 'regulated upon activation, normally T expressed, and secreted' (RANTES), and IGF-1, compared with their precursor cells. Their levels were reduced upon incubation with low glucose and enhanced by fatty acids. Moreover, both undifferentiated cells and differentiated adipocytes from obese individuals displayed about twofold higher IGF-1 release and MCF-7 cell growth induction than lean individuals. Finally, inhibition of the IGF-1 pathway almost completely prevented the growth-promoting effect of adipocytes on breast cancer cells.


CONCLUSIONS
IGF-1 release by adipocytes is regulated by glucose and fatty acids and may contribute to the control of cancer cell growth in obese individuals.
Department of Cellular and Molecular Biology and Pathology, Federico II University of Naples, Via Pansini 5, 80131, Naples, Italy.|Istituto di Endocrinologia ed Oncologia Sperimentale del C.N.R, Federico II University of Naples, Naples, Italy.
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D'Esposito
Department of Cellular and Molecular Biology and Pathology, Federico II University of Naples, Via Pansini 5, 80131, Naples, Italy.|Department of Pharmaceutical and Biomedical Sciences, University of Salerno, Salerno, Italy.
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Passaretti
The Lundberg Laboratory for Diabetes Research, Department of Molecular and Clinical Medicine/Diabetes, The Sahlgrenska Academy, University of Göteborg, Göteborg, Sweden.
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Hammarstedt
Istituto di Endocrinologia ed Oncologia Sperimentale del C.N.R, Federico II University of Naples, Naples, Italy.
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Liguoro
Department of Cellular and Molecular Biology and Pathology, Federico II University of Naples, Via Pansini 5, 80131, Naples, Italy.
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Terracciano
Department of Systematic Pathology, Federico II University of Naples, Naples, Italy.
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Molea
Department of Systematic Pathology, Federico II University of Naples, Naples, Italy.
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Canta
Istituto di Endocrinologia ed Oncologia Sperimentale del C.N.R, Federico II University of Naples, Naples, Italy.
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Miele
The Lundberg Laboratory for Diabetes Research, Department of Molecular and Clinical Medicine/Diabetes, The Sahlgrenska Academy, University of Göteborg, Göteborg, Sweden.
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Smith
Department of Cellular and Molecular Biology and Pathology, Federico II University of Naples, Via Pansini 5, 80131, Naples, Italy.|Istituto di Endocrinologia ed Oncologia Sperimentale del C.N.R, Federico II University of Naples, Naples, Italy.
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Beguinot
Department of Cellular and Molecular Biology and Pathology, Federico II University of Naples, Via Pansini 5, 80131, Naples, Italy. fpietro@unina.it.|Istituto di Endocrinologia ed Oncologia Sperimentale del C.N.R, Federico II University of Naples, Naples, Italy. fpietro@unina.it.
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Formisano
D000230:Adenocarcinoma / Q000473:pathology; D017667:Adipocytes / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology; D000328:Adult; D000368:Aged; D001943:Breast Neoplasms / Q000473:pathology*; D002450:Cell Communication / Q000502:physiology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects*; D002470:Cell Survival / Q000187:drug effects / Q000502:physiology; D018946:Chemokine CCL5 / Q000378:metabolism; D018920:Coculture Techniques; D005260:Female; D005947:Glucose / Q000494:pharmacology*; D006801:Humans; D007334:Insulin-Like Growth Factor I / Q000378:metabolism*; D016209:Interleukin-8 / Q000378:metabolism; D061986:MCF-7 Cells; D008875:Middle Aged; D009765:Obesity / Q000378:metabolism / Q000473:pathology; D019301:Oleic Acid / Q000494:pharmacology*; D010168:Palmitates / Q000494:pharmacology*; D015398:Signal Transduction / Q000502:physiology
D018946:Chemokine CCL5; D016209:Interleukin-8; D010168:Palmitates; D019301:Oleic Acid; D007334:Insulin-Like Growth Factor I; D005947:Glucose