Elucidating the role of adipose tissue secreted factors in malignant transformation

Chakraborty, Debrup; Benham, Vanessa; Bernard, Jamie J.

doi:10.1080/21623945.2017.1388971

Cited by 3 publications

(4 citation statements)

References 27 publications

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“…While traditionally thought to be a paracrine acting growth factor, these data suggest that FGF2 may be released from adipose tissue and act via endocrine mechanisms. Additionally, we have demonstrated that FGF2 levels are positively associated with the neoplastic transforming capacity of human adipose tissue on mouse mammary epithelial cells, as measured by anchorage-independent growth in soft agar [20]. We also demonstrated that the activity of adipose tissue on human mammary epithelial cell (MCF-10A) transformation is dependent on FGFR1 activity [21].…”

Section: Introductionmentioning

confidence: 70%

The Relationship between Leptin, the Leptin Receptor and FGFR1 in Primary Human Breast Tumors

Boothby‐Shoemaker

Benham

Paithankar

et al. 2020

Cells

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Obesity is associated with increased breast cancer risk and poorer cancer outcomes; however, the precise etiology of these observations has not been fully identified. Our previous research suggests that adipose tissue-derived fibroblast growth factor-2 (FGF2) promotes the malignant transformation of epithelial cells through the activation of fibroblast growth factor receptor-1 (FGFR1). FGF2 is increased in the context of obesity, and increased sera levels have been associated with endocrine-resistant breast cancer. Leptin is a marker of obesity and promotes breast carcinogenesis through several mechanisms. In this study, we leverage public gene expression datasets to evaluate the associations between FGFR1, leptin, and the leptin receptor (LepR) in breast cancer. We show a positive association between FGFR1 and leptin protein copy number in primary breast tumors. These observations coincided with a positive association between Janus kinase 2 (Jak2) mRNA with both leptin receptor (LepR) mRNA and FGFR1 mRNA. Moreover, two separate Jak2 inhibitors attenuated both leptin+FGF2-stimulated and mouse adipose tissue-stimulated MCF-10A transformation. These results demonstrate how elevated sera FGF2 and leptin in obese patients may promote cancer progression in tumors that express elevated FGFR1 and LepR through Jak2 signaling. Therefore, Jak2 is a potential therapeutic target for FGFR1 amplified breast cancer, especially in the context of obesity.

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Section: Introductionmentioning

confidence: 70%

The Relationship between Leptin, the Leptin Receptor and FGFR1 in Primary Human Breast Tumors

Boothby‐Shoemaker

Benham

Paithankar

et al. 2020

Cells

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“…JB6 P + (mouse skin epithelial) cells were plated in soft agar with 10 µL of human serum and cultured for 10 days. The colony formation assay was performed and quantified as previously described [13]. Samples were blinded and run in duplicate and then averaged to quantify % colony formation.…”

Section: Methodsmentioning

confidence: 99%

The Use of Human Serum Samples to Study Malignant Transformation: A Pilot Study

Holowatyj

Gigic

Warby

et al. 2021

Cells

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Obesity and excess adiposity account for approximately 20% of all cancer cases; however, biomarkers of risk remain to be elucidated. While fibroblast growth factor-2 (FGF2) is emerging as an attractive candidate biomarker for visceral adipose tissue mass, the role of circulating FGF2 in malignant transformation remains unknown. Moreover, functional assays for biomarker discovery are limited. We sought to determine if human serum could stimulate the 3D growth of a non-tumorigenic cell line. This type of anchorage-independent 3D growth in soft agar is a surrogate marker for acquired tumorigenicity of cell lines. We found that human serum from cancer-free men and women has the potential to stimulate growth in soft agar of non-tumorigenic epithelial JB6 P+ cells. We examined circulating levels of FGF2 in humans in malignant transformation in vitro in a pilot study of n = 33 men and women. Serum FGF2 levels were not associated with colony formation in epithelial cells (r = 0.05, p = 0.80); however, a fibroblast growth factor receptor-1 (FGFR1) selective inhibitor significantly blocked serum-stimulated transformation, suggesting that FGF2 activation of FGFR1 may be necessary, but not sufficient for the transforming effects of human serum. This pilot study indicates that the FGF2/FGFR1 axis plays a role in JB6 P+ malignant transformation and describes an assay to determine critical serum factors that have the potential to promote tumorigenesis.

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“…Although there are theories to explain the obesity-cancer association, the underlying mechanisms are poorly elucidated. While investigating this mechanism, our studies demonstrated that circulating fibroblast growth factor 2 (FGF2) from visceral adipose tissue (VAT) stimulates fibroblast growth factor receptor 1 (FGFR1) on epithelial cells to drive malignant transformation 5–7 . We demonstrated that VAT depleted of FGF2 failed to transform epithelial cells and epithelial cells lacking FGFR1, the primary receptor for FGF2, also failed to exhibit VAT-induced transformation 5 .…”

Section: Introductionmentioning

confidence: 99%

“…This gives 3D models a distinct advantage for modeling transformation over 2D culture methods and can distinguish transformed and non-transformed cells 19,20 . We previously used the soft agar assay to show that factors derived from VAT as well as FGF2 itself can stimulate epithelial cells to transform 5–7 . This experiment can identify chemopreventive compounds that prevent or inhibit FGF2-stimulated transformation, but the soft agar assay is unsuitable for high-throughput screening because it is laborious and inefficient, using a 6–24 well format with a 2-week incubation period.…”

Section: Introductionmentioning

confidence: 99%

Identifying chemopreventive agents for obesity-associated cancers using an efficient, 3D high-throughput transformation assay

Benham¹,

Bullard²,

Dexheimer³

et al. 2019

Sci Rep

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Obesity is associated with ~40% of cancer diagnoses but there are currently no effective preventive strategies, illustrating a need for chemoprevention. We previously demonstrated that fibroblast growth factor 2 (FGF2) from adipose tissue stimulates malignant transformation, as measured by growth in soft agar, the gold-standard in vitro transformation assay. Because the soft agar assay is unsuitable for high throughput screens (HTS), we developed a novel method using 3D growth in ultra-low attachment conditions as an alternative to growth in agar to discover compounds that inhibit transformation. Treating non-tumorigenic, skin epithelial JB6 P + cells with FGF2 stimulates growth in ultra-low attachment conditions analogous to growth in the soft agar. This transformation HTS identified picropodophyllin, an insulin growth factor 1 receptor (IGF1R) inhibitor, and fluvastatin, an HMG-CoA reductase inhibitor, as potential chemopreventive agents. These compounds were validated for efficacy using two non-tumorigenic cell lines in soft agar. Another IGF1R inhibitor and other statins were also tested and several were able to inhibit growth in soft agar. This novel 3D HTS platform is fast, robust and has the potential to identify agents for obesity-associated cancer prevention.

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Elucidating the role of adipose tissue secreted factors in malignant transformation

Cited by 3 publications

References 27 publications

The Relationship between Leptin, the Leptin Receptor and FGFR1 in Primary Human Breast Tumors

The Relationship between Leptin, the Leptin Receptor and FGFR1 in Primary Human Breast Tumors

The Use of Human Serum Samples to Study Malignant Transformation: A Pilot Study

Identifying chemopreventive agents for obesity-associated cancers using an efficient, 3D high-throughput transformation assay

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