The Obesity-Cancer Link: Lessons Learned from a Fatless Mouse

Hursting, Stephen D.; Núñez, Nomelí P.; Varticovski, Lyuba; Vinson, Charles

doi:10.1158/0008-5472.can-06-4237

Cited by 108 publications

(75 citation statements)

References 18 publications

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“…It should be noted that the paracrine effects are still considered speculative as the data for in vivo is different from cell culture. For example, in the fatless A-Zip/F1 mouse, adipose tissue and adipokines such as leptin, are unavailable for tumor development making insulin resistance and inflammation the main mechanisms accounting for tumor growth and progression (Hursting et al 2007). Although leptin is produced primarily by adipocytes, it can also be secreted by fibroblasts, the principle component of stroma surrounding the tumor.…”

Section: Leptinmentioning

confidence: 99%

The cellular and molecular mechanisms by which insulin influences breast cancer risk and progression

Rose

Vona-Davis

2012

Endocrine-Related Cancer

142

125

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Epidemiological studies have related hyperinsulinemia and type 2 diabetes to an increased breast cancer risk, an aggressive and metastatic phenotype, and a poor prognosis. Furthermore, diabetic retinopathy arises from pathological angiogenesis, which is also essential for breast cancer growth and metastasis. Insulin stimulates the proliferation of some human breast cancer cell lines in vitro by mechanisms that use both the phosphatidylinositol-3 kinase and the mitogen-activated protein kinase/Akt signaling pathways; it is also a cell survival (anti-apoptotic) agent and enhances tumor cell migration and invasive capacity. Hyperinsulinemia affects breast cancer cells via the endocrine system, but experimental studies suggest the importance of paracrine mechanisms operating by the effects of insulin on the secretion of adipokines from tumor-associated adipose tissue. In such a system, one adipokine, leptin, has stimulatory paracrine effects on breast cancer cell proliferation and survival, while a second, adiponectin, is inhibitory. Leptin, vascular endothelial growth factor, another insulin-regulated adipokine, and insulin itself also stimulate angiogenesis. Insulin has complex interactions with estrogens: it induces adipose stromal cell aromatase and tumor cell sex steroid hormone receptor expression and suppresses sex hormonebinding globulin, which may enhance estrogen synthesis and bioactivity with consequent promotion of estrogen-dependent breast cancer. All these actions influence the later steps in breast cancer development but genetic studies are also revealing connections between gene abnormalities related to type 2 diabetes and the initiation stage of breast carcinogenesis. Understanding the various mechanisms by which insulin participates in breast cancer cell biology provides opportunities for novel approaches to treatment.

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Section: Leptinmentioning

confidence: 99%

The cellular and molecular mechanisms by which insulin influences breast cancer risk and progression

Rose

Vona-Davis

2012

Endocrine-Related Cancer

142

125

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“…64,65 Another study found that obesity was positively associated with death due to prostate cancer metastases. 66 Hursting et al 67 2007 now suggested that the observed increase in obesity associated cancers is the result of chronic inflammation that follows obesity. Also SCDs may play a role in cancer development.…”

Section: Role Of Scd1 In the Link Between Obesity And Cancermentioning

confidence: 99%

Role of stearoyl-CoA desaturases in obesity and the metabolic syndrome

2008

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The prevalence of obesity and related metabolic disorders increases rapidly in western societies. A proper choice of foods may now prevent or delay many of the health consequences related to these disorders. In this respect, replacing dietary saturated fatty acids (SFAs) by cis-monounsaturated fatty acids (cis-MUFAs) has beneficial effects. In addition to diet-derived cis-MUFAs, the human body can also generate cis-MUFAsfrom SFAs through the action of stearoyl-CoA desaturases (SCDs). SCDs may play an adverse role in obesity and obesity-related insulin resistance. Here, we review the current knowledge on the molecular aspects and the role of SCD1 in obesity and the metabolic syndrome (MS). In mice, many studies have suggested a negative role for SCD1 in the development of obesity and insulin resistance. In humans, however, evidence is less convincing. If anything, increased, rather than decreased, levels of SCD1 mRNA levels are negatively associated with MS-related diseases such as insulin resistance. However, an unequivocal conclusion is currently not possible as the number of human studies is limited. Therefore, more human studies are needed at the molecular as well as at the physiological level to understand the true role of SCD1 during the development of obesity and the MS.

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“…4 The obesity-cancer progression link may be due in part to dysregulated hormones and obesity-induced inflammation. 5,6 Similar to obese men, obese mice fed a high fat diet also results in increased adiposity, circulating growth factors and inflammation when compared with control mice and may contribute to prostate cancer progression. [7][8][9][10] Studies suggest that cancer cells undergo an epithelialmesenchymal-transition (EMT) program at the initiation of invasion, which is a critical process for metastasis.…”

Section: Introductionmentioning

confidence: 99%

Obesity-related systemic factors promote an invasive phenotype in prostate cancer cells

Price

Cavazos

Angel

et al. 2012

Prostate Cancer Prostatic Dis

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BACKGROUND: Obesity is associated with larger tumors, shorter time to PSA failure, and higher Gleason scores. However, the mechanism(s) by which obesity promotes aggressive prostate cancer remains unknown. We hypothesize that circulating factors related to obesity promote prostate cancer progression by modulating components of the metastatic cascade.METHODS: Male C57BL/6 mice (6 weeks) were fed an ad libitum diet-induced obesity (60% fat) or control diet (10% fat) for 12 weeks. Serum was collected, metabolic and inflammatory proteins were measured by an antibody array. Sera were used to measure, in vitro, characteristics of a metastatic phenotype. RESULTS:Comparable to obese men, obese sera contained higher levels or leptin, vascular endothelial growth factor, PAI-1, interleukin-6 (IL-6) and lower levels of testosterone. In prostate cells, serum was used to assess: proliferation, invasion, migration, epithelial-mesenchymal-transition (EMT) and matrix metalloproteinase (MMP) activity. LNCaP and PacMetUT1 cells exposed to obese sera increased proliferation, whereas PrEC and DU145 were unaffected. LNCaP, PacMetUT1 and DU145 cancer cells exposed to obese sera resulted in increased invasion, migration and MMP-9 activity. Prostate cancer cells exposed to obese sera showed increased vimentin, dispersion of e-cadherin and b-catenin from the plasma membrane. CONCLUSION:We report, prostate cancer cells exposed to sera from obese mice increases proliferation, invasion, migration, MMP activity and induces changes in proteins critical for EMT.

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The Obesity-Cancer Link: Lessons Learned from a Fatless Mouse

Cited by 108 publications

References 18 publications

The cellular and molecular mechanisms by which insulin influences breast cancer risk and progression

The cellular and molecular mechanisms by which insulin influences breast cancer risk and progression

Role of stearoyl-CoA desaturases in obesity and the metabolic syndrome

Obesity-related systemic factors promote an invasive phenotype in prostate cancer cells

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