High-calorie diet exacerbates prostate neoplasia in mice with haploinsufficiency of Pten tumor suppressor gene

Liu, Jehnan; Ramakrishnan, S; Khuder, Saja S.; Kaw, Meenakshi; Muturi, Harrison T.; Lester, Sumona Ghosh; Lee, Sang Jun; Fedorova, Larisa; Kim, Andrea J.; Mohamed, Iman E.; Gatto‐Weis, Cara; Eisenmann, Kathryn M.; Conran, Philip B.; Najjar, Sonia M.

doi:10.1016/j.molmet.2014.12.011

Cited by 15 publications

(14 citation statements)

References 52 publications

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“…The interaction of oncogenic events with a HFD has also been reported in other oncogenic events, such as loss of phosphatase and tensin homolog (PTEN)‐mediated prostate cancer. HFDs promote the differentiation of basal cells to luminal cells to initiate PTEN‐mediated hyperplasia, and exacerbate prostate neoplasia by increasing the inflammatory response, or accelerating metastasis in loss of PTEN‐mediated tumors . Our studies and others emphasize the importance of dietary choice for cancer patients and indicate that a diet low in saturated fat is potentially beneficial in reducing the risk of progression of aggressive cancer.…”

Section: Discussionmentioning

confidence: 54%

Dietary palmitate cooperates with Src kinase to promote prostate tumor progression

et al. 2019

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Numerous genetic alterations have been identified during prostate cancer progression. The influence of environmental factors, particularly the diet, on the acceleration of tumor progression is largely unknown. Expression levels and/or activity of Src kinase are highly elevated in numerous cancers including advanced stages of prostate cancer. In this study, we demonstrate that high-fat diets (HFDs) promoted pathological transformation mediated by the synergy of Src and androgen receptor in vivo. Additionally, a diet high in saturated fat significantly enhanced proliferation of Src-mediated xenograft tumors in comparison with a diet high in unsaturated fat. The saturated fatty acid palmitate, a major constituent in a HFD, significantly upregulated the biosynthesis of palmitoyl-CoA in cancer cells in vitro and in xenograft tumors in vivo. The exogenous palmitate enhanced Src-dependent mitochondrial β-oxidation. Additionally, it elevated the amount of C16-ceramide and total saturated ceramides, increased the level of Src kinase localized in the cell membrane, and Src-mediated downstream signaling, such as the activation of mitogen-activated protein kinase and focal adhesion kinase. Our results uncover how the metabolism of dietary palmitate cooperates with elevated Src kinase in the acceleration of prostate tumor progression. K E Y W O R D S palmitate/fatty acid metabolism/Src kinase/prostate cancer 1 | INTRODUCTION Prostate cancer is the most common cancer in men and one of the leading causes of cancer-related deaths in developed countries. 1 Diet is considered a critical environmental risk factor in prostate cancer progression. 2 Numerous epidemiological studies indicate that obesity, higher body mass index, or adult weight gain significantly increases the risk of aggressive prostate cancer, mortality, and recurrence of prostate cancer. 3-8 A high-fat diet (HFD) or certain dietary saturated fatty acids (FAs) including palmitic acid (PA) and myristic acid (MA) are associated with advanced stages of prostate cancer and increase the risk of prostate cancer-specific mortality. 3,5,7,9 Incorporation of excess free FAs into cancer cell membranes promotes cancer invasion by reduction of cell-cell contact and increase of surface adhesion. 10 However, the interaction of dietary factors with oncogenic events to regulate tumor progression is not well-understood. Numerous genetic alterations including aberrant expression and/ or loss of tumor suppressor genes have been identified in the initiation and progression of prostate tumors. 11 Among those oncogenic events, overexpression and/or activation of Src kinase is common in advanced stages of prostate cancer. 12,13 Src kinase is a pleiotropic activator to mediate numerous signal transduction pathways initiated by G-protein coupled receptors, β1-integrin, growth factor receptors, and others. 14,15 The activation of Src kinase promotes cell survival, proliferation, migration, and invasion in The Prostate. 2019;79:896-908. wileyonlinelibrary.com/journal/pros

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Section: Discussionmentioning

confidence: 54%

Dietary palmitate cooperates with Src kinase to promote prostate tumor progression

et al. 2019

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“…These studies utilizing either injectable immortalized human cancer cells [7, 8] or transgenic mice including TRAMP [9, 10, 12], Pten [15] and Hi-Myc [13] have generally shown that prolonged high-fat feeding accelerates prostate cancer progression as demonstrated by increased tumor volume, proliferation, neoplastic progression, epithelial-mesenchymal transition, metastasis and mortality (see review [25]). While supporting a causative link between obesity and prostate cancer progression, it is notable that these oncogene-driven transgenic mouse models do not faithfully model human prostate cancer development.…”

Section: Discussionmentioning

confidence: 99%

“…PC3 or LNCaP) are generally increased in mice rendered obese by high-fat feeding compared with lean mice fed a low-fat diet [7–10], while diet-induced obesity accelerates prostate cancer progression /aggressiveness in transgenic mouse strains of prostate cancer (e.g. TRAMP, Hi-Myc, Pten − /+ ) [9–15]. While these data are convincing, they are limited to immortalized metastatic cell lines and genetically modified mice, and studies using additional models that more closely replicate the biology of human prostate cancer are required to confirm these initial observations.…”

Section: Introductionmentioning

confidence: 99%

Obesity does not promote tumorigenesis of localized patient-derived prostate cancer xenografts

Clark

Ascui

et al. 2016

Oncotarget

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There are established epidemiological links between obesity and the severity of prostate cancer. We directly tested this relationship by assessing tumorigenicity of patient-derived xenografts (PDXs) of moderate-grade localized prostate cancer in lean and obese severe combined immunodeficiency (SCID) mice. Mice were rendered obese and insulin resistant by high-fat feeding for 6 weeks prior to transplantation, and PDXs were assessed 10 weeks thereafter. Histological analysis of PDX grafts showed no differences in tumor pathology, prostate-specific antigen, androgen receptor and homeobox protein Nkx-3.1 expression, or proliferation index in lean versus obese mice. Whilst systemic obesity per se did not promote prostate tumorigenicity, we next asked whether the peri-prostatic adipose tissue (PPAT), which covers the prostate anteriorly, plays a role in prostate tumorigenesis. In vitro studies in a cellularized co-culture model of stromal and epithelial cells demonstrated that factors secreted from human PPAT are pro-tumorigenic. Accordingly, we recapitulated the prostate-PPAT spatial relationship by co-grafting human PPAT with prostate cancer in PDX grafts. PDX tissues were harvested 10 weeks after grafting, and histological analysis revealed no evidence of enhanced tumorigenesis with PPAT compared to prostate cancer grafts alone. Altogether, these data demonstrate that prostate cancer tumorigenicity is not accelerated in the setting of diet-induced obesity or in the presence of human PPAT, prompting the need for further work to define the at-risk populations of obesity-driven tumorigenesis and the biological factors linking obesity, adipose tissue and prostate cancer pathogenesis.

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“…A number of studies have demonstrated a role for diet-induced obesity in promoting prostate tumor growth in the transgenic adenocarcinoma of the prostate (TRAMP) mouse model (Bonorden, et al 2012; Llaverias, et al 2010). In addition, diet-induced obesity reduced tumor latency in the Hi-Myc mouse model, via increased Akt/mTOR signaling (Blando, et al 2011; Kobayashi, et al 2008), and promoted tumor progression in a transgenic mouse model with PTEN haploinsufficiency, via increased inflammatory and insulin signaling pathways (Liu, et al 2015). These transgenic models may have relevance to human prostate cancer given that Myc copy number is amplified in up to one third of human prostate cancers (Ellwood-Yen, et al 2003) and PTEN loss is the most common genetic alteration in human prostate cancer (Wang, et al 2003).…”

Section: Transdisciplinary Insights Into Associations Between Obesmentioning

confidence: 99%

Obesity and cancer: mechanistic insights from transdisciplinary studies

Allott¹,

Hursting²

2015

Endocrine-Related Cancer

140

101

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Obesity is associated with a range of health outcomes that are of clinical and public health significance, including cancer. Herein, we summarize epidemiologic and preclinical evidence for an association between obesity and increased risk of breast and prostate cancer incidence and mortality. Moreover, we describe data from observational studies of weight change in humans and from calorie restriction studies in mouse models which support a potential role for weight loss in counteracting tumor-promoting properties of obesity in breast and prostate cancers. Given that weight loss is challenging to achieve and maintain, we also consider evidence linking treatments for obesity-associated co-morbidities, including metformin, statins and non-steroidal anti-inflammatory drugs, with reduced breast and prostate cancer incidence and mortality. Finally, we highlight several challenges that should be considered when conducting epidemiologic and preclinical research in the area of obesity and cancer, including the measurement of obesity in population-based studies, the timing of obesity and weight change in relation to tumor latency and cancer diagnosis, and the heterogeneous nature of obesity and its associated co-morbidities. Given that obesity is a complex trait, comprised of behavioral, epidemiologic and molecular/metabolic factors, we argue that a transdisciplinary approach is the key to understanding the mechanisms linking obesity and cancer. As such, this review highlights the critical need to integrate evidence from both epidemiologic and preclinical studies to gain insight into both biologic and non-biologic mechanisms contributing to the obesity-cancer link.

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High-calorie diet exacerbates prostate neoplasia in mice with haploinsufficiency of Pten tumor suppressor gene

Cited by 15 publications

References 52 publications

Dietary palmitate cooperates with Src kinase to promote prostate tumor progression

Dietary palmitate cooperates with Src kinase to promote prostate tumor progression

Obesity does not promote tumorigenesis of localized patient-derived prostate cancer xenografts

Obesity and cancer: mechanistic insights from transdisciplinary studies

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