Omega-3 Fatty Acids Inhibit Tumor Growth in a Rat Model of Bladder Cancer

Parada, B.; Reis, Flávio; Cerejo, Raquel; Garrido, Patrícia; Xavier-Cunha, Maria; Neto, Paula; Mota, A.; Figueiredo, Arnaldo; Teixeira, Frederico

doi:10.1155/2013/368178

Cited by 26 publications

(12 citation statements)

References 56 publications

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“…However, DHA is a versatile molecule that also interferes in multiple pro-tumor properties, such as inflammation, ROS, and mitogenic signaling pathways (protein kinase C and extracellular signal-regulated kinase 1/2) (53, 55). DHA has been linked to the alleviation of cancer; for instance, administration of omega-3 fatty acids, including both DHA and eicopentaenoic acid, significantly reduces carcinogen-induced bladder tumor in rats (56). We speculate that DHA may also regulate EV internalization and biogenesis through maintaining sodium/potassium pump activity and modifying plasma membrane lipid raft structure (57,58).…”

Section: Discussionmentioning

confidence: 90%

Bladder cancer extracellular vesicles drive tumorigenesis by inducing the unfolded protein response in endoplasmic reticulum of nonmalignant cells

Wu¹,

Silvers

Messing

et al. 2019

Journal of Biological Chemistry

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The field cancerization effect has been proposed to explain bladder cancer's multifocal and recurrent nature, yet the mechanisms of this effect remain unknown. In this work, using cell biology, flow cytometry, and qPCR analyses, along with a xenograft mouse tumor model, we show that chronic exposure to tumor-derived extracellular vesicles (TEVs) results in the neoplastic transformation of nonmalignant human SV-HUC urothelial cells. Inhibition of EV uptake prevented this transformation. Transformed cells not only possessed several oncogenic properties, such as increased genome instability, loss of cellcell contact inhibition, and invasiveness, but also displayed altered morphology and cell structures, such as an enlarged cytoplasm with disrupted endoplasmic reticulum (ER) alignment and the accumulation of smaller mitochondria. Exposure of SV-HUC cells to TEVs provoked the unfolded protein response in the endoplasmic reticulum (UPR ER). Prolonged induction of UPR ER signaling activated the survival branch of the UPR ER pathway, in which cells had elevated expression of inositol-requiring enzyme 1 (IRE1), NF-B, and the inflammatory cytokine leptin, and incurred loss of the pro-apoptotic protein C/EBP homologous protein (CHOP). More importantly, inhibition of ER stress by docosahexaenoic acid prevented TEVinduced transformation. We propose that TEVs promote malignant transformation of predisposed cells by inhibiting pro-apoptotic signals and activating tumor-promoting ER stressinduced unfolded protein response and inflammation. This study provides detailed insight into the mechanisms underlying the bladder cancer field effect and tumor recurrence.

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Section: Discussionmentioning

confidence: 90%

Bladder cancer extracellular vesicles drive tumorigenesis by inducing the unfolded protein response in endoplasmic reticulum of nonmalignant cells

Wu¹,

Silvers

Messing

et al. 2019

Journal of Biological Chemistry

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“…The study demonstrated the anti-inflammatory, antioxidant, anti-proliferative, and anti-angiogenic properties of O-3FAs. This highlights that PUFAs inhibits inflammatory markers, including CRP, transforming growth factor-β1, and tumorexpressed cluster of differentiation (CD)-31 [40].…”

Section: Carcinoma Of Bladdermentioning

confidence: 97%

“…Parada et al [40] studied the chemopreventive effect of n-3 DHA and n-3 EPA on bladder cancer in an animal study using Wistar rats. Bladder cancer was induced by N-butyl-N-(4-hydroxybutyl) nitrosamine (BBN).…”

Section: Carcinoma Of Bladdermentioning

confidence: 99%

Influence of polyunsaturated fatty acids on urologic inflammation

et al. 2015

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“…Bladder cancer, the fourth most common cancer diagnosed in men and the eighth in women, remains a concern due to its prevalence and tendency to progress and recur [1–3]. Advances in drug delivery are needed and nanomedicine in particular holds promise as a means to improve bioavailability and half-life in circulation [4,5].…”

Section: Introductionmentioning

confidence: 99%

Synergistic anti-tumor effects of combined gemcitabine and cisplatin nanoparticles in a stroma-rich bladder carcinoma model

Zhang

Miao

Guo

et al. 2014

Journal of Controlled Release

106

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Tumors grown in a stroma-rich mouse model resembling clinically advanced bladder carcinoma with UMUC3 and NIH 3T3 cells have high levels of fibroblasts and an accelerated tumor growth rate. We used this model to investigate the synergistic effect of combined gemcitabine monophosphate (GMP) nanoparticles and Cisplatin nanoparticles (Combo NP) on tumor-associated fibroblasts (TAFs). A single injection of Combo NP had synergistic anti-tumor effects while the same molar ratio of combined GMP and Cisplatin delivered as free drug (Combo Free) fell outside of the synergistic range. Combo NP nearly halted tumor growth with little evidence of general toxicity while Combo Free had only a modest inhibitory effect at 16 mg/kg GMP and 1.6 mg/kg Cisplatin. Combo NP increased levels of apoptosis within the tumor by approximately 1.3 fold (TUNEL analysis) and decreased α-SMA-positive fibroblast recruitment by more than 87% (immunofluorescence) after multiple injections compared with Combo Free, GMP NP or Cisplatin NP alone. The TAF-targeting capability of Combo NP was evaluated by double staining for TUNEL and α-SMA at various time points after a single injection. On day one after injection, 57% of the TUNEL-positive cells were identified as α-SMA-positive fibroblasts. By day four, tumor stroma was 85% depleted and 87% of the remaining TAFs were TUNEL-positive. Combo NP-treated tumors became 2.75 fold more permeable than those treated with Combo Free as measured by Evans Blue. We conclude that the antineoplastic effect of Combo NP works by first targeting TAFs and is more effective as an anti-tumor therapy than Combo Free, GMP NP or Cisplatin NP alone.

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Omega-3 Fatty Acids Inhibit Tumor Growth in a Rat Model of Bladder Cancer

Cited by 26 publications

References 56 publications

Bladder cancer extracellular vesicles drive tumorigenesis by inducing the unfolded protein response in endoplasmic reticulum of nonmalignant cells

Bladder cancer extracellular vesicles drive tumorigenesis by inducing the unfolded protein response in endoplasmic reticulum of nonmalignant cells

Influence of polyunsaturated fatty acids on urologic inflammation

Synergistic anti-tumor effects of combined gemcitabine and cisplatin nanoparticles in a stroma-rich bladder carcinoma model

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