Mesenchymal Stem Cells Induce Resistance to Chemotherapy through the Release of Platinum-Induced Fatty Acids

Roodhart, Jeanine M.L.; Daenen, Laura G.M.; Stigter, E.C.A.; Prins, Henk-Jan; Gerrits, Johan; Houthuijzen, Julia M.; Gerritsen, Marije G.; Bateman, Scott; Bäcker, M; Amersfoort, Miranda van; Vermaat, Joost S.P.; Moerer, Petra; Ishihara, Kenji; Kalkhoven, Eric; Beijnen, Jos H.; Derksen, Patrick W.B.; Medema, René H.; Martens, Anton C.; Brenkman, Arjan B.; Voest, Emile E.

doi:10.1016/j.ccr.2011.08.010

Cited by 279 publications

(292 citation statements)

References 43 publications

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“…Indeed, we and others have shown previously that bone marrow-derived MSCs home to and become incorporated into the stroma of developing breast carcinoma xenografts (7)(8)(9). MSCs were also found at elevated levels in the circulation of patients with advanced breast cancer (10) and in the stroma of human primary breast carcinomas (11), observations that are consistent with the systemic mobilization of MSCs by and their recruitment into breast tumors in the clinical setting.…”

supporting

confidence: 84%

Critical role for lysyl oxidase in mesenchymal stem cell-driven breast cancer malignancy

El-Haibi

Bell

Zhang

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

197

161

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Mesenchymal stem cells (MSCs) are multipotent progenitor cells with the ability to differentiate into multiple mesoderm lineages in the course of normal tissue homeostasis or during injury. We have previously shown that MSCs migrate to sites of tumorigenesis, where they become activated by cancer cells to promote metastasis. However, the molecular and phenotypic attributes of the MSCinduced metastatic state of the cancer cells remained undetermined. Here, we show that bone marrow-derived human MSCs promote de novo production of lysyl oxidase (LOX) from human breast carcinoma cells, which is sufficient to enhance the metastasis of otherwise weakly metastatic cancer cells to the lungs and bones. We also show that LOX is an essential component of the CD44-Twist signaling axis, in which extracellular hyaluronan causes nuclear translocation of CD44 in the cancer cells, thus triggering LOX transcription by associating with its promoter. Processed and enzymatically active LOX, in turn, stimulates Twist transcription, which mediates the MSC-triggered epithelial-to-mesenchymal transition (EMT) of carcinoma cells. Surprisingly, although induction of EMT in breast cancer cells has been tightly associated with the generation of cancer stem cells, we find that LOX, despite being critical for EMT, does not contribute to the ability of MSCs to promote the formation of cancer stem cells in the carcinoma cell populations. Collectively, our studies highlight a critical role for LOX in cancer metastasis and indicate that the signaling pathways controlling stroma-induced EMT are distinct from pathways regulating the development of cancer stem cells.

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supporting

confidence: 84%

Critical role for lysyl oxidase in mesenchymal stem cell-driven breast cancer malignancy

El-Haibi

Bell

Zhang

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

197

161

View full text Add to dashboard Cite

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“…More recently, a report showed that cis-platinum could induce poly-unsaturated FAs at the tumor sites, which protected tumor cells against a range of chemotherapeutics. 39 This study implies that, in addition to dietary DHA and EPA, activated cells in the tumor microenviroment could also release poly-unsaturated FAs to modify tumor development through GPR120 signaling.…”

Section: Gpr120 Is Induced In Human Crc Tissues and Its Expression Ismentioning

confidence: 85%

Identification of G-protein-coupled receptor 120 as a tumor-promoting receptor that induces angiogenesis and migration in human colorectal carcinoma

et al. 2013

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G-protein-coupled receptor 120 (GPR120) functions as a receptor for unsaturated long-chain free fatty acids and has an important role in regulating lipid and glucose metabolism. However, a role for GPR120 in the development of tumors has not yet been clarified. Here, we show that GPR120 signaling promotes angiogenic switching and motility of human colorectal carcinoma (CRC) cells. We show that the expression of GPR120 is significantly induced in CRC tissues and cell lines, which is associated with tumor progression. Activation of GPR120 signaling in human CRC promotes angiogenesis in vitro and in vivo, largely by inducing the expression and secretion of proangiogenic mediators such as vascular endothelial growth factor (VEGF), interleukin-8 and cyclooxygenase-2-derived prostaglandin E 2 . The PI3K/Akt-NF-kB pathway is activated by GPR120 signaling and is required for GPR120 signaling-induced angiogenic switching in CRC cells. And, GPR120 activation enhances the motility of CRC cells and induces epithelial-mesenchymal transition. Furthermore, in vivo study shows that activation of GPR120 promotes angiogenesis and tumor growth. Finally, we find that GPR120 expression is positively correlated with VEGF expression and inversely correlated with the epithelial marker E-cadherin in CRC tissues. Collectively, our results demonstrate that GPR120 functions as a tumor-promoting receptor in CRC and, therefore, shows promise as a new potential target for cancer therapeutics.

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“…Unfortunately, we did not measure the rate of incorporation of EPA and DHA in the tumor, but rather their peroxidation product, MDA, and total peroxides. Moreover, the clinical use of FO products or algae is still under debate, especially because Roodhart et al [30] recently reported that the release of specific PUFAs by endogenous mesenchymal stem cells could induce tumor resistance to different chemotherapeutic drugs. Although phospholipases A2, thromboxane synthase, and COX-1 are involved in this chemoresistance [30], our results showed that the modulation of eicosanoid synthesis is not the only mechanism involved and that others have to be taken into account, such as the lipoperoxidative effects on tumor growth.…”

Section: Discussionmentioning

confidence: 99%

Vitamin E content in fish oil emulsion does not prevent lipoperoxidative effects on human colorectal tumors

et al. 2013

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a b s t r a c tObjective: The anticancer action exerted by polyunsaturated fatty acid peroxidation may not be reproduced by commercially available lipid emulsions rich in vitamin E. Therefore, we evaluated the effects of fish oil (FO) emulsion containing a-tocopherol 0.19 g/L on human colorectal adenocarcinoma cells and tumors. Methods: HT-29 cell growth, survival, apoptosis, and lipid peroxidation were analyzed after a 24-h incubation with FO 18 to 80 mg/L. Soybean oil (SO) emulsion was used as an isocaloric and isolipidic control. In vivo, nude mice bearing HT-29 tumors were sacrificed 7 d after an 11-d treatment with intravenous injections of FO or SO 0.2 g • kg À1 • d À1 FO or SO to evaluate tumor growth, necrosis, and lipid peroxidation. Results: The FO inhibited cell viability and clonogenicity in a dose-dependent manner, whereas SO showed no significant effect compared with untreated controls. Lipid peroxidation and cell apoptosis after treatment with FO 45 mg/L were increased 2.0-fold (P < 0.01) and 1.6-fold (P ¼ 0.04), respectively. In vivo, FO treatment did not significantly affect tumor growth. However, immunohistochemical analyses of tumor tissue sections showed a decrease of 0.6-fold (P < 0.01) in the cell proliferation marker Ki-67 and an increase of 2.3-fold (P ¼ 0.03) in the necrotic area, whereas malondialdehyde and total peroxides were increased by 1.9-fold (P ¼ 0.09) and 7.0-fold (P < 0.01), respectively, in tumors of FO-treated compared with untreated mice. Conclusion: These results suggest that FO but not SO has an antitumor effect that can be correlated with lipid peroxidation, despite its vitamin E content.

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Mesenchymal Stem Cells Induce Resistance to Chemotherapy through the Release of Platinum-Induced Fatty Acids

Cited by 279 publications

References 43 publications

Critical role for lysyl oxidase in mesenchymal stem cell-driven breast cancer malignancy

Critical role for lysyl oxidase in mesenchymal stem cell-driven breast cancer malignancy

Identification of G-protein-coupled receptor 120 as a tumor-promoting receptor that induces angiogenesis and migration in human colorectal carcinoma

Vitamin E content in fish oil emulsion does not prevent lipoperoxidative effects on human colorectal tumors

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