Senescence‐associated tissue microenvironment promotes colon cancer formation through the secretory factor GDF15

Guo, Yi; Ayers, Jessica; Carter, Kelly; Wang, Ting; Maden, Sean K.; Edmond, Darwin; P, Polly Newcomb; Li, Christopher; Ulrich, Cornelia M.; Yu, Ming; Grady, William M.

doi:10.1111/acel.13013

Cited by 82 publications

(80 citation statements)

References 45 publications

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“…In humans, GDF15 is expressed in response to cellular damage and serum levels are positively correlated with age (Schafer et al, 2020). GDF15 also associated with senescence to promote colon cancer formation, and human airway epithelial senescence (Guo et al, 2019;Wu et al, 2016). However, secretion of this protein by senescent vascular endothelial cells seemed to be beneficial by promoting function of vascular progenitor (Ha et al, 2019).…”

Section: Discussionmentioning

confidence: 99%

Effect of menopausal hormone therapy on proteins associated with senescence and inflammation

et al. 2020

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Background Estrogen may inhibit cell senescence that contributes to age‐related disorders. This study determined the effects of menopausal hormone treatments on circulating levels of markers of cell senescence. Methods Growth differentiation factor 15 (GDF15), tumor necrosis factor receptor 1 (TNFR1), FAS, and macrophage inflammatory protein 1α (MIP1α) were measured in serum using multiplexed bead‐based assays and compared among menopausal women participating in the Kronos Early Estrogen Prevention Study randomized to either placebo (n = 38), oral conjugated equine estrogen (oCEE, n = 37), or transdermal 17β‐estradiol (tE2, n = 34). Serum levels of the senescent markers for each treatment were compared to placebo 36 months after randomization using the Wilcoxon rank sum test. Results Serum levels of GDF15, TNFR1, and FAS, but not MIP1α, were lower in both the oCEE and tE2 groups compared to placebo. The difference in levels between treatment and placebo for GDF15, TNFR1, and FAS were greater for oCEE [−108 pg/mL (p = .008), −234 pg/mL (p = .0006), and −1374 pg/mL (p < .0001), respectively] than for tE2 [−76 pg/mL (p = .072), −105 pg/mL (p = .076), and −695 pg/mL (p = .036), respectively]. Additionally, TNFR1 showed a positive association with time past menopause (correlation = 0.255, p = .019). Conclusions Circulating levels of some markers of cell senescence were lower in menopausal women treated with oCEE and tE2 compared to placebo. Differences in the magnitude of effect of the two active treatments may reflect the differences in circulating levels of estrogen metabolites due to formulation and mode of delivery. These data generate new hypotheses with regard to the effects of menopause on the biology of aging.

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Section: Discussionmentioning

confidence: 99%

Effect of menopausal hormone therapy on proteins associated with senescence and inflammation

et al. 2020

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“…A previous study indicated that GDF15 could serve as a potential biomarker for EC ( 10 ). GDF15 not only promoted bone metastasis of prostate cancer but also induced colon cancer formation in senescence-associated tissue microenvironment ( 6 , 24 ). However, the role of GDF15 in the invasion and metastasis of EC remains poorly understood.…”

Section: Discussionmentioning

confidence: 99%

SCAP Mediated GDF15-Induced Invasion and EMT of Esophageal Cancer

et al. 2020

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Background: GDF15 is a potential biomarker for patients with esophageal cancer (EC). However, the mechanistic role of GDF15 in the invasion and metastasis of EC remains poorly understood. Methods: We determined the expression and function of GDF15 in esophageal cancer cells (ESCCs) and in patient tissue samples using western blotting, migration, and invasion assays, immunohistochemistry, Co-IP assays, and quantitative real-time-PCR. In addition, a pulmonary metastatic nude mouse model was used to determine the function of GDF15. We then supplemented our experimental results with database analysis to validate our findings. Results: GDF15 was upregulated in EC, and was associated with poor differentiation, high metastasis rates, and worse prognosis. GDF15 knock-down reduced the migration and invasion of ESCCs. Co-IP assays demonstrated its association with SCAP, while GDF15 knock-down decreased SCAP levels. SCAP overexpression reversed the migration, invasion and EMT in GDF15-siRNA ESCCs. However, after incubation with β-cyclodextrin (β-CD), the ability of migration and invasion was weakened, EMT was reversed again. Migration, invasion, and EMT were enhanced in GDF15-siRNA ESCCs cultured in the presence of cholesterol and were similar to GDF15-siRNA ESCCs overexpressing SCAP. In vivo , knockdown of GDF15 inhibited lung metastasis of ESCCs and was reversed by SCAP overexpression or high cholesterol diet. Increased lung metastasis after SCAP overexpression was partially suppressed by intraperitoneal injection of β-CD. In addition, we determined that GDF15 was a direct target of miR-1324, miR-1324 was down-regulated in EC tissues. MiR-1324 upregulation resulted in decreased GDF15 expression and metastasis in ESCCs. Conclusions: We demonstrated that SCAP mediated GDF15-induced the invasion and metastasis of EC by regulating cholesterol metabolism. In addition, GDF15 was shown to be a direct target of miR-1324.

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“…A previous study indicated that GDF15 could serve as a potential biomarker for EC [10]. GDF15 not only promoted bone metastasis of prostate cancer but also induced colon cancer formation in senescence-associated tissue microenvironment [6,23]. However, the role of GDF15 in the invasion and metastasis of EC remains poorly understood, with potential mechanisms yet to be deciphered.…”

Section: Discussionmentioning

confidence: 99%

GDF15-Mediated Cholesterol Metabolism Promotes EMT and Metastasis in Esophageal Cancer

Dong

Huang

Jiang

et al. 2020

Preprint

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Background: GDF15 is a potential biomarker for patients with esophageal cancer (EC). However, the mechanistic role of GDF15 in the invasion and metastasis of EC remains poorly understood. Methods: We determined the expression and function of GDF15 in esophageal cancer cells (ESCCs) and in patient tissue samples using western blotting, migration and invasion assays, immunohistochemistry, Co-IP assays, and quantitative real-time-PCR. In addition, a pulmonary metastatic nude mouse model was used to determine the function of GDF15. We then supplemented our experimental results with database analysis to validate our findings.Results: GDF15 was upregulated in EC, and was associated with poor differentiation, high metastasis rates and worse prognosis. GDF15 knock-down reduced the migration and invasion of ESCCs. Co-IP assays demonstrated its association with SCAP, while GDF15 knock-down decreased SCAP levels. SCAP overexpression reversed the migration, invasion and EMT in GDF15-siRNA ESCCs. However, after incubation with β-cyclodextrin (β-CD), the ability of migration and invasion was weakened, EMT was reversed again. Migration, invasion, and EMT were enhanced in GDF15-siRNA ESCCs cultured in the presence of cholesterol and were similar to GDF15-siRNA ESCCs overexpressing SCAP. In vivo, knockdown of GDF15 inhibited lung metastasis of ESCCs and was reversed by SCAP overexpression or high cholesterol diet. Increased lung metastasis after SCAP overexpression was partially suppressed by intraperitoneal injection of β-CD. In addition, we determined that GDF15 was a direct target of miR-1324, miR-1324 was down-regulated in EC tissues. MiR-1324 upregulation resulted in decreased GDF15 expression and metastasis in ESCCs. Conclusions: We demonstrated that SCAP mediated GDF15-induced the invasion and metastasis of EC by regulating cholesterol metabolism. In addition, GDF15 was shown to be a direct target of miR-1324.

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Senescence‐associated tissue microenvironment promotes colon cancer formation through the secretory factor GDF15

Cited by 82 publications

References 45 publications

Effect of menopausal hormone therapy on proteins associated with senescence and inflammation

Effect of menopausal hormone therapy on proteins associated with senescence and inflammation

SCAP Mediated GDF15-Induced Invasion and EMT of Esophageal Cancer

GDF15-Mediated Cholesterol Metabolism Promotes EMT and Metastasis in Esophageal Cancer

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