Solid stress-induced migration is mediated by GDF15 through Akt pathway activation in pancreatic cancer cells

Kalli, Maria; Minia, Angeliki; Pliaka, Vaia; Fotis, Christos; Alexopoulos, Leonidas G.; Stylianopoulos, Triantafyllos

doi:10.1038/s41598-018-37425-6

Cited by 64 publications

(87 citation statements)

References 43 publications

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“…However, conflicting results have been obtained. For example, inconsistent with the above results, GDF15, a migration-promoting factor, 182 was found to be downregulated in PC cells via a lncRNA HOTAIR-induced increase in the H3K27me3 level in its promoter. 129 Moreover, researchers have proven that EZH2-mediated H3K27me3 suppresses RUNX3 gene expression in PC and GC.…”

Section: Histone Methylation Mediates the Development Of Digestive Cacontrasting

confidence: 58%

The role of histone methylation in the development of digestive cancers: a potential direction for cancer management

Chen

Ren

Yang

et al. 2020

Sig Transduct Target Ther

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Digestive cancers are the leading cause of cancer-related death worldwide and have high risks of morbidity and mortality. Histone methylation, which is mediated mainly by lysine methyltransferases, lysine demethylases, and protein arginine methyltransferases, has emerged as an essential mechanism regulating pathological processes in digestive cancers. Under certain conditions, aberrant expression of these modifiers leads to abnormal histone methylation or demethylation in the corresponding cancer-related genes, which contributes to different processes and phenotypes, such as carcinogenesis, proliferation, metabolic reprogramming, epithelial-mesenchymal transition, invasion, and migration, during digestive cancer development. In this review, we focus on the association between histone methylation regulation and the development of digestive cancers, including gastric cancer, liver cancer, pancreatic cancer, and colorectal cancer, as well as on its clinical application prospects, aiming to provide a new perspective on the management of digestive cancers.

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Section: Histone Methylation Mediates the Development Of Digestive Cacontrasting

confidence: 58%

The role of histone methylation in the development of digestive cancers: a potential direction for cancer management

Chen

Ren

Yang

et al. 2020

Sig Transduct Target Ther

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“…In breast cancer, compression leads to the development of leader cells and invasive phenotypes [ 13 ]. In pancreatic and brain cancers, compression induces migration, arbitrated by GDF15 through the Akt [ 20 ] and the MEK1/Erk1 pathways respectively [ 14 ]. Tumor microenvironment compression-induced solid stress has been linked to alternative activation of surrounding stromal cells including fibroblasts which further promote cancer cell migration [ 21 ].…”

Section: Introductionmentioning

confidence: 99%

Compressive Stimulation Enhances Ovarian Cancer Proliferation, Invasion, Chemoresistance, and Mechanotransduction via CDC42 in a 3D Bioreactor

Novak

Horst

Lin

et al. 2020

Cancers

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This report investigates the role of compressive stress on ovarian cancer in a 3D custom built bioreactor. Cells within the ovarian tumor microenvironment experience a range of compressive stimuli that contribute to mechanotransduction. As the ovarian tumor expands, cells are exposed to chronic load from hydrostatic pressure, displacement of surrounding cells, and growth induced stress. External dynamic stimuli have been correlated with an increase in metastasis, cancer stem cell marker expression, chemoresistance, and proliferation in a variety of cancers. However, how these compressive stimuli contribute to ovarian cancer progression is not fully understood. In this report, high grade serous ovarian cancer cell lines were encapsulated within an ECM mimicking hydrogel comprising of agarose and collagen type I, and stimulated with confined cyclic or static compressive stresses for 24 and 72 h. Compression stimulation resulted in a significant increase in proliferation, invasive morphology, and chemoresistance. Additionally, CDC42 was upregulated in compression stimulated conditions, and was necessary to drive increased proliferation and chemoresistance. Inhibition of CDC42 lead to significant decrease in proliferation, survival, and increased chemosensitivity. In summary, the dynamic in vitro 3D platform developed in this report, is ideal for understanding the influence of compressive stimuli, and can be widely applicable to any epithelial cancers. This work reinforces the critical need to consider compressive stimulation in basic cancer biology and therapeutic developments.

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“…GDF15 may be involved in the proliferation, migration, invasion, and angiogenesis of tumors, with with recent research finding GDF15 promoted EMT and invasion of breast cancers [43], and supported the maintenance of breast cancer stem-like cells [44]. Furthermore, GDF15 promoted the proliferation of cervical cancer cells by interaction with ErB2 to activate PI3K/AKT and MAPK/ERK pathways [28], and enhanced the migration of pancreatic cancer cells via an AKT pathway [29]. Similarly, our study found that increased pAKT levels in MDA-MB-231 co-culture were responsible for tumor cell migration-promoting effects.…”

Section: Visfatin-primed Adscs Promote Tumor Stemness and Emt Throughmentioning

confidence: 86%

“…This reversed the enhancement of migration and invasion of MDA-MB-231 by co-culture ( Figure 3D). Since GDF15 has been reported to activate the AKT pathway [28,29], we examined the expression of phosphor-AKT (pAKT) of MDA-MB-231 and found its induction within two hours after GDF15 treatment ( Figure 3E). We checked the level of pAKT in MDA-MB-231 after co-culture and found it was higher in co-culture with vADSCs than with uADSCs ( Figure 3F).…”

Section: Growth Differentiation Factor 15 (Gdf15) Plays a Crucial Rolmentioning

confidence: 99%

Visfatin Mediates Malignant Behaviors through Adipose-Derived Stem Cells Intermediary in Breast Cancer

Huang

et al. 2019

Cancers

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Adipose-derived stem cells (ADSCs) have been implicated in tumor growth and metastasis in breast cancer. ADSCs exhibit tumor tropism, and are of increasing clinical relevance due to the autologous fat grafting for breast reconstruction. Although we have previously shown that a high level of the adipocytokine visfatin in human breast cancer tissues correlated with tumor progression mediated by cAbl and STAT3, the effects of visfatin in the tumor microenvironment are unclear. To understand how visfatin modulates breast cancer within the tumor-stromal environment, we examined determinants of breast cancer progression using a visfatin-primed ADSCs-tumor co-culture model. ADSCs were isolated from tumor-free adipose tissue adjacent to breast tumors. ADSCs were treated with or without visfatin for 48 h and then collected for co-culture with breast cancer cell line MDA-MB-231 for 72 h in a transwell system. We found that the MDA-MB-231 cells co-cultured with visfatin-treated ADSCs (vADSCs) had higher levels of cell viability, anchorage independent growth, migration, invasion, and tumorsphere formation than that co-cultured with untreated ADSCs (uADSCs). Growth differentiation factor 15 (GDF15) upregulation was found in the co-culture conditioned medium, with GDF15 neutralizing antibody blocking the promoting effect on MDA-MB-231 in co-culture. In addition, a GDF15-induced AKT pathway was found in MDA-MB-231Cancers 2020, 12, 29 2 of 18 and treatment with PI3K/AKT inhibitor also reversed the promoting effect. In an orthotopic xenograft mouse model, MDA-MB-231 co-injected with vADSCs formed a larger tumor mass than with uADSCs. Positive correlations were noted between visfatin, GDF15, and phosphor-AKT expressions in human breast cancer specimens. In conclusion, visfatin activated GDF15-AKT pathway mediated via ADSCs to facilitate breast cancer progression.

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Solid stress-induced migration is mediated by GDF15 through Akt pathway activation in pancreatic cancer cells

Cited by 64 publications

References 43 publications

The role of histone methylation in the development of digestive cancers: a potential direction for cancer management

The role of histone methylation in the development of digestive cancers: a potential direction for cancer management

Compressive Stimulation Enhances Ovarian Cancer Proliferation, Invasion, Chemoresistance, and Mechanotransduction via CDC42 in a 3D Bioreactor

Visfatin Mediates Malignant Behaviors through Adipose-Derived Stem Cells Intermediary in Breast Cancer

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