Metformin Reduces Desmoplasia in Pancreatic Cancer by Reprogramming Stellate Cells and Tumor-Associated Macrophages

Incio, João; Suboj, Priya; Chin, Shan M.; Trupti, Vardam-Kaur; Liu, Hao; Hato, Tai; Babykutty, Suboj; Chen, Ivy; Deshpande, Vikram; Jain, Rakesh K.; Fukumura, Dai

doi:10.1371/journal.pone.0141392

Cited by 121 publications

(104 citation statements)

References 94 publications

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“…Incio and colleagues report that activating AMPK signaling pathways with metformin is able to reduce the M2 markers Arg1 and IL-10 in TAMs isolated from orthotopic models of mouse PDAC. 44 This is associated with an alleviation of desmoplasia at the tumor site, and reduction of both EMT and systemic metastasis. 44 These results point toward possible AMPK signaling in Panc1 and MiaPaCa2-TAMs.…”

Section: Discussionmentioning

confidence: 99%

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Warburg metabolism in tumor-conditioned macrophages promotes metastasis in human pancreatic ductal adenocarcinoma

et al. 2016

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Patients with pancreatic ductal adenocarcinoma (PDAC) face a clinically intractable disease with poor survival rates, attributed to exceptionally high levels of metastasis. Epithelial-to-mesenchymal transition (EMT) is pronounced at inflammatory foci within the tumor; however, the immunological mechanisms promoting tumor dissemination remain unclear. It is well established that tumors exhibit the Warburg effect, a preferential use of glycolysis for energy production, even in the presence of oxygen, to support rapid growth. We hypothesized that the metabolic pathways utilized by tumor-infiltrating macrophages are altered in PDAC, conferring a pro-metastatic phenotype. We generated tumor-conditioned macrophages in vitro, in which human peripheral blood monocytes were cultured with conditioned media generated from normal pancreatic or PDAC cell lines to obtain steady-state and tumor-associated macrophages (TAMs), respectively. Compared with steady-state macrophages, TAMs promoted vascular network formation, augmented extravasation of tumor cells out of blood vessels, and induced higher levels of EMT. TAMs exhibited a pronounced glycolytic signature in a metabolic flux assay, corresponding with elevated glycolytic gene transcript levels. Inhibiting glycolysis in TAMs with a competitive inhibitor to Hexokinase II (HK2), 2-deoxyglucose (2DG), was sufficient to disrupt this pro-metastatic phenotype, reversing the observed increases in TAM-supported angiogenesis, extravasation, and EMT. Our results indicate a key role for metabolic reprogramming of tumor-infiltrating macrophages in PDAC metastasis, and highlight the therapeutic potential of using pharmacologics to modulate these metabolic pathways.

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Section: Discussionmentioning

confidence: 99%

“…44 This is associated with an alleviation of desmoplasia at the tumor site, and reduction of both EMT and systemic metastasis. 44 These results point toward possible AMPK signaling in Panc1 and MiaPaCa2-TAMs. However, detailed exploration into the signaling pathways involved in these TAMs is beyond the scope of this study.…”

Section: Discussionmentioning

confidence: 99%

Warburg metabolism in tumor-conditioned macrophages promotes metastasis in human pancreatic ductal adenocarcinoma

et al. 2016

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“…10,11 The effect of metformin is hypothesized to be the result of decreased insulin-like growth factor signaling as well as the halting of desmoplastic cell growth and division. 12 Specifically, metformin targets the AMP-activated protein kinase/mechanistic target of rapamycin (AMPK/mTOR) pathway and induces cell cycle arrest, preventing tumor progression. 13 While previous studies have suggested that metformin use in patients with neoplastic disease may lead to a longer overall survival and a lower risk of death, data on patients with pancreatic cancer have been limited.…”

Section: Introductionmentioning

confidence: 99%

Metformin Use Is Associated with Improved Survival in Patients Undergoing Resection for Pancreatic Cancer

Cerullo

Gani

Chen

et al. 2016

Journal of Gastrointestinal Surgery

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Preclinical evidence has demonstrated anti-tumorigenic effects of metformin. The effects of metformin following pancreatic cancer, however, remain undefined. We sought to assess the association between metformin use and survival using a large, nationally representative sample of patients undergoing surgery for pancreatic cancer. Patients undergoing a pancreatic resection between January 01, 2010, and December 31, 2012, were identified using the Truven Health MarketScan database. Clinical data, including history of metformin use, as well as operative details and information on long-term outcomes were collected. Multivariable Cox proportional hazards regression analysis was performed to assess the effect of metformin use on overall survival (OS). A total of 3393 patients were identified. The mean age of patients was 54.2 years (SD = 9.1 years). Roughly one half of patients were female (n = 1735, 51.1 %); 49.1 % (n = 1665) presented with a Charlson comorbidity index of 3 or greater (CCI ≥3); and 19.6 % (n = 664) had diabetes. At the time of surgery, 60.0 % (n = 2034) of patients underwent a pancreaticoduodenectomy, 35.7 % (n = 1212) a partial/distal pancreatectomy, while 4.3 % (n = 147) had a total pancreatectomy. On pathology, 1057 (31.2 %) had lymph node metastasis. Metformin use was identified in 456 patients (13.4 %) and was more commonly administered among patients without locally advanced disease (14.3 vs. 11.6 %, p = 0.038). While OS was comparable between patients within the first year of surgery (OS at 1 year 65.4 % [95 % confidence interval (CI) 63.4-67.3 %] vs. 69.2 % [95 % CI 64.2-73.4 %]), patients who received metformin demonstrated an improved OS beginning at 18 months following surgery. On multivariable analysis adjusting for patient and clinicopathologic characteristics, metformin use was independently associated with a decreased risk of mortality (hazard ratio [HR] = 0.79, 95 % CI 0.67-0.93, p = 0.005). Metformin use was associated with an improved overall survival among patients undergoing pancreatic surgery for pancreatic cancer. Further work is necessary to better understand its role in modifying cancer-specific and overall health outcomes.

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“…Joao Incio t al. e [13] found that metformin alleviated the fibro-inflammatory microenvironment in obese/diabetic individuals with PC by reprogramming PSCs. Wanxing Duan et al [17] found that metformin induction of AMPK activation represented a novel therapeutic approach for treating advanced PC through desmoplasia suppression.…”

Section: Discussionmentioning

confidence: 99%

“…Metformin could also inhibit hepatocellular carcinoma angiogenesis by targeting HSCs through the AMPK pathway [12]. However, the influence of metformin on PSCs is not well known [13].…”

Section: Introductionmentioning

confidence: 99%

OCT1-Mediated Metformin Uptake Regulates Pancreatic Stellate Cell Activity

Wu¹,

Qiu²,

Zhu³

et al. 2018

Cell Physiol Biochem

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Background/Aims: Metformin treatment is reported to be associated with a lower incidence of and mortality from pancreatic cancer (PC) in type 2 diabetes patients. Activated pancreatic stellate cells (PSCs) are key stroma cells responsible for pancreatic fibrogenesis and PC progression. However, little research is about the influence of metformin on PSCs. Given the potential beneficial effects of metformin on PC, pancreatic tumour stroma is an important target for new therapeutics. We observed the effects of metformin on PSCs. We investigated the effects of metformin on human PSCs proliferation and the production of extracellular matrix (ECM) proteins. Methods: Cells were cultured with different concentrations of metformin (0-10 mmol/L). Cell proliferation was determined by immunofluorescence staining for nuclear Ki67 labelling. ECM production was studied by quantitative real-time polymerase chain reaction, immunoblotting and immunofluorescence microscopy. Adenosine monophosphate–activated protein kinase (AMPK), an important regulatory molecule responsible for metformin action, and the organic cation transporter member 1 (OCT1), which is believed to be the most important transporter for the pharmacological action of metformin, were investigated for their possible involvements in metformin-induced proliferation and ECM production. Results: Our results showed that metformin inhibited PSCs proliferation and decreased the production of ECM proteins by activation of AMPK phosphorylation. Silencing of OCT1 expression resulted in a reduction in the effects of metformin on PSCs activity. Conclusions: Collectively, the data indicate that OCT1 may contribute to uptake metformin and regulate PSCs activity. OCT1 is a target of metformin in regulating PSCs activity.

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Metformin Reduces Desmoplasia in Pancreatic Cancer by Reprogramming Stellate Cells and Tumor-Associated Macrophages

Cited by 121 publications

References 94 publications

Warburg metabolism in tumor-conditioned macrophages promotes metastasis in human pancreatic ductal adenocarcinoma

Warburg metabolism in tumor-conditioned macrophages promotes metastasis in human pancreatic ductal adenocarcinoma

Metformin Use Is Associated with Improved Survival in Patients Undergoing Resection for Pancreatic Cancer

OCT1-Mediated Metformin Uptake Regulates Pancreatic Stellate Cell Activity

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