Autophagy Is Required for Activation of Pancreatic Stellate Cells, Associated With Pancreatic Cancer Progression and Promotes Growth of Pancreatic Tumors in Mice

Endo, Shunsuke; Nakata, Kohei; Ohuchida, Kenoki; Takesue, Shin; Nakayama, Hiromichi; Abe, Toshiya; Koikawa, Kazuhiro; Okumura, Takashi; Sada, Masafumi; Horioka, Kohei; Zheng, Biao; Mizuuchi, Yusuke; Iwamoto, Chika; Murata, Masaru; Moriyama, Taiki; Miyasaka, Yoshihiro; Ohtsuka, Takao; Mizumoto, Kazuhiro; Oda, Yoshinao; Hashizume, Makoto; Nakamura, Masafumi

doi:10.1053/j.gastro.2017.01.010

Cited by 187 publications

(171 citation statements)

References 53 publications

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“…Thus, this work demonstrates an autophagy-dependent metabolic crosstalk between pancreatic cancer and stellate cells that supports pancreatic cancer metabolism and promotes tumor growth. In line with this work, Endo et al have recently shown that autophagy inhibition in pancreatic stellate cells decreases tumor growth in transplantation models (Endo et al, 2017). While this work did not focus on the metabolic cross-talk and focused on the role of autophagy in stellate cell activation, it confirms the importance of both stromal and tumor cell autophagy in pancreatic cancer growth.…”

Section: Autophagy and Cancer Metabolismsupporting

confidence: 64%

“…While the aforementioned studies have focused predominantly on the direct contribution of autophagy to the metabolism in the tumor cell itself, several studies have also shown a critical impact of autophagy on tumor growth in a cell non-autonomous manner and in many cases this is related to effects on both tumor cell and host metabolism (Endo et al, 2017; Karsli-Uzunbas et al, 2014; Katheder et al, 2017; Sousa et al, 2016). Using a tamoxifen inducible cre recombinase, Atg7 was systemically deleted in the whole body of adult mice (Karsli-Uzunbas et al, 2014).…”

Section: Autophagy and Cancer Metabolismmentioning

confidence: 99%

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Autophagy and Tumor Metabolism

2017

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Autophagy is a critical cellular process that generally protects cells and organisms from stressors such as nutrient deprivation. In addition to its role in normal physiology, autophagy plays a role in pathological processes such as cancer. Indeed, there has been substantial work exploring the complex and context-dependent role of autophagy in cancer. One of the emerging themes is that in certain cancer types, autophagy is important to support tumor growth and therefore inhibiting autophagy as a therapeutic approach is actively being tested in clinical trials. A key mechanism of how autophagy promotes the growth and survival of various cancers is its ability to support cellular metabolism. The diverse metabolic fuel sources that can be produced by autophagy provides tumors with metabolic plasticity and can allow them to thrive in what can be an austere microenvironment. Therefore, understanding how autophagy can fuel cellular metabolism will enable more effective combinatorial therapeutic strategies.

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Section: Autophagy and Cancer Metabolismsupporting

confidence: 64%

Section: Autophagy and Cancer Metabolismmentioning

confidence: 99%

Autophagy and Tumor Metabolism

2017

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“…Preclinical studies have now started to emerge showing that this is possible and that targeted therapeutic strategies directed towards specific components of the stroma or pathways of CAFs can be fruitful 79–83. Furthermore, tumour cell metabolism can also be driven by PSCs,84 and autophagy is required for the activation of PSCs, tumour progression and growth 83. Importantly, CAFs can be therapeutically targeted to enhance the response to standard chemotherapy.…”

Section: Introductionmentioning

confidence: 99%

Stromal biology and therapy in pancreatic cancer: ready for clinical translation?

Neeße

Bauer

Öhlund

et al. 2018

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265

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Pancreatic ductal adenocarcinoma (PDA) is notoriously aggressive and hard to treat. The tumour microenvironment (TME) in PDA is highly dynamic and has been found to promote tumour progression, metastasis niche formation and therapeutic resistance. Intensive research of recent years has revealed an incredible heterogeneity and complexity of the different components of the TME, including cancer-associated fibroblasts, immune cells, extracellular matrix components, tumour vessels and nerves. It has been hypothesised that paracrine interactions between neoplastic epithelial cells and TME compartments may result in either tumour-promoting or tumour-restraining consequences. A better preclinical understanding of such complex and dynamic network systems is required to develop more powerful treatment strategies for patients. Scientific activity and the number of compelling findings has virtually exploded during recent years. Here, we provide an update of the most recent findings in this area and discuss their translational and clinical implications for basic scientists and clinicians alike.

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“…PSCs promote the proliferation of cancer cells by secreting kindlin-2 [114]5. Autophagic PSCs produce ECM molecules and IL6 to promote the proliferation and invasion of cancer cells [115]1. PSCs promote the migration of cancer cells via EMT process [116]2.…”

Section: Interactions and Mechanisms Between Stromal Cells And Pancrementioning

confidence: 99%

Chemotherapy and tumor microenvironment of pancreatic cancer

2017

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Pancreatic cancer is an extremely dismal malignance. Chemotherapy has been widely applied to treat this intractable tumor. It has exclusive tumor microenvironment (TME), characterized by dense desmoplasia and profound infiltrations of immunosuppressive cells. Interactions between stromal cells and cancer cells play vital roles to affect the biological behaviors of pancreatic cancer. Targeting the stromal components of pancreatic cancer has shown promising results. In addition to the direct toxic effects of chemotherapeutic drugs on cancer cells, they can also remodel the TME, eventually affecting their efficacy. Herein, we reviewed the following four aspects; (1) clinical landmark advances of chemotherapy in pancreatic cancer, since 2000; (2) interactions and mechanisms between stromal cells and pancreatic cancer cells; (3) remodeling effects and mechanisms of chemotherapy on TME; (4) targeting stromal components in pancreatic cancer.Electronic supplementary materialThe online version of this article (doi:10.1186/s12935-017-0437-3) contains supplementary material, which is available to authorized users.

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Autophagy Is Required for Activation of Pancreatic Stellate Cells, Associated With Pancreatic Cancer Progression and Promotes Growth of Pancreatic Tumors in Mice

Abstract: Autophagic PSCs produce ECM molecules and interleukin 6 and are associated with shorter survival times and disease recurrence in patients with pancreatic cancer. Inhibitors of PSC autophagy might reduce pancreatic tumor invasiveness by altering the tumor stroma.

Cited by 187 publications

References 53 publications

Autophagy and Tumor Metabolism

Autophagy and Tumor Metabolism

Stromal biology and therapy in pancreatic cancer: ready for clinical translation?

Chemotherapy and tumor microenvironment of pancreatic cancer

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