Microenvironmental autophagy promotes tumour growth

Katheder, Nadja Sandra; Khezri, Rojyar; O’Farrell, Fergal; Schultz, Sebastian W.; Jain, Ashish; Rahman, Mohammed Mahidur; Schink, Kay Oliver; Theodossiou, Theodossis A.; Johansen, Terje; Juhász, Gábor; Bilder, David; Brech, Andreas; Stenmark, Harald; Rusten, Tor Erik

doi:10.1038/nature20815

Cited by 397 publications

(375 citation statements)

References 31 publications

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“…We identified IL-6, IL-8, and bFGF, known HNSCC secreted factors, are all at least in part responsible for CAF autophagy. This corroborates recent findings in a Drosophila tumor model that IL-6 secretion from the tumor promotes stromal autophagy (42). We demonstrate HNSCC secreted bFGF activates STAT3, induces the transcription of SOX2, which inhibits mTOR transcription (34).…”

Section: Discussionsupporting

confidence: 92%

“…In this study, we observe that primary patient-derived CAFs sustain an increased level of basal autophagy as compared to NFs from cancer-free patients. This is the first observation of enhanced fibroblast autophagy from primary CAFs-derived from patient stroma, and corroborates recent observations of breast cancer cells inducing autophagy in skin fibroblasts, and a Drosophila melanogaster tumor model where microenvironmental autophagy was observed (41,42). …”

Section: Discussionsupporting

confidence: 89%

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Secretory Autophagy in Cancer-Associated Fibroblasts Promotes Head and Neck Cancer Progression and Offers a Novel Therapeutic Target

et al. 2017

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Despite therapeutic advancements, there has been little change in the survival of patients with head and neck squamous cell carcinoma (HNSCC). Recent results suggest that cancer-associated fibroblasts (CAF) drive progression of this disease. Here, we report that autophagy is upregulated in HNSCC-associated CAFs where it is responsible for key pathogenic contributions in this disease. Autophagy is fundamentally involved in cell degradation, but there is emerging evidence that suggests it is also important for cellular secretion. Thus, we hypothesized that autophagy-dependent secretion of tumor-promoting factors by HNSCC-associated CAFs may explain their role in malignant development. In support of this hypothesis, we observed a reduction in CAF-facilitated HNSCC progression after blocking CAF autophagy. Studies of cell growth media conditioned after autophagy blockade revealed levels of secreted IL-6, IL-8 and other cytokines were modulated by autophagy. Notably, when HNSCC cells were co-cultured with normal fibroblasts they upregulated autophagy through IL-6, IL-8 and bFGF. In a mouse xenograft model of HNSCC, pharmacological inhibition of Vps34, a key mediator of autophagy, enhanced the antitumor efficacy of cisplatin. Our results establish an oncogenic function for secretory autophagy in HNSCC stromal cells that promotes malignant progression.

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Section: Discussionsupporting

confidence: 92%

Section: Discussionsupporting

confidence: 89%

Secretory Autophagy in Cancer-Associated Fibroblasts Promotes Head and Neck Cancer Progression and Offers a Novel Therapeutic Target

et al. 2017

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“…Autophagy is considered to play a dual role in the process of tumor formation. A lack of autophagy genes would destroy the environmental balance and may lead to the occurrence of tumors; furthermore, autophagy can promote tumor cells resistance to stress, meaning improved survival of cancer cells (19). It is thought that autophagy is a type of anti-tumor mechanism (20).…”

Section: Discussionmentioning

confidence: 99%

Expression of autophagy-associated proteins in papillary thyroid carcinoma

Yang

Bai

Yu³

et al. 2017

Oncology Letters

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Abstract. The present study was designed to assess the protein expression of the autophagy-associated genes, Beclin-1 and microtubule-associated protein 1 light chain 3 (LC3)-II, as well as the association with clinicopathological features in papillary thyroid carcinoma (PTC). A total of 50 subjects were recruited, including 50 human PTC samples and paired adjacent noncancerous tissue samples. The protein expression of Beclin-1 and LC3-II was analyzed using immunohistochemistry and western blotting. Beclin-1 and LC3-II expression in PTC tissues significantly reduced compared with normal tissues (P<0.05). Expression of Beclin-1 and LC3-II was associated with lymph node metastasis of PTC (P<0.05), but had no association with age, gender, tumor size, tumor number and Tumor-Node-Metastasis stage (P>0.05). Expression of Beclin-1 and LC3-II were positively correlated (r=0.327;P=0.020) in PTC. In conclusion, the activity of autophagy was declined in PTC; this decrease in autophagic capacity may be associated with tumorigenesis and the development of PTC.

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“…It is a catabolic process that provides nutrients during starvation [8]. Katheder et al reported that the microenvironmental contributes to early tumor growth through nutrient-generating autophagy [9]. Autophagy preserves cardiac structure and function under baseline conditions and is activated during stress, limiting damage under most conditions.…”

Section: Introductionmentioning

confidence: 99%

Pim1 Overexpression Prevents Apoptosis in Cardiomyocytes After Exposure to Hypoxia and Oxidative Stress via Upregulating Cell Autophagy

Zhu¹,

Wang²,

Sun³

et al. 2018

Cell Physiol Biochem

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Background/Aims: Microvascular obstruction (MVO), an undesirable complication of percutaneous coronary intervention, is independently associated with adverse left ventricle remodeling and poor prognosis after acute myocardial infarction. Hypoxia and oxidative stress major roles in the pathophysiology of MVO. Pim1 serves an important protective role in the ischemic myocardium, but the underlying mechanisms remain poorly defined. Autophagy in early hypoxia or during moderate oxidative stress has been demonstrated to protect the myocardium. In this study, we investigated the association between the protective effect of Pim1 and autophagy after hypoxia and oxidative stress. Methods: Ventricular myocytes from neonatal rat heart (NRVMs) were isolated. NRVMs were exposed to hypoxia and H₂O₂. Rapamycin and 3-methyladenine (3-MA) were used as an activator and inhibitor of autophagy, respectively. pHBAd-Pim1 was transfected into NRVMs. We assessed cardiomyocyte apoptosis by Annexin V-FITC/PI flow cytometry. Autophagy was evaluated by mRFP-GFP-LC3 adenovirus infection by confocal microscopy. Western blotting was used to quantify apoptosis or autophagy protein (caspase-3, LC3, P62, AMPK, mTOR, ATG5) concentrations. Results: Autophagy and apoptosis in NRVMs significantly increased and peaked at 3 h and 6 h, respectively, after exposure to hypoxia and H₂O₂. The mTOR inhibitor rapamycin induced autophagy and decreased cardiomyocyte apoptosis, but the autophagy inhibitor 3-MA decreased autophagy and increased apoptosis at 3 h after exposure to hypoxia and H₂O₂. Pim1 levels in NRVMs increased at 3 h and decreased gradually after exposure to hypoxia and H₂O₂. Pim1 overexpression enhanced autophagy and decreased apoptosis. Pim1-induced promotion of autophagy is partly the result of activation of the AMPK/mTOR/ATG5 pathway after exposure to hypoxia and H₂O₂. Conclusion: Our results revealed that Pim1 overexpression prevented NRVMs from apoptosis via upregulating autophagy after exposure to hypoxia and oxidative stress, partly through activation of the AMPK/mTOR/ATG5 autophagy pathway.

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Microenvironmental autophagy promotes tumour growth

Cited by 397 publications

References 31 publications

Secretory Autophagy in Cancer-Associated Fibroblasts Promotes Head and Neck Cancer Progression and Offers a Novel Therapeutic Target

Secretory Autophagy in Cancer-Associated Fibroblasts Promotes Head and Neck Cancer Progression and Offers a Novel Therapeutic Target

Expression of autophagy-associated proteins in papillary thyroid carcinoma

Pim1 Overexpression Prevents Apoptosis in Cardiomyocytes After Exposure to Hypoxia and Oxidative Stress via Upregulating Cell Autophagy

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