Research

24 pages, 1292 KiB

Open AccessEditor’s ChoiceCommunication

Assessing Autophagy in Archived Tissue or How to Capture Autophagic Flux from a Tissue Snapshot

by Magali Humbert, María Morán, Patricia de la Cruz-Ojeda, Jordi Muntané, Tabea Wiedmer, Nadezda Apostolova, Sharon L. McKenna, Guillermo Velasco, Walter Balduini, Leopold Eckhart, Bassam Janji, Belém Sampaio-Marques, Paula Ludovico, Eva Žerovnik, Rupert Langer, Aurel Perren, Nikolai Engedal and Mario P. Tschan

Biology 2020, 9(3), 59; https://doi.org/10.3390/biology9030059 - 21 Mar 2020

Cited by 11 | Viewed by 5411

Abstract

Autophagy is a highly conserved degradation mechanism that is essential for maintaining cellular homeostasis. In human disease, autophagy pathways are frequently deregulated and there is immense interest in targeting autophagy for therapeutic approaches. Accordingly, there is a need to determine autophagic activity in [...] Read more.

Autophagy is a highly conserved degradation mechanism that is essential for maintaining cellular homeostasis. In human disease, autophagy pathways are frequently deregulated and there is immense interest in targeting autophagy for therapeutic approaches. Accordingly, there is a need to determine autophagic activity in human tissues, an endeavor that is hampered by the fact that autophagy is characterized by the flux of substrates whereas histology informs only about amounts and localization of substrates and regulators at a single timepoint. Despite this challenging task, considerable progress in establishing markers of autophagy has been made in recent years. The importance of establishing clear-cut autophagy markers that can be used for tissue analysis cannot be underestimated. In this review, we attempt to summarize known techniques to quantify autophagy in human tissue and their drawbacks. Furthermore, we provide some recommendations that should be taken into consideration to improve the reliability and the interpretation of autophagy biomarkers in human tissue samples. Full article

(This article belongs to the Special Issue Autophagy in Cancer)

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15 pages, 2412 KiB

Open AccessArticle

Autophagy Inhibition Induces the Secretion of Macrophage Migration Inhibitory Factor (MIF) with Autocrine and Paracrine Effects on the Promotion of Malignancy in Breast Cancer

by Israel Cotzomi-Ortega, Arely Rosas-Cruz, Dalia Ramírez-Ramírez, Julio Reyes-Leyva, Miriam Rodriguez-Sosa, Patricia Aguilar-Alonso and Paola Maycotte

Biology 2020, 9(1), 20; https://doi.org/10.3390/biology9010020 - 18 Jan 2020

Cited by 26 | Viewed by 4426

Abstract

Breast cancer is the main cause of cancer-related death in women in the world. Because autophagy is a known survival pathway for cancer cells, its inhibition is currently being explored in clinical trials for treating several types of malignancies. In breast cancer, autophagy [...] Read more.

Breast cancer is the main cause of cancer-related death in women in the world. Because autophagy is a known survival pathway for cancer cells, its inhibition is currently being explored in clinical trials for treating several types of malignancies. In breast cancer, autophagy has been shown to be necessary for the survival of cancer cells from the triple negative subtype (TNBC), which has the worst prognosis among breast cancers and currently has limited therapeutic options. Autophagy has also been involved in the regulation of protein secretion and, of importance for this work, the inhibition of autophagy is known to promote the secretion of proinflammatory cytokines from distinct cell types. We found that the inhibition of autophagy in TNBC cell lines induced the secretion of the macrophage migration inhibitory factor (MIF), a pro-tumorigenic cytokine involved in breast cancer invasion and immunomodulation. MIF secretion was dependent on an increase in reactive oxygen species (ROS) induced by the inhibition of autophagy. Importantly, MIF secreted from autophagy-deficient cells increased the migration of cells not treated with autophagy inhibitors, indicating that autophagy inhibition in cancer cells promoted malignancy in neighboring cells through the release of secreted factors, and that a combinatorial approach should be evaluated for cancer therapy. Full article

(This article belongs to the Special Issue Autophagy in Cancer)

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14 pages, 3171 KiB

Open AccessArticle

Cytotoxic Potential of the Coelomic Fluid Extracted from the Sea Cucumber Holothuria tubulosa against Triple-Negative MDA-MB231 Breast Cancer Cells

by Claudio Luparello, Debora Ragona, Dalia Maria Lucia Asaro, Valentina Lazzara, Federica Affranchi, Monica Celi, Vincenzo Arizza and Mirella Vazzana

Biology 2019, 8(4), 76; https://doi.org/10.3390/biology8040076 - 09 Oct 2019

Cited by 24 | Viewed by 4430

Abstract

Growing evidence has demonstrated that the extracts of different holothurian species exert beneficial effects on human health. Triple negative breast cancers (TNBC) are highly malignant tumors that present a poor prognosis due to the lack of effective targeted therapies. In the attempt to [...] Read more.

Growing evidence has demonstrated that the extracts of different holothurian species exert beneficial effects on human health. Triple negative breast cancers (TNBC) are highly malignant tumors that present a poor prognosis due to the lack of effective targeted therapies. In the attempt to identify novel compounds that might counteract TNBC cell growth, we studied the effect of the exposure of the TNBC cell line MDA-MB231 to total and filtered aqueous extracts of the coelomic fluid obtained from the sea cucumber Holoturia tubulosa, a widespread species in the Mediterranean Sea. In particular, we examined cell viability and proliferative behaviour, cell cycle distribution, apoptosis, autophagy, and mitochondrial metabolic/cell redox state. The results obtained indicate that both total and fractionated extracts are potent inhibitors of TNBC cell viability and growth, acting through both an impairment of cell cycle progression and mitochondrial transmembrane potential and a stimulation of cellular autophagy, as demonstrated by the increase of the acidic vesicular organelles and of the intracellular protein markers beclin-1, and total LC3 and LC3-II upon early exposure to the preparations. Identification of the water-soluble bioactive component(s) present in the extract merit further investigation aiming to develop novel prevention and/or treatment agents efficacious against highly metastatic breast carcinomas. Full article

(This article belongs to the Special Issue Autophagy in Cancer)

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Review

Jump to: Research, Other

11 pages, 530 KiB

Open AccessReview

The Role of Autophagy in Pancreatic Cancer—Recent Advances

by Maria New and Sharon Tooze

Biology 2020, 9(1), 7; https://doi.org/10.3390/biology9010007 - 28 Dec 2019

Cited by 22 | Viewed by 4608

Abstract

Pancreatic ductal adenocarcinoma (PDAC) remains one of the deadliest cancers with a 5-year survival rate of only 9%, despite ongoing efforts to improve treatment. This dismal prognosis is due to the difficulty of early stage diagnosis, drug resistance, and likelihood of metastasis development. [...] Read more.

Pancreatic ductal adenocarcinoma (PDAC) remains one of the deadliest cancers with a 5-year survival rate of only 9%, despite ongoing efforts to improve treatment. This dismal prognosis is due to the difficulty of early stage diagnosis, drug resistance, and likelihood of metastasis development. It is therefore of great importance to identify appropriate therapeutic targets and gain a greater understanding of PDAC biology. Autophagy is a membrane-mediated degradation and recycling mechanism, which is crucial for cell homeostasis. There is evidence for both a tumor-suppressive and a tumor-promoting role of autophagy in cancer, and this is likely context dependent. Within PDAC, a large body of evidence points towards autophagy being required for tumor survival and metabolism. In this review, we describe the recent advances in the understanding of the role and regulation of autophagy in PDAC. Full article

(This article belongs to the Special Issue Autophagy in Cancer)

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13 pages, 710 KiB

Open AccessReview

The Role of Beclin 1-Dependent Autophagy in Cancer

by Silvia Vega-Rubín-de-Celis

Biology 2020, 9(1), 4; https://doi.org/10.3390/biology9010004 - 22 Dec 2019

Cited by 59 | Viewed by 7310

Abstract

Autophagy (self-eating) is an intracellular degradation process used by cells to keep a “clean house”; as it degrades abnormal or damaged proteins and organelles, it helps to fight infections and also provides energy in times of fasting or exercising. Autophagy also [...] Read more.

Autophagy (self-eating) is an intracellular degradation process used by cells to keep a “clean house”; as it degrades abnormal or damaged proteins and organelles, it helps to fight infections and also provides energy in times of fasting or exercising. Autophagy also plays a role in cancer, although its precise function in each cancer type is still obscure, and whether autophagy plays a protecting (through the clearing of damaged organelles and protein aggregates and preventing DNA damage) or a promoting (by fueling the already stablished tumor) role in cancer remains to be fully characterized. Beclin 1, the mammalian ortholog of yeast Atg6/Vps30, is an essential autophagy protein and has been shown to play a role in tumor suppression. Here, an update of the tumorigenesis regulation by Beclin 1-dependent autophagy is provided. Full article

(This article belongs to the Special Issue Autophagy in Cancer)

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13 pages, 1219 KiB

Open AccessReview

Autophagy in Cancer Cell Death

by Benedikt Linder and Donat Kögel

Biology 2019, 8(4), 82; https://doi.org/10.3390/biology8040082 - 29 Oct 2019

Cited by 75 | Viewed by 10814

Abstract

Autophagy has important functions in maintaining energy metabolism under conditions of starvation and to alleviate stress by removal of damaged and potentially harmful cellular components. Therefore, autophagy represents a pro-survival stress response in the majority of cases. However, the role of autophagy in [...] Read more.

Autophagy has important functions in maintaining energy metabolism under conditions of starvation and to alleviate stress by removal of damaged and potentially harmful cellular components. Therefore, autophagy represents a pro-survival stress response in the majority of cases. However, the role of autophagy in cell survival and cell death decisions is highly dependent on its extent, duration, and on the respective cellular context. An alternative pro-death function of autophagy has been consistently observed in different settings, in particular, in developmental cell death of lower organisms and in drug-induced cancer cell death. This cell death is referred to as autophagic cell death (ACD) or autophagy-dependent cell death (ADCD), a type of cellular demise that may act as a backup cell death program in apoptosis-deficient tumors. This pro-death function of autophagy may be exerted either via non-selective bulk autophagy or excessive (lethal) removal of mitochondria via selective mitophagy, opening new avenues for the therapeutic exploitation of autophagy/mitophagy in cancer treatment. Full article

(This article belongs to the Special Issue Autophagy in Cancer)

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20 pages, 1883 KiB

Open AccessReview

Autophagy and Its Relationship to Epithelial to Mesenchymal Transition: When Autophagy Inhibition for Cancer Therapy Turns Counterproductive

by Guadalupe Rojas-Sanchez, Israel Cotzomi-Ortega, Nidia G. Pazos-Salazar, Julio Reyes-Leyva and Paola Maycotte

Biology 2019, 8(4), 71; https://doi.org/10.3390/biology8040071 - 24 Sep 2019

Cited by 24 | Viewed by 3581

Abstract

The manipulation of autophagy for cancer therapy has gained recent interest in clinical settings. Although inhibition of autophagy is currently being used in clinical trials for the treatment of several malignancies, autophagy has been shown to have diverse implications for normal cell homeostasis, [...] Read more.

The manipulation of autophagy for cancer therapy has gained recent interest in clinical settings. Although inhibition of autophagy is currently being used in clinical trials for the treatment of several malignancies, autophagy has been shown to have diverse implications for normal cell homeostasis, cancer cell survival, and signaling to cells in the tumor microenvironment. Among these implications and of relevance for cancer therapy, the autophagic process is known to be involved in the regulation of protein secretion, in tumor cell immunogenicity, and in the regulation of epithelial-to-mesenchymal transition (EMT), a critical step in the process of cancer cell invasion. In this work, we have reviewed recent evidence linking autophagy to the regulation of EMT in cancer and normal epithelial cells, and have discussed important implications for the manipulation of autophagy during cancer therapy. Full article

(This article belongs to the Special Issue Autophagy in Cancer)

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Other

Jump to: Research, Review

6 pages, 190 KiB

Open AccessOpinion

The Switch between Protective and Nonprotective Autophagy; Implications for Autophagy Inhibition as a Therapeutic Strategy in Cancer

by David A. Gewirtz

Biology 2020, 9(1), 12; https://doi.org/10.3390/biology9010012 - 04 Jan 2020

Cited by 14 | Viewed by 2560

Abstract

Autophagy, a process of cellular self-degradation and cell survival whereby the cell generates energy and metabolic intermediates under conditions of stress (i.e., nutrient deprivation), is also commonly induced in tumor cells in response to chemotherapy and radiation. While chemotherapy-induced autophagy and radiation-induced autophagy [...] Read more.

Autophagy, a process of cellular self-degradation and cell survival whereby the cell generates energy and metabolic intermediates under conditions of stress (i.e., nutrient deprivation), is also commonly induced in tumor cells in response to chemotherapy and radiation. While chemotherapy-induced autophagy and radiation-induced autophagy are generally considered to have cytoprotective functions, thereby reducing tumor cell sensitivity (and potentially conferring resistance) to various treatment modalities, autophagy can also be nonprotective; furthermore, the nature of the autophagy can be altered via the “autophagic switch” depending on such factors as the p53 status of the tumor cells. Defective or compromised autophagy has also been associated with neurodegenerative diseases, raising concerns as to the impact of autophagy inhibition on normal tissue function. Furthermore, the impact of autophagy inhibition on the immune system response to therapy as well as the influence of autophagy inhibition in combination with chemotherapy or radiation on critical tissue sites such as the bone marrow remain uncertain. These are factors requiring serious consideration within the context of current clinical efforts to exploit autophagy inhibition as a therapeutic strategy in cancer. Full article

(This article belongs to the Special Issue Autophagy in Cancer)

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