Introduction The first use of the

Introduction The first use of the term “autophagy” by a French physiologist, M. Anselmier, in a short article describing the effects of fasting in mice published in 1859, took place almost a century before Christian De Duve described it from a mechanistic point of view in a symposium on lysosomes in 1963 (reviewed in Ref. [1]). Currently, a search on PubMed database can retrieve more than 30.000 scientific articles containing the term “autophagy”, witnessing the importance of such biological process in life sciences. The scientific interest in autophagy research lastly culminated in 2016 with the award of Nobel Prize for Medicine and Physiology to Professor Y. Oshumi for the discovery, in the early ‘90, of ATG mibefradil sale (autophagy-related genes), controlling and regulating autophagy in yeasts [2]. From the original Anselmier's farsighted description to the current “autophagy molecular dissection”, scientists learned that autophagy plays a preeminent role in cellular homeostasis of specific tissues (mainly liver, brain, muscles). Its functions regard cell survival regulation (response to metabolic alterations, recycling damaged macromolecules and organelles) and various programmed forms of cell death (type II cell death), different from apoptosis, which occur in physiological (aging) or pathological conditions, or in response to drug and ionizing radiations [3]. The sometimes-paradoxical effects of autophagy in physiology and pathology are examples of its levels of complexity. However, its dual role in sustaining cell survival or inducing cell death is largely observed in cancer, which, per se, represents an extremely complex disease from the molecular and clinical point of view. Among the different forms of autophagy, the present article focuses on “macroautophagy”, a process which involves the formation of “autophagosomes”, dedicated vesicles that occupy large regions of the cytoplasm. Other variants, such are microautophagy and chaperone-mediated autophagy are not associated with major morphological changes in vesicular compartments [4]. Although very interesting and promising, the study of the modulation of the latter autophagy processes in cancer are too preliminary to be analyzed here; however, we predict that in few years the impact of microautophagy and chaperone-mediated autophagy in cancer will significantly grow.
Connecting the dots between autophagy and cancer According to International Agency for Research on Cancer (IARC), by 2030 cancer could be the leading cause of death worldwide with 13 million potential cancer-related deaths [5]. This will lead to a 60% increase from 2014 with a further 21.7 million new cancer cases each year and the largest economic cost on a global scale due to life expectancy and productivity loss, together with cancer-related disabilities. Cancer is expected to surpass cardiovascular disease as the leading cause of death in the world. Despite this warring picture, there has been significant progress in the understanding of cancer biology, identification of risk factors, new treatments and early diagnosis of some types of cancer. Although still insufficient in terms of worldwide cancer prevention and therapy, progresses have been made in reducing cancer mortality [6], [7] and new challenges can arise from pursuing multiple strategies including the revisiting of the anticancer effects of drugs already present in clinics to cure diseases different than cancer. This apparently paradoxical approach finds its rationale considering the existence of complex biological processes, which can support or delay cancer growth and development depending on a significant number of “external” factors including diet, genetic background, predisposition to other chronic and degenerative diseases. One of these cellular processes is autophagy. The metaphoric definition of “double-edged sword” (Fig. 1) is recurrent in many scientific articles and describes the opposite role of autophagy in cancer. These studies are largely based on: 1. genetically engineered mouse models (GEMM); 2. detection of DNA mutations which allowed the classification of different ATG genes, which are directly involved in biochemical regulation of autophagy [8], as both “tumour suppressors” or “oncogenes”. “Macroautophagy”, the process in which cellular contents are degraded by lysosomes or vacuoles and recycled, includes several phases regulated by different ATG genes controlling the complete autophagy pathway. The final destiny is the formation of double-membrane vesicles (phagophore, autophagosome) that finally fuse with lysosomes where acidic hydrolases are able to degrade and recycle their cargo [4], [9], [10]. Until now, 20 “core ATG genes” and highly conserved Atg proteins have been identified in yeast and mammals. The different members of the Atg family members can be classified considering their specific “space-temporal” role in autophagy. Initiation depends upon Atg1/Ulk1 kinase and its regulators, Atg13, Atg17, Atg29, Atg31 [11], [12], [13]. The Atg6/Beclin-1-Atg14/Atg14L-Vps34-Vps15 [14], [15] and Beclin-1-UVRAG-Bif-1-Vps34-Vps15 [16], [17] complexes are required for phagophore formation/expansion; autophagosome maturation is regulated by the Atg12 conjugation system, Atg5, Atg7, Atg10, Atg12, Atg16 [18], [19]. Finally, fusion and degradation in lysosomes and cargo efflux in the cytoplasm is controlled by the Atg8/LC3 conjugation system comprising Atg3, Atg4, Atg7, Atg8; Atg9, and the Atg2-Atg18 complex ([20], [21], [22], [23]; also reviewed in Refs. [4], [24], [25], [26] and figures and schemes therein). From a biochemical point of view, this picture is even more complex since Atg proteins are at the crossroads of important metabolic pathways: amino-acids sensing regulated by mTOR kinase complex (mammalian Target of Rapamycin), ATP intracellular content controlled by AMPK (AMP-activated kinase) [27], [28] (Fig. 2) and stress signalling mechanism by HIF (hypoxia inducing factor) [29]. All these pathways could turn on/off Atg proteins, in order to obtain a “homeostatic effect”. In other terms, autophagy “basal state” in a cell is strictly dependent upon metabolic/energy or environmental stress. In cancer, it is extremely important to assess whether malignant cells depend on autophagy to overcome metabolic and energy stress during carcinogenesis or, on the opposite, autophagy (and autophagy-associated cell death) is an essential process to block carcinogenesis. Recently, the neologism “oncophagy” has coined to describe the role of autophagy in cancer, referring to the close connection between cancer biology/therapy and autophagy [30] (Fig. 2).