Page 51 - Read Online
P. 51

Page 2 of 10                            Chien et al. J Cancer Metastasis Treat 2019;5:66  I  http://dx.doi.org/10.20517/2394-4722.2019.016

               INTRODUCTION
                                                                                           [1]
               The term autophagy is derived from Greek words, “auto” and “phagy”, meaning self-eating , representing a
               process of degradation and clearance that is activated in response to aggregated protein and dysfunctional
                                                      [2]
               organelles to maintain cellular homeostasis . The autophagy pathway is initiated by a series of active
                                                                                               [3]
               proteins, such as autophagy-related (ATG) proteins, UVRAG, Beclin 1, PIK3C3, LC3 and p62 . Together,
               they contribute to the formation of double-membrane autophagosomes, and eventually, fusion with
               lysosomes for degradation of inner substances [Figure 1]. Hence, autophagy has been implicated in several
                                                                                             [5]
                                     [4]
               diseases including cancer . In the past, autophagy was believed to be related to apoptosis . Recently, an
                                                                                       [6]
               opposite impact of autophagy, i.e., promoting cell survival, has been widely studied . This “double-edged
               sword” effect in tumorigenesis varies depending on the cellular reaction to specific stimulation as well as
               in different cancer types. High levels of autophagy in the tumor environment (with limited nutrient and
                                                                                        [7]
               oxygen conditions) allow cancer cells to survive, resuming proliferation and initiation .

               Glioblastoma (GBM) is a disease composed of extremely varied tumor microenvironments and
               heterogeneous cancer cells. It is a fatal disease known to have a poor prognosis, and is not considered
               curable. Despite advanced treatment strategies, a notable improvement was not observed in terms of the
               outcome. Hence, it is not surprising that the tumor cells in the apex of the hierarchy, or those that are
               capable of self-renewal and differentiation, display highly-activated autophagy signaling to survive and
                                                                        [8]
               thrive from the given treatment, such as temozolomide (TMZ) . Moreover, the molecular characters
               of GBM involved in the growth and survival via intracellular pathways are distinct genetic aberrations
                                                                                  [9]
               in epidermal growth factor receptor (EGFR), PTEN, TP53, IDH1 and so on . Among these frequently
               reported genes in clinical disease, EGFR is well-known as a driving receptor tyrosine kinase (RTK) in
                                                          [10]
               GBM that dictates multiple oncogenic signaling . The signaling amplification of EGFR accounts for
               approximately 60% of GBM cases. The mutant form EGFRvIII receptor, which is constitutively active
               that is independent of the ligand binding condition, is also common. In association with EGFR signaling
               pathway, it was found that levels of MDA-9, a protein related to tumor cell behavior and stemness, were
               increased in glioma stem-like cells to regulate the protective autophagy [11]  [Figure 1]. Moreover, it was
               found that STAT3 levels were related to beclin 1 expression via EGFR amplification [12,13]  [Figure 1]. Other
                                                                                  [14]
               RTKs in GBM, such as vascular endothelial growth factor receptor (VEGFR) , platelet-derived growth
                                                                        [16]
                                     [15]
               factor receptor (PDGFR) and discoidin domain RTK 1 (DDR1) , also contributes to modulating the
                                                                  [18]
               autophagy formation through AKT/mTOR [16,17] , RAF/MEK  and HIF-1/BCL2 Interacting Protein 3 [19-21]
                                                                                                    [14]
               signalings [Figure 1]. As thus, therapeutic agents targeting these factors, for example bevacizumab  and
                                        [15]
               PDGF neutralizing antibody , has been reported to enhance autophagy signaling [Figure 1]. Despite
               of the implications by disease- or treatment-related autophagic alterations, clinical trials with autophagy
                                                                                     [22]
               inhibitors, such as chloroquine (CQ) or its analogs, showed only limiting benefits . So far, the exact role
                                                                                      [23]
               of autophagy in GBM remains ambiguous, especially regarding treatment resistance .

               The effect of autophagy on tumors is not universal. On one hand, autophagy protects cells by clearing
               damaged organelles, thereby promoting cell survival. On the other hand, it achieves damage control by
               eliciting self-eating, leading to the process of autophagic cell death. The pros and cons of this biologic
               reaction does not have a clear boundary and may be dynamic. Regarding drug treatment, the appearance of
               autophagy also had divergent effect. For example, in a study of PI3K/mTOR inhibitor BGT226, application
                                                                                [24]
               of the drug led to autophagic cell death in head and neck cancer cell lines . In contrast, application of
                                                                                                       [25]
               PI3K/AKT/mTOR inhibitors sensitized cells to radiotherapy as well as reduced autophagy formation .
               Various effects of autophagy in the cancer treatment have been demonstrated, making the reaction
               complicated in each circumstance. However, in the case of GBM, the appearance of autophagy during
                                                                         [26]
               specific treatment seems to support the development of resistance . In this article, we will discuss the
               molecular significance of autophagy in the current treatment of GBM. We will also discuss the formation of
               the reaction and the potential benefit of inhibiting autophagy along with the treatment.
   46   47   48   49   50   51   52   53   54   55   56