FVII, factor VII; FX, factor X; FXa, factor X activated; TF, tissue factor; PAR1, protease-activated receptor 1; TRPC, transient receptor potential canonical; PLC, phospholipase C; PKC, protein kinase C; CaMKKB, calcium/calmodulin-dependent protein kinase kinase B; AMPK, AMP-activated protein kinase; mTORC1, mammalian target of rapamycin complex 1; VE-cadherin, vascular endothelial cadherin; vWF, von Willebrand factor; WBP, Weibel-Palade bodies; Sirt1, sirtuin 1; FoxO1, forkhead box protein O1; ox-LDL, oxidized low-density lipoprotein. Poor vascular integrity contributes to the TME. in cancer treatment. In this review, we aim to bring to light possible new areas of cancer investigation and elucidate strategies for future therapeutic intervention. fusion with endosomes and subsequently with lysosomes to form a degradative autolysosome (64, 65). Maturation and autophagosome-lysosome fusion requires several proteins including Rab GTPases, membrane-tethering complexes and soluble N-ethylmaleimide-sensitive factor attachment protein receptors (SNAREs) (66C68). Finally, the lysosomal hydrolases degrade the autophagic cargo, and the resulting metabolites get recycled and returned to the cytosol through autolysosome efflux transporters, and thus cellular homeostasis is maintained (34, 69, 70). Autophagy is usually highly regulated by different signaling pathways implicated in cancer (36, 71, 72). Nutrient starvation is the best-characterized autophagy inductor, where the serine/threonine protein kinase mTOR plays a critical role as an energy sensor (73). Within the human cell, mTOR can be found in at least two distinct multiprotein complexes, referred to as mTOR complex 1 (mTORC1) and mTOR complex 2 (mTORC2) (74). The mTORC1 complex is considered the primary negative regulator of autophagy (75, 76). Under nutrient-rich conditions, class I PI3K and AKT/PKB activate mTORC1 complex ALK which by phosphorylating ULK1 and ATG13, prevents the induction of autophagy as shown in Figure 2 (77C80). A sensor of available energy is the AMP-activated protein kinase (AMPK), which is directly activated by a low ATP:ADP ratio (81, 82). Under starving, AMPK directly phosphorylates and inactivates mTORC1 (83). Through AMPK regulation, the inhibition of mTORC1 and the activation of the ULK complex can initiate the autophagy process ( Figure 2 ) (46, 77). Numerous factors that regulate autophagy are also classified as either oncoproteins or products of tumor suppressor genes [reviewed in (36, 71, 84)]. Thus, autophagy-signaling pathways are caught up in cancer regulation and control ( Figure 2 ). Oncoproteins, including the small GTPase RAS, RHEB, and Nuclear Factor-B (NF-B), can activate mTORC1 and in consequence inhibit autophagy (85). NF-B activates autophagy by inducing the expression of proteins involved in autophagosome formation, including BECN1, ATG5, and LC3. Conversely, NF-B can also inhibit the autophagic process by increasing the expression of autophagy repressors, such like B cell lymphoma 2 (Bcl-2) family members (86). The anti-apoptotic members of the B Cell Lymphoma 2 (Bcl-2)-family bind and sequester BECN1 to prevent autophagy induction (87). On the contrary, tumor suppressors such as the transcription factor Forkhead box O1 (FOXO1) and nuclear p53 are known to induce autophagy (88). Interestingly, ROS production, a hallmark of cancer, and the subsequent activation of the oncogene c-Jun N-terminal kinase1 (JNK1) (89) can lead to the phosphorylation of Bcl-2; this prevents the interaction of this latter protein with BECN1 and thereby induces autophagy (88). Pharmacological agents are frequently used to either enhance or suppress autophagy ( Figure 2 ) (90). A frequent used approach for autophagy induction is mTOR inhibition by rapamycin (91). Conversely, 3-methyladenine (3-MA) can suppress the nucleation stage by inhibiting the PI3K complex, thereby inhibiting autophagosome formation (92). Autophagy can be blocked at later stages resulting in the inhibition of autophagic flux. This refers to the entire process from autophagosome synthesis to lysosomal degradation (93). Bafilomycin A1 (BafA1) is a potent V-ATPase inhibitor that impairs lysosomal acidification and thus the degradation of autophagic cargo (94). By a similar approach, chloroquine (CQ) BKI-1369 can inhibit autophagy by increasing the lysosomal pH and therefore reducing the activity of degradative enzymes (95). Accordingly, BafA1 and CQ are commonly used to decrease the autophagic flux. Although canonically characterized as a degradation mechanism, recent evidence has demonstrated a role for the autophagic machinery in extracellular secretion, a process termed as secretory autophagy or more linguistically precise ATG gene-dependent secretion (96C98). Accordingly, canonical autophagy involves the fusion of the autophagosomes with lysosomes for cargo BKI-1369 degradation, whereas the secretory pathway bypasses this degradative process to allow unconventional extracellular delivery of cytosolic proteins LC3-positive vesicles ( Figure 2 ) (99, 100). Even though the molecular pathways in secretory autophagy are not entirely deciphered, the molecular machinery of the degradative processes is required (99). ATG5 and BKI-1369 BCN1, together with other factors participating in canonical autophagy, are also activated as part of the secretory pathway (98, 101). The secretory autophagy pathway plays a key role in the progression of several diseases, including cancer (102, 103)..