Autophagy as a mechanism for anti-angiogenic therapy resistance

Abstract

Autophagy is a lysosomal-dependent degradation process that is highly conserved and maintains cellular homeostasis by sequestering cytosolic material for degradation either non-specifically by non-selective autophagy, or targeting specific proteins aggregates by selective autophagy. Autophagy serves as a protective mechanism defending the cell from stressors and also plays an important role in enabling tumor cells to overcome harsh conditions arising in their microenvironment during growth as well as oxidative and non-oxidative injuries secondary to therapeutic stressors. Recently, autophagy has been implicated to cause tumor resistance to anti-angiogenic therapy, joining an existing literature implicating autophagy in cancer resistance to conventional DNA damaging chemotherapy and ionizing radiation. In this review, we discuss the role of angiogenesis in malignancy, mechanisms of resistance to anti-angiogenic therapy in general, the role of autophagy in driving malignancy, and the current literature in autophagy-mediated anti-angiogenic therapy resistance. Finally, we provide future insight into the current challenges of using autophagy inhibitors in the clinic and provides tips for future studies to focus on to effectively target autophagy in overcoming resistance to anti-angiogenic therapy.

Keywords: Angiogenesis; Anti-angiogenesis; Autophagy; Cancer; Drug resistance; VEGF.

Fig. 1.. Adaptive mechanisms of evasion to anti-angiogenic therapy in cancer.

While some cancers may be intrinsically resistance to anti-angiogenic therapy, other tumors that are initially responsive may acquire adaptive resistance to anti-angiogenic therapy. These established mechanisms of resistance are as follows. Mechanism 1: Activation of other pro-angiogenic factors like basic fibroblast growth factor (bFGF), ephrins, placental growth factor (PlGF), angiopoietins, or interleukin 8 (IL-8) resulting in tumor vessels to replenish (from brown to red). Mechanism 2: Recruitment of bone marrow-derived progenitor cells for vasculogenesis. This is mediated by secreted factors such as interleukin 6 (IL-6) and stromal derived factor-1α (SDF-1α) which recruit bone marrow-derived endothelial progenitor cells (EPCs) into the tumor for vasculogenesis and replenishing vessels (brown to red). Mechanism 3: Increased pericyte coverage, driven by platelet derived growth factor (PDGF), which also nurtures depleted (brown) vessels. Mechanism 4: Hypoxia-induced autophagy, mediated by Hypoxia Induced Factor-1α and BNIP3, which helps tumor cells thrive in a hypoxic environment. Mechanism 5: Increased invasiveness of the tumor, mediated by matrix metalloproteinases (MMPs) and hepatocyte growth factor (HGF), which helps tumor cells invade despite depleted (brown) vessels and survive.

Fig. 2.. Mechanisms underlying autophagy-mediated resistance to anti-angiogenic therapy.

Hypoxia results in anti-angiogenic therapy resistance by either selective autophagy (green), that is mediated by p62/NBR1, which sequesters targeted protein aggregates for autophagy, or by (B) non-selective autophagy (pink), which is mediated by two mechanisms (i) First is driven by HIF-1α that activates downstream mediators such as BNIP3. This mediator interacts with Beclin-1 and activates downstream autophagy pathways. Alternatively, hypoxia-induced mitochondrial stress can lead to autophagy activation. (ii) Second, starvation and cellular stress can modulate the Akt/mTOR pathway that can subsequently activate the autophagy pathway as an adaptive mechanism. Additionally, hypoxia can directly activate AMPK that interacts with the Akt/mTOR pathway and leads to activation of autophagy.