The multifaceted role of autophagy in cancer and the microenvironment

Abstract

Autophagy is a crucial recycling process that is increasingly being recognized as an important factor in cancer initiation, cancer (stem) cell maintenance as well as the development of resistance to cancer therapy in both solid and hematological malignancies. Furthermore, it is being recognized that autophagy also plays a crucial and sometimes opposing role in the complex cancer microenvironment. For instance, autophagy in stromal cells such as fibroblasts contributes to tumorigenesis by generating and supplying nutrients to cancerous cells. Reversely, autophagy in immune cells appears to contribute to tumor‐localized immune responses and among others regulates antigen presentation to and by immune cells. Autophagy also directly regulates T and natural killer cell activity and is required for mounting T‐cell memory responses. Thus, within the tumor microenvironment autophagy has a multifaceted role that, depending on the context, may help drive tumorigenesis or may help to support anticancer immune responses. This multifaceted role should be taken into account when designing autophagy‐based cancer therapeutics. In this review, we provide an overview of the diverse facets of autophagy in cancer cells and nonmalignant cells in the cancer microenvironment. Second, we will attempt to integrate and provide a unified view of how these various aspects can be therapeutically exploited for cancer therapy.

The Role of Autophagy in Pancreatic Cancer—Recent Advances

“…On the other hand, it appears that cancer cells rely on autophagy for survival more than normal cells, and this reliance may further increase during therapy [3]. Autophagy is often upregulated in tumors, and, in solid cancers, such as breast and melanoma, increased LC3 puncta numbers positively correlate with a more aggressive phenotype [18].…”

“…Autophagy is often upregulated in tumors, and, in solid cancers, such as breast and melanoma, increased LC3 puncta numbers positively correlate with a more aggressive phenotype [18]. Autophagy supplies metabolites to sustain the energy needs of the cancer cells and provides energy for malignant transformation [3]. In addition to autophagy induction by low nutrient and oxygen levels, autophagy can also be induced by high levels of reactive oxygen species (ROS), for example those generated by necroptosis, a regulated necrotic cell death process [19].…”

“…In order to enable the prediction of the outcome of any potential autophagy-related therapies, it is important to bear in mind not simply the role of autophagy in isolated tumor cells, but to also consider the tumor microenvironment. Particularly interesting in this regard is the role of autophagy in anticancer immunity, which is the recognition of antigenic peptides on cancer cells by T cells, leading to the elimination of the cancer cell [3]. There is evidence for both an inhibitory and an activating role of autophagy in this process.…”

“…More specifically, autophagy has been shown to inhibit the formation of the immunological synapse and reduce cytolytic activity of T cells [22]. On the other hand, autophagy is essential for T cell and antigen-presenting cell function, which means that therapeutic autophagy inhibition is likely to affect the activity of intratumoral immune cells [3].…”

“…There are several forms of autophagy: macroautophagy, referred to as autophagy, which involves the removal of cytoplasmic constituents and organelles, mitophagy, which refers to specifically mitochondria removal, microautophagy, which refers to molecules being directly invaginated by the lysosome, and chaperone-mediated autophagy [3]. Autophagy is a dynamic, highly conserved degradation and recycling mechanism for cellular components [4] which may be unnecessary or damaged.…”