Emerging Autophagy Functions Shape the Tumor Microenvironment and Play a Role in Cancer Progression - Implications for Cancer Therapy

Abstract

The tumor microenvironment (TME) is a complex environment where cancer cells reside and interact with different types of cells, secreted factors, and the extracellular matrix. Additionally, TME is shaped by several processes, such as autophagy. Autophagy has emerged as a conserved intracellular degradation pathway for clearance of damaged organelles or aberrant proteins. With its central role, autophagy maintains the cellular homeostasis and orchestrates stress responses, playing opposite roles in tumorigenesis. During tumor development, autophagy also mediates autophagy-independent functions associated with several hallmarks of cancer, and therefore exerting several effects on tumor suppression and/or tumor promotion mechanisms. Beyond the concept of degradation, new different forms of autophagy have been described as modulators of cancer progression, such as secretory autophagy enabling intercellular communication in the TME by cargo release. In this context, the synthesis of senescence-associated secretory proteins by autophagy lead to a senescent phenotype. Besides disturbing tumor treatment responses, autophagy also participates in innate and adaptive immune signaling. Furthermore, recent studies have indicated intricate crosstalk between autophagy and the epithelial-mesenchymal transition (EMT), by which cancer cells obtain an invasive phenotype and metastatic potential. Thus, autophagy in the cancer context is far broader and complex than just a cell energy sensing mechanism. In this scenario, we will discuss the key roles of autophagy in the TME and surrounding cells, contributing to cancer development and progression/EMT. Finally, the potential intervention in autophagy processes as a strategy for cancer therapy will be addressed.

Keywords: cancer; epithelial-mesenchymal transition; immune system; new autophagy functions; secretion; tumor microenvironment.

Figure 1

Dual role of autophagy in cancer. Autophagy is implicated in several stages of tumorigenesis executing different processes. The extensive and opposite functions in cancer makes autophagy an important target to develop new therapies. A deeper knowledge about this complex feature of autophagy in cancer research is essential to find more accurate therapeutic approaches.

Figure 2

Overview of autophagy roles in the tumor microenvironment. The scheme summarizes the role of autophagy in secretion (left), immune system (middle), epithelial-mesenchymal transition (EMT) and tumor dormancy (right). There is an intricate and dynamic network of signaling circuits that drive tumor development and progression within the tumor microenvironment. The connectivity among various processes may regulate the fate of the microenvironment components, indicating the importance of viewing this as an emerging system, where the resulting interactions are larger than the sum of the individual parcels. Autophagy can act in many ways in different types of cells displaying anti-tumoral (shown in blue) or pro-tumoral functions (shown in red). Protein secretion by CAF or tumor cells can modulate cellular states inducing or inhibiting senescence, which ultimately can control tumor survival, immune cell response and interfere with the epithelial-mesenchymal transition, affecting tumor invasion capacity. In the context of the immune system, autophagy has a key role in immune cell differentiation, proliferation, activation and effector function, covering the range of homeostatic to reactive functions of the immune system. At the same time, autophagy is also connected with the innate immune response being controlled by receptors such as TLRs. Importantly, in advanced stages, the autophagy system in tumor cells is involved with EMT and the consequent ability of cancer cells to invade tissues and metastasize. The interplay among these functions contributes to tumor aggressiveness. Moreover, autophagy was also appointed as a characteristic of cancer stem cells (CSC) playing a central role in tumor dormancy. Altogether, the myriad of connected process regulated by autophagy in the TME modulate tumor response and may determine its regression or progression. Altogether, understanding the integrated mechanisms that regulate autophagy within the TME constitute a niche for development of novel strategies for combination therapy.