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.

ATP2C2 Has Potential to Define Tumor Microenvironment in Breast Cancer

“…TME is the key regulator of carcinogenesis and consists of tumor cells, stromal cells, and immune cells (13,14). TICs are closely associated with tumorigenesis, angiogenesis and the growth and metastatic potential of tumor cells, which could alternately modulate the pattern of immune cells (15)(16)(17)(18). Now, immunotherapy has been widely used to treat a broad spectrum of cancers including BRCA (19)(20)(21)(22).…”

The CD44high Subpopulation of Multifraction Irradiation-Surviving NSCLC Cells Exhibits Partial EMT-Program Activation and DNA Damage Response Depending on Their p53 Status

“…On the other hand, some recent data indicated that radioresistance appeared to be most closely associated with senescence occurring earlier and more significant in the p53wt NSCLC cells [ 99 ]. In the light of a tumor dormancy model, a phase of proliferative recovery in a subset of cells frequently following after the radiation-induced senescence can contribute to therapy resistance and conceivably the disease relapse [ 100 , 101 ]. In this regard, such an impact of senescence will open up a new avenue for novel senolytics that await clinical prove as an adjuvant to radiotherapy to prolong remission by delaying disease recurrence in patients.…”

The Role of IGF/IGF-IR-Signaling and Extracellular Matrix Effectors in Bone Sarcoma Pathogenesis

“…Reprogramming the matrix component of the TME could enhance the antitumor effects of available therapies. Matrix mediators' effects on autophagy and apoptosis could also be recruited in an ongoing effort to harness these processes for new therapeutic strategies [237,238]. Therefore, as new agents are continuously developing, such as anti-tumor-specific antibodies or even specific CAR-T cells, matrix-derived approaches can be part of the combinatorial strategies that enhance antitumor responses.…”