Autophagy as a physiological response of the body to starvation

Macroautophagy is a cellular degradation pathway that deliver cytoplasmic components such as damaged organelles, misfolded proteins, and pathogens to the lysosomes for degradation. Autophagy is associated with the survival of the cell under stress conditions and infections. Nutrient deprivation is one of the main inducers of autophagy, which recycles cytoplasmic components to provide building blocks required for cell survival and maintains cellular homeostasis. Due to its cytoprotective effects, autophagic responses are necessary in resisting diseases and ensuring health. Understanding the regulation of autophagic responses in mammalian cells is required to improve human health through innovations in treatment strategies. This chapter focuses on recent findings about autophagy mechanisms and their role in the body’s response to starvation as well as the current knowledge of autophagy-related malnutrition disorders

Tumor-derived CTF1 (cardiotrophin 1) is a critical mediator of stroma-assisted and autophagy-dependent breast cancer cell migration, invasion and metastasis

Macroautophagy/autophagy is an evolutionarily conserved cellular stress response mechanism. Autophagy induction in the tumor microenvironment (stroma) has been shown to support tumor metabolism. However, cancer cell-derived secreted factors that initiate communication with surrounding cells and stimulate autophagy in the tumor microenvironment are not fully documented. We identified CTF1/CT-1 (cardiotrophin 1) as an activator of autophagy in fibroblasts and breast cancer-derived carcinoma-associated fibroblasts (CAFs). We showed that CTF1 stimulated phosphorylation and nuclear translocation of STAT3, initiating transcriptional activation of key autophagy proteins. Additionally, following CTF1 treatment, AMPK and ULK1 activation was observed. We provided evidence that autophagy was important for CTF1-dependent ACTA2/alpha-SMA accumulation, stress fiber formation and fibroblast activation. Moreover, promotion of breast cancer cell migration and invasion by activated fibroblasts depended on CTF1 and autophagy. Analysis of the expression levels of CTF1 in patient-derived breast cancer samples led us to establish a correlation between CTF1 expression and autophagy in the tumor stroma. In line with our in vitro data on cancer migration and invasion, higher levels of CTF1 expression in breast tumors was significantly associated with lymph node metastasis in patients. Therefore, CTF1 is an important mediator of tumor-stroma interactions, fibroblast activation and cancer metastasis, and autophagy plays a key role in all these cancer-related events