Role of tumor and host autophagy in cancer metabolism

Abstract

Macroautophagy (referred to here as autophagy) degrades and recycles cytoplasmic constituents to sustain cellular and mammalian metabolism and survival during starvation. Deregulation of autophagy is involved in numerous diseases, such as cancer. Cancers up-regulate autophagy and depend on it for survival, growth, and malignancy in a tumor cell-autonomous fashion. Recently, it has become apparent that autophagy in host tissues as well as the tumor cells themselves contribute to tumor growth. Understanding how autophagy regulates metabolism and tumor growth has revealed new essential tumor nutrients, where they come from, and how they are supplied and used, which can now be targeted for cancer therapy.

Keywords: autophagy; cancer; metabolism.

Figure 1.

Autophagy is required to sustain circulating nutrients during fasting, critical for the survival of adult mice. (A) Mammalian survival during fasting requires autophagy. Treatment with tamoxifen (TAM) leads to conditional whole-body deletion of Atg7 in adult Ub-CreERT2^+/−;Atg7^flox/flox mice. While autophagy-proficient hosts can survive during fasting, autophagy-deficient hosts die from hypoglycemia when fasted (Karsli-Uzunbas et al. 2014). (B) Autophagy is essential to sustain circulating nutrients during fasting. Fasting autophagy-deficient hosts leads to the loss of WAT, glycogen in the liver, and proteins in muscle (cachexia) and the failure to maintain circulating glucose.

Figure 2.

Tumor cell-autonomous autophagy as well as systemic autophagy promote tumor growth. (A) Tumor cell-autonomous autophagy promotes tumor growth. AdenoCre virus inhalation initiates lung tumorigenesis by activation of Kras^G12D and deletion of Trp53, and tumor-specific autophagy deficiency is induced by deletion of Atg7. Loss of tumor cell-autonomous autophagy inhibits tumor growth and leads to the development of benign oncocytomas (Guo et al. 2013). (B) Pronounced antitumor activity of systemic autophagy ablation in tumor-bearing mice. AdenoFLPo virus inhalation initiates lung tumorigenesis by activation of Kras^G12D and deletion of Trp53. When lung cancer is established, conditional whole-body autophagy deficiency is achieved by tamoxifen (TAM) injection and deletion of Atg7. Loss of host autophagy and tumor cell-autonomous autophagy inhibits tumor growth to a greater extent than tumor cell-autonomous autophagy alone (Karsli-Uzunbas et al. 2014).

Figure 3.

Whole-body autophagy and liver autophagy are essential for the growth of arginine-auxotrophic tumors. (A) Host autophagy promotes tumor growth. Treatment with TAM leads to conditional whole-body deletion of Atg7. Loss of host autophagy dramatically decreases the growth of autophagy-competent tumor cells, demonstrating the role of nontumor cell-autonomous autophagy in tumor growth (Poillet-Perez et al. 2018). (B) Arginine auxotrophy in cancer. Many cancer cells are auxotrophs for arginine, as they do not express argininosuccinate synthase 1 (ASS1) or argininosuccinate lyase (ASL), two enzymes required for de novo arginine biosynthesis. Tumors downregulate expression of these enzymes in order to use aspartate for nucleotide biosynthesis instead of the urea cycle (Rabinovich et al. 2015). (ARG1) Arginase 1; (OTC) ornithine transcarbamylase. (C) Liver autophagy promotes tumor growth. Tail vein injection of AAV-TBG-cre leads to the specific deletion of Atg7 in the liver. Loss of autophagy in the liver mimics the effect of host autophagy loss on tumor growth (Poillet-Perez et al. 2018).

Figure 4.

Host autophagy promotes tumor growth through circulating arginine. (A) Dietary arginine supplementation partially rescues tumor growth on autophagy-deficient host mice. Treatment with TAM leads to conditional whole-body deletion of Atg7. Supplementation of the mice with arginine partially rescues tumor growth in autophagy-deficient host mice (Poillet-Perez et al. 2018). (B) Nontumor cell-autonomous autophagy promotes tumor growth by sustaining the supply of amino acids that are essential tumor nutrients. When autophagy is active in the liver, the release of ARG1 from hepatocytes is prevented, thereby maintaining circulating arginine that is important for the growth of arginine-auxotrophic tumors. Loss of autophagy in the liver causes the release of ARG1 from hepatocytes into the circulation, leading to the depletion of circulating arginine and inhibition of the growth of tumors auxotrophic for arginine (Poillet-Perez et al. 2018). Similarly, loss of autophagy in the stroma cells inhibits the secretion of alanine necessary for PDAC growth (Sousa et al. 2016).