Elsevier

Seminars in Cancer Biology

Volume 85, October 2022, Pages 196-208
Seminars in Cancer Biology

Recent progress of autophagy signaling in tumor microenvironment and its targeting for possible cancer therapeutics

https://doi.org/10.1016/j.semcancer.2021.09.003Get rights and content

Abstract

Autophagy, a lysosomal catabolic process, involves degradation of cellular materials, protein aggregate, and dysfunctional organelles to maintain cellular homeostasis. Strikingly, autophagy exhibits a dual-sided role in cancer; on the one hand, it promotes clearance of transformed cells and inhibits tumorigenesis, while cytoprotective autophagy has a role in sustaining cancer. The autophagy signaling in the tumor microenvironment (TME) during cancer growth and therapy is not adequately understood. The review highlights the role of autophagy signaling pathways to support cancer growth and progression in adaptation to the oxidative and hypoxic context of TME. Furthermore, autophagy contributes to regulating the metabolic switch for generating sufficient levels of high-energy metabolites, including amino acids, ketones, glutamine, and free fatty acids for cancer cell survival. Interestingly, autophagy has a critical role in modulating the tumor-associated fibroblast resulting in different cytokines and paracrine signaling mediated angiogenesis and invasion of pre-metastatic niches to secondary tumor sites. Moreover, autophagy promotes immune evasion to inhibit antitumor immunity, and autophagy inhibitors enhance response to immunotherapy with infiltration of immune cells to the TME niche. Furthermore, autophagy in TME maintains and supports the survival of cancer stem cells resulting in chemoresistance and therapy recurrence. Presently, drug repurposing has enabled the use of lysosomal inhibitor-based antimalarial drugs like chloroquine and hydroxychloroquine as clinically available autophagy inhibitors in cancer therapy. We focus on the recent developments of multiple autophagy modulators from pre-clinical trials and the challenges in developing autophagy-based cancer therapy.

Introduction

Autophagy, a lysosome-based conserved catabolic process involving degradation of the cellular materials and protein aggregates to maintain homeostasis. During stress, long-lived proteins or damaged cellular components are sequestered within a double-membrane structure called autophagosome and fuses with the lysosome to produce autolysosome, which is involved in the de novo release of amino acids, fatty acids and substrates to fuel cellular metabolism. The term “autophagy” was first coined by Nobel Laureate Christian de Duve during Ciba Foundation Symposium on Lysosomes, in London on February 12–14, 1963 [1]. The 1990s saw a tremendous exploration in the field of autophagy and its direct involvement in different diseases to highlight its physiological impact. The process of autophagy is controlled by 41 ATG (AuTophaGy-related) proteins which are highly conserved from yeast to mammals. Talking about yeast, it has played a vital role as a model organism to understand the process of autophagy progression. In 2016, Yoshinori Ohsumi was awarded the Nobel prize in physiology or medicine for his contributions to elucidate and explain the basis of the genetic mechanism of autophagy. Besides the above-explained process of autophagy (which is part of macroautophagy), the other two less known categories of autophagy are microautophagy and chaperone-mediated autophagy. Microautophagy involves direct uptake of autophagic cargo by lysosomes through invagination of their limiting membrane, whereas in chaperone-mediated autophagy, the autophagic cargo is loaded onto the lysosome in a process involving chaperone Hsc70 and lysosomal membrane protein LAMP2A [2]. Autophagy has a Janus character in cancer. On the one hand, autophagy involves in the elimination of cells that are prone to undergo tumor development, but once it develops, bypassing all regulation, then autophagy helps in nurturing them. This makes the role of autophagy not limited to only protection to the host individual, but it diversifies into an undesired phenotype promoting cancer recurrence, development of stem-like lineage properties, promotes malignancy and invasiveness (as shown in Fig. 1).

Autophagy is context-dependent on the tumor microenvironment (TME) and differs from the early to late stage of tumorigenesis. The TME exploits autophagy to fuel the metabolic demands of cancer stem cells (CSCs), fibroblasts, immune cells, lipid bodies, neuronal supplies controlling communication, blood vessels essential for nutrition, and the presence of microbiota, is housed in an impenetrable niche (as shown in Fig. 1). The concept of TME dates to Steven Paget’s (1889) soil, and seed theory of metastasis, where the relevance of TME (soil) to support the cancer cells (seed) was emphasized [3]. The seeding of the premetastatic niches to far distant organs leads to the development of polyclonal metastatic sub-clones. The importance of TME is also recognized as an essential feature among the evolving hallmarks of cancer [4]. It is becoming increasingly important that there is a shift from tumor-centric to TME centric treatment. For example, glioblastoma (GBM) represents one of the most aggressive forms of cancer with minimal therapeutic options. Pyonteck et al. showed that the tumor-associated macrophages (TAM) depend on the colony-stimulating factor (CSF) for survival, and administration of CSF-1R (an inhibitor of CSF1) has been reported in tumor repression in patient-derived glioma xenografts [5]. In addition, it showed that there is a decrease of M2-activated macrophage markers in impaired TAMs. Interestingly, the phosphatidylinositol 3-kinase (PI3K) pathway gets activated in these recurrent GBMs, which are driven by macrophage-derived insulin-like growth factor (IGF-1) and tumor cell IGF-1 receptor (IGF-1R) [6]. In this connection, the combination of CSF-1R with IGF1 and PI3K pathway inhibitors leads to enhanced survival advantage and a better therapeutic route for treating recurrent forms of GBM. Likely, the combination of CSF-1R with paclitaxel reduces metastatic breast cancer progression in the mouse model [7]. The TAMs inside a hypoxia tumor are responsible for the secretion of vascular endothelial growth factor A (VEGFA), which binds to the nearby cognate receptors in nearby blood vessels. VEGF produces a cascade of growth in neighboring endothelial cells that help in the vascularization of TME. Interestingly, cellular lactate leads to the secretion of C-C motif chemokine Ligand 5 (CCL5) in macrophages by stimulating Notch signaling [8]. Wang et al. deciphered that the epithelial to mesenchymal transition (EMT), a hallmark of metastasis in gemcitabine resistant pancreatic cancer cells, requires the Notch signaling activation [9]. Interestingly, CD44+ CD54+ gastric CSCs display high autophagic activity and combined treatment of chloroquine, and 5-fluorouracil (5-FU) promotes high Notch1 expression indicating the role of autophagy in regulating Notch-mediated chemoresistance [10].

This review has discussed evidence highlighting the role of autophagy signaling in modulating TME by reprogramming tumor metabolism, bypassing host immunity surveillance, and cancer stem cell development. We have discussed the present-day challenges of clinical trial strategies targeting autophagy to modulate TME and focus on future research goals for efficient cancer therapy.

Section snippets

Understanding the basics of autophagy signaling in cancer

During stress, cancer cells activate autophagy through a four-step catabolic process involving initiation, elongation, maturation, fusion with the lysosome, and degradation of the sequestered autophagic cargo. Stress, including high temperature, high interstitial fluid pressure, increase in the cancer cell population, hypoxia, accumulation of toxic waste products, radiation, and chemotherapy, evokes inactivation of the chief cellular signaling regulator mammalian target of rapamycin (mTOR) and

Identifying the role of autophagy in metabolic plasticity for rewiring cancer ecosystem

Altered metabolism is one of the hallmarks of cancer, and here, we have discussed the physiological implications of autophagy in regulating metabolic switch in cancer cells to survive in the TME (Fig. 2). Tumors prefer to use the anaerobic glycolysis and remain dependent on glucose, while the oxidative phosphorylation undergoing cancer relies on glucose, lipids, glutamine, and lactate. Glucose is one of the primary sources of carbon that fuels the metabolic demand in a proliferating cell.

Pro-survival autophagy signaling in hypoxic tumor microenvironment

Besides the role of autophagy in metabolic function, it plays an essential feature in adapting cancer cells in hypoxia (Fig. 3). Autophagy facilitates the survival of cancer cells in hypoxic TME through its main effector, hypoxia-inducible factor-1 (HIF-1). Tumor cells are reported to survive hypoxia by inducing Beclin1 mediated cytoprotective autophagy through BNIP3 and BNIP3L [59]. Furthermore, BNIP3L/NIX is highly expressed in patient-derived glioma tumor samples, which is required to

Autophagy, reactive oxygen species, and tumor microenvironment relationship

ROS comprise a family of highly reactive, short-lived molecules involving superoxide anion (O2), hydrogen peroxide (H2O2), and the hydroxyl radical (OHradical dot). ROS is involved in the pathogenesis of cancer by oxidizing cellular lipids, damaging DNA integrity and proteins, making them susceptible to carcinogenesis and a more aggressive form of cancer. During tumorigenesis, the accumulation of dysfunctional organelles leads to ROS generation, which activates autophagy-mediated clearance of damaged

Autophagy promotes immune evasion to inhibit antitumor immunity

Evading immune surveillance is one of the hallmarks of cancer. The tumor evasion mechanism includes T cell anergy and resistance to apoptosis, deficiency of major histocompatibility complex (MHC) class I proteins, expression of immunomodulatory molecules in tumor cells. Moreover, the immune-suppressive factors present in the TME control the function of myeloid-derived suppressor cells (MDSCs), regulatory T (Treg) cells, and TAMs to promote tumor growth and metastasis. The current evidence has

Autophagy maintains and support survival of cancer stem cells in the tumor microenvironment

CSCs are a subset of malignant cells which drive cancer initiation, progression, and therapy resistance. The CSCs contribute and maintain tumor heterogeneity through activation of EMT, Juxtacrine, and inflammatory signaling in TME [109]. Here, we have discussed the role of autophagy in controlling growth, survival, and pluripotency in CSCs (Fig. 5). Autophagy in breast cancer positively regulates maintenance of CSCs, and Atg12 knockdown or chloroquine treatment showed a decrease in transforming

Present clinical status and challenges in autophagy targeted cancer therapy

The most recent progress of autophagy-targeted oncotherapy can be traced by understanding the clinical trials. Some of the critical ongoing clinical trials are listed in Table 1, while this section does a critical evaluation highlighting the success, failures of different trials. One such study named CHOICES (CHlorOquine and Imatinib Combination to Eliminate Stem cells) trial (NCT01227135) involved a phase II trial which is compared with co-treatment of imatinib mesylate (IM) and

Conclusion and future perspective

The heterocellular crosstalk through autophagy in TME often reprograms the cellular physiology for metabolic fitness and adaptation for tumor survival and growth. Autophagy in TME modulates metabolism, regulates oxidative stress and hypoxia, sustains cancer stem cells, and evades the host immune surveillance to support cancer growth (Fig. 5). Furthermore, it has become apparent that autophagy in host tissues present in TME and the surrounding contribute to tumor growth. Although targeting

Declaration of Competing Interest

The authors report no declarations of interest.

Acknowledgments

Research support was partly provided by the Indian Council of Medical Research (ICMR), Govt. of India [Number: 5/13/20/2020/NCD-III]. Figures were developed using Servier Medical Art by Servier (https://smart.servier.com/) which is licensed under a Creative Commons Attribution 3.0 Unported License. Authors acknowledge ClinicalTrials.gov (resource provided by the U.S. National Library of Medicine) which is a database of global clinical studies, for the data in Table-1. Authors apologize to those

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    Present address: Laura and Isaac Perlmutter Cancer Center, Department of Radiation Oncology, NYU Medical School, New York, NY 10016, USA.

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