Mini Review

Dual Role of Autophagy in Cancer: From Tumor Promotion to Suppression

Swarna Beesetti*

Department of Immunology, St Jude Children’s Research Hospital, USA, 38105

Submission:July 07, 2023; Published:August 28, 2023

*Corresponding author:Swarna Beesetti, department of Immunology, St Jude Children’s Research Hospital, USA

How to cite this article:Swarna B. Dual Role of Autophagy in Cancer: From Tumor Promotion to Suppression. J Tumor Med Prev. 2023; 4(2): 555632. DOI: 10.19080/ JTMP.2023.04.555632

Abstract

Autophagy, a fundamental cellular process responsible for cellular component degradation and recycling, has gained considerable importance in the field of cancer research. Initially identified as a tumor suppressive mechanism, the role of autophagy in cancer has proven to be complex, exhibiting both pro-survival and pro-death effects depending on the specific context. This review aims to explore the intricate interplay between autophagy and cancer, shedding light on its diverse implications in tumor development, progression, and response to treatment. A comprehensive understanding of the dynamic nature of autophagy in cancer is crucial for the development of targeted therapeutic strategies that capitalize on autophagy modulation to improve patient outcomes.

Introduction

Autophagy, a tightly regulated cellular process crucial for cellular homeostasis and stress adaptation, acts as an internal recycling system. It selectively engulfs and transports damaged organelles, protein aggregates, and cellular components to lysosomes for degradation [1, 2]. In the context of cancer, the role of autophagy is multifaceted, exhibiting both tumor-promoting and tumor-suppressive effects contingent on the specific tumor stage and microenvironment. Understanding the intricate relationship between autophagy and cancer is essential for unraveling its diverse implications in tumor progression and response to therapy [3]. In certain contexts, autophagy promotes tumor growth by facilitating the survival of cancer cells under unfavorable conditions such as nutrient deprivation and hypoxia, as well as aiding in immune evasion and therapy resistance [4]. Consequently, targeting autophagy has been explored as a potential therapeutic strategy to hinder cancer progression.

Conversely, autophagy also exhibits tumor suppressor functions. By eliminating damaged organelles and proteins, autophagy preserves genomic stability and prevents the accumulation of harmful cellular components that could trigger tumorigenesis [5]. Furthermore, autophagy can induce cell death in cancer cells, acting as a safeguard against the survival of malignant cells [6]. Defects in autophagy have been associated with increased cancer incidence and poorer patient outcomes, underscoring the significance of autophagy in cancer biology.

The intricate interplay between autophagy, the tumor microenvironment, genetic alterations, and signaling pathways further contribute to the complexity of autophagy’s impact on tumor development and progression. Understanding the context-dependent role of autophagy in cancer is crucial for developing targeted therapeutic interventions and optimizing patient outcomes. This review provides a comprehensive perspective on the dual nature of autophagy in cancer, emphasizing its implications for future research and clinical applications.

Autophagy in Tumor Initiation and Progression: In the early stages of cancer, autophagy serves as a crucial tumor suppressor mechanism by eliminating damaged organelles, reducing genomic instability, and maintaining cellular homeostasis [6]. Impairment of autophagy has been associated with increased accumulation of damaged proteins, genomic instability, and activation of oncogenic signaling pathways [7]. This highlights the importance of intact autophagy in preventing the initiation and progression of cancer. However, as tumors progress and face challenging microenvironments, autophagy can be exploited by cancer cells to promote their survival and growth [3]. Cancer cells upregulate and enhance autophagy as a survival strategy to cope with adverse conditions such as nutrient scarcity, low oxygen levels (hypoxia), and metabolic stress [8]. By utilizing autophagy, cancer cells can break down cellular components and recycle their constituents, thus generating crucial energy and building blocks necessary for their survival and aggressive behavior [9].

Enhanced autophagy in cancer cells promotes their adaptation to the hostile tumor microenvironment, enabling them to overcome nutrient limitations and evade cell death signals. This autophagy-mediated metabolic rewiring supports the metabolic demands of rapidly dividing cancer cells, facilitating their proliferation and invasive properties [10]. Moreover, autophagy can facilitate the resistance of cancer cells to various therapies, including chemotherapy and radiation, by aiding in the removal of damaged molecules caused by these treatments and promoting cell survival [11]. The interplay between autophagy and cancer progression is complex and context dependent. While autophagy initially acts as a protective mechanism, preventing the accumulation of detrimental cellular components, its dysregulation can lead to a shift towards pro-tumorigenic effects. The intricate balance between autophagy’s tumor-suppressive and tumor-promoting functions is influenced by factors such as the tumor microenvironment, genetic alterations, and signaling pathways involved.

Role of Autophagy in Therapy Resistance

Autophagy is a key player in the development of resistance to different anticancer therapies, encompassing chemotherapy, radiation, and targeted therapies. Cancer cells can exploit autophagy as a survival mechanism, allowing them to withstand the stress imposed by these treatments [12]. However, this reliance on autophagy for therapy resistance also presents an opportunity for therapeutic intervention.

Autophagy-mediated drug resistance is achieved through various mechanisms

Firstly, autophagy can act as a protective mechanism by removing damaged molecules and organelles induced by anticancer treatments. By eliminating these harmful components, cancer cells can evade therapy-induced cell death pathways and maintain their survival [13]. Additionally, autophagy enables cancer cells to adapt to the hostile tumor microenvironment caused by therapy, such as nutrient deprivation and hypoxia [14]. By recycling cellular constituents through autophagy, cancer cells can sustain their energy production and metabolic requirements, thereby promoting their survival and regrowth [15].

However, the reliance of cancer cells on autophagy for therapy resistance also represents a potential vulnerability that can be targeted. Modulating autophagy in combination with standard cancer treatments has emerged as a promising strategy to overcome therapy resistance. Preclinical and clinical studies have explored approaches to either inhibit or activate autophagy to sensitize cancer cells to therapy-induced cell death [16]. Autophagy inhibition can sensitize cancer cells to therapy by preventing their ability to cope with stress conditions. Inhibiting autophagy can lead to the accumulation of damaged components and organelles, overwhelming the cellular defense mechanisms and ultimately triggering cell death pathways [17]. This approach has shown efficacy in enhancing the effectiveness of various anticancer treatments.

On the other hand, autophagy activation can also be exploited to sensitize cancer cells to therapy. Under certain circumstances, stimulating autophagy in cancer cells can overwhelm their adaptive capabilities, making them more susceptible to therapyinduced cell death through several mechanisms [18].

Autophagy Activation

Firstly, autophagy activation can lead to the excessive degradation of cellular components and organelles, including damaged proteins and dysfunctional organelles. This process helps to eliminate the building blocks that cancer cells rely on for survival and growth. By degrading these essential components, autophagy induction deprives cancer cells of the necessary resources to maintain their viability, ultimately leading to their demise [19]. Secondly, autophagy activation can disrupt the cellular energy balance in cancer cells. Cancer cells require a substantial amount of energy to support their rapid proliferation and survival. By activating autophagy, cellular energy stores, such as glycogen and lipids, can be broken down and utilized as an energy source. This energy deprivation weakens the adaptive capabilities of cancer cells, making them more susceptible to the cytotoxic effects of anticancer therapies [20].

Moreover, excessive autophagy induction can trigger an overload of the cellular degradation machinery, overwhelming the capacity of cancer cells to cope with the stress imposed by therapy. This overload can lead to the accumulation of toxic autophagic intermediates and the generation of reactive oxygen species (ROS), both of which can induce cellular damage and promote cell death pathways [21]. Additionally, autophagy activation can enhance the immune response against cancer cells. Autophagy plays a critical role in antigen presentation and the activation of immune cells. By inducing autophagy, cancer cells can increase the presentation of tumor-specific antigens to immune cells, leading to a stronger immune response against the tumor [22]. This immune-mediated cytotoxicity can synergize with the effects of anticancer therapies, further promoting cancer cell death.

It is important to note that the effects of autophagy stimulation on cancer cell susceptibility to therapy-induced cell death can vary depending on the specific context, including the tumor type, genetic alterations, and the microenvironment. Therefore, a comprehensive understanding of these factors is necessary to determine the optimal strategies for autophagy modulation in combination with anticancer therapies. Combining autophagy activators with conventional treatments has demonstrated promising results in preclinical models and is being investigated in clinical trials [23]. It is important to note that the modulation of autophagy in cancer therapy is a complex endeavor, as the effects of autophagy modulation can vary depending on the tumor type, microenvironment, and stage of cancer. Therefore, a deeper understanding of the molecular mechanisms and context-specific effects of autophagy modulation is necessary for the development of effective therapeutic strategies.

*N = 2 468 531 **N = 69 573 152 ***Tendency

The Influence of Tumor Microenvironment on Autophagy

The tumor microenvironment significantly influences the role of autophagy in cancer. Various components, including stromal cells, immune cells, and extracellular matrix, can modulate autophagy within the tumor microenvironment. For instance, autophagy in cancer-associated fibroblasts can promote tumor growth and metastasis, while autophagy in immune cells can affect anti-tumor immune responses [24]. Understanding the intricate interplay between autophagy and the tumor microenvironment is crucial for deciphering its impact on tumor progression and therapeutic response.

Targeting Autophagy for Cancer Therapy

The dual role of autophagy in cancer presents an opportunity for therapeutic interventions. Strategies to manipulate autophagy in cancer therapy include autophagy inhibitors, which can sensitize cancer cells to therapy, and autophagy inducers, which can promote tumor cell death [25]. However, the challenge lies in identifying specific contexts and patient populations that would benefit from autophagy modulation, considering the dynamic and context-dependent nature of autophagy in cancer.

Conclusion

Autophagy has emerged as a complex and contextdependent process in cancer biology. Its roles in tumor initiation, progression, therapy resistance, and interaction with the tumor microenvironment are multifaceted. Harnessing the therapeutic potential of autophagy modulation requires a deeper understanding of the precise mechanisms and context-specific functions of autophagy in different cancer types. Integrating autophagy-targeted strategies with existing treatment modalities holds promise for improving patient outcomes in the future. Further, autophagy plays a critical role in the development of therapy resistance in cancer. While cancer cells can exploit autophagy as a survival mechanism, targeting autophagy represents a potential strategy to overcome resistance and enhance the efficacy of anticancer treatments. The modulation of autophagy, either through inhibition or activation, holds promise as an innovative approach to sensitize cancer cells to therapy-induced cell death. Additionally, identifying biomarkers that can predict autophagyrelated responses in tumors may enable personalized treatment strategies and improve patient outcomes. Further investigation into the molecular mechanisms and regulation of autophagy in different cancer types and stages is essential for harnessing its potential as a therapeutic target and improving patient outcomes.

Conclusion

There is a strong increase in cancer-related treatments in Germany which can only in part be attributed to facemasks and lockdowns. Further research is needed to determine whether the novel coronavirus vaccines might be a factor regarding the rise in cancers in Germany, or what other factors (e.g. stress due to job loss, [6]) could be involved.

References

1. Ryter SW, Cloonan SM, Choi AM (2013) Autophagy: A Critical regulator of Cellular Metabolism and Homeostasis. Mol Cells 36(1): 7-16.
2. Levine B, Kroemer G (2019) Biological Functions of Autophagy Genes: A Disease Perspective, Cell 176(1-2): 11- 42.
3. Yun CW, Lee SH (2018) The Roles of Autophagy in Cancer Int J Mol Sci 19(11): 3466.
4. Levy JMM, Towers CG, Thorburn A (2017) Targeting autophagy in cancer, Nat Rev Cancer 17(9): 528- 542.
5. Maiuri MC, Tasdemir E, Criollo A, Morselli E, Vicencio JM, et al. (2009) Control of autophagy by oncogenes and tumor suppressor genes, Cell Death Differ 16(1): 87- 93.
6. Li X, He S, Ma, B (2020) Autophagy and autophagy-related proteins in cancer, Mol Cancer 19(1): 12.
7. Vessoni AT, Filippi-Chiela EC, Menck CF, Lenz G (2013) Autophagy and genomic integrity. Cell Death Differ 20(11): 1444- 1454.
8. Dröge W (2002) Free radicals in the physiological control of cell function, Physiol Rev 82(1): 47- 95.
9. Mathew R, Karantza-Wadsworth V, White E (2007) Role of autophagy in cancer. Nat Rev Cancer 7(12): 961- 197.
10. Lozy F, Karantza V (2012) Autophagy and cancer cell metabolism. Semin Cell Dev Biol 23(4): 395- 401.
11. Nazio F, Bordi M, Cianfanelli V, Locatelli F, Cecconi F (2019) Autophagy and cancer stem cells: molecular mechanisms and therapeutic applications. Cell Death Differ 26: 690- 702.
12. Nam HJ (2021) Autophagy Modulators in Cancer: Focus on Cancer Treatment, Life (Basel) 11.
13. Yun CW, Jeon J, Go G, Lee JH, Lee SH (2020) The Dual Role of Autophagy in Cancer Development and a Therapeutic Strategy for Cancer by Targeting Autophagy. Int J Mol Sci 22(1): 179.
14. Wang X, Zhang H, Chen X (2019) Drug resistance and combating drug resistance in cancer, Cancer Drug Resist 2(2): 141- 160.
15. White E, Mehnert JM, Chan CS (2015) Autophagy, Metabolism, and Cancer. Clin Cancer Res 21(22): 5037- 5046.
16. Chen N, Karantza V (2011) Autophagy as a therapeutic target in cancer. Cancer Biol Ther 11(2): 157- 168.
17. Yang ZJ, Chee CE, Huang S, Sinicrope FA (2011) The role of autophagy in cancer: therapeutic implications. Mol Cancer Ther 10(9): 1533- 1541.
18. Lim SM, Mohamad Hanif EA, Chin SF (2021) Is targeting autophagy mechanism in cancer a good approach? The possible double-edge sword effect. Cell Biosci 11(1): 56.
19. Miller DR, Thorburn A (2021) Autophagy and organelle homeostasis in cancer. Dev Cell 56(7): 906- 918.
20. Lahiri V, Hawkins WD, Klionsky DJ (2019) Watch What You (Self) Eat: Autophagic Mechanisms that Modulate Metabolism, Cell Metab 29(4): 803- 826.
21. Hasan A, Rizvi SF, Parveen S, Pathak N, Nazir A, et al. (2022) Crosstalk Between ROS and Autophagy in Tumorigenesis: Understanding the Multifaceted Paradox. Front Oncol 12: 852424.
22. De Souza ASC, Gonçalves LB, Lepique AP, De Araujo-Souza PS (2020) The Role of Autophagy in Tumor Immunology-Complex Mechanisms That May Be Explored Therapeutically. Front Oncol 10: 603661.
23. Liu T, Zhang J, Li K, Deng L, Wang H (2020) Combination of an Autophagy Inducer and an Autophagy Inhibitor: A Smarter Strategy Emerging in Cancer Therapy. Front Pharmacol 11: 408.
24. Martinez-Outschoorn UE, Trimmer C, Lin Z, Whitaker-Menezes D, Chiavarina B, et al. (2010) Autophagy in cancer associated fibroblasts promotes tumor cell survival: Role of hypoxia, HIF1 induction and NFκB activation in the tumor stromal microenvironment. Cell Cycle 9(17): 3515-3533.
25. Silva VR, Neves SP, Santos LS, Dias RB, Bezerra DP (2020) Challenges and Therapeutic Opportunities of Autophagy in Cancer Therapy. Cancers (Basel) 12(11): 3461.