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Review
. 2021 Dec 25;14(1):79.
doi: 10.3390/nu14010079.

Therapeutic Potential of Thymoquinone in Triple-Negative Breast Cancer Prevention and Progression through the Modulation of the Tumor Microenvironment

Getinet M Adinew  1 , Equar Taka  1 , Bereket Mochona  2 , Ramesh B Badisa  1 , Elizabeth A Mazzio  1 , Rashid Elhag  3 , Karam F A Soliman  1
Affiliations
Review

Therapeutic Potential of Thymoquinone in Triple-Negative Breast Cancer Prevention and Progression through the Modulation of the Tumor Microenvironment

Getinet M Adinew et al. Nutrients. .

Abstract

To date, the tumor microenvironment (TME) has gained considerable attention in various areas of cancer research due to its role in driving a loss of immune surveillance and enabling rapid advanced tumor development and progression. The TME plays an integral role in driving advanced aggressive breast cancers, including triple-negative breast cancer (TNBC), a pivotal mediator for tumor cells to communicate with the surrounding cells via lymphatic and circulatory systems. Furthermore, the TME plays a significant role in all steps and stages of carcinogenesis by promoting and stimulating uncontrolled cell proliferation and protecting tumor cells from the immune system. Various cellular components of the TME work together to drive cancer processes, some of which include tumor-associated adipocytes, fibroblasts, macrophages, and neutrophils which sustain perpetual amplification and release of pro-inflammatory molecules such as cytokines. Thymoquinone (TQ), a natural chemical component from black cumin seed, is widely used traditionally and now in clinical trials for the treatment/prevention of multiple types of cancer, showing a potential to mitigate components of TME at various stages by various pathways. In this review, we focus on the role of TME in TNBC cancer progression and the effect of TQ on the TME, emphasizing their anticipated role in the prevention and treatment of TNBC. It was concluded from this review that the multiple components of the TME serve as a critical part of TNBC tumor promotion and stimulation of uncontrolled cell proliferation. Meanwhile, TQ could be a crucial compound in the prevention and progression of TNBC therapy through the modulation of the TME.

Keywords: breast cancer; thymoquinone; triple-negative breast cancer; tumor-microenvironment.

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Conflict of interest statement

The authors declare that there is no conflict of interest.

Figures

Figure 1
Figure 1
The role of tumor microenvironment components and their secreted factors in the carcinogenesis of TNBC cells. TAM, CAA, and CAF are the major cellular components of TME, while also shown in the figure are secreted factors and signals. CAA: Cancer-associated adipocytes; CAF: Cancer-associated fibroblast; eEF2k: eukaryotic elongation facto 2k; TAMs: tumor-associated macrophages; TGF-β: transforming growth factor-β; IGF: insulin-like growth factor; ROS: reactive oxygen species; IL-6: Interleukin-6; TNBC: triple-negative breast cancer; VEGF: Vascular endothelial growth factor; IDO: Indoleamine 2,3-dioxygenase.
Figure 2
Figure 2
Possible anti-cancer mechanism of thymoquinone (TQ). TQ caused apoptosis in TNBC cells by inducing apoptotic genes, downregulating anti-apoptotic genes, and generating reactive oxygen species (ROS). TQ also suppresses Akt activation, deactivates Nf-kB, and increases antioxidant enzymes, inhibiting TNBC carcinogenesis.
Figure 3
Figure 3
TQ inhibition of reactive oxygen species (ROS) production in the tumor microenvironment (TME). The TME is a complicated web of inflammatory and non-inflammatory cells. ROS boosts cancer cell proliferation, EMT stimulation, metabolic system dysregulation, and angiogenesis stimulation through altering vascular endothelial growth factors like VEGF and promoting inflammatory chemicals. The metabolic processes of glycolysis and oxidative phosphorylation are strictly controlled by ROS, with an excess of ROS resulting in a dysregulated metabolic pathway [93]. TQ counteracts all of these effects by inhibiting the generation of reactive oxygen species (ROS) via activating cytoprotective enzymes and nuclear factor-erythroid 2 related factor 2 (Nrf2).
Figure 4
Figure 4
The major role of eEF2K in promoting angiogenesis, metastasis, invasion, and drug resistance in cancer cells, including TNBC. These effects promote cancer progression, resulting in tumor growth, poor prognosis, and short survival in TNBC patients. TQ reverses this action by regulating and inhibiting the upregulation of eEF2K in the TME.
Figure 5
Figure 5
Overview of Tumor-Associated Macrophage (TAM). TAM is produced from monocytes recruited at the tumor site by molecules produced by TME. Major factors involved in TAM are the chemokines (CCLs), vascular endothelial growth factor (VEGF), interleukins (ILs), transforming growth factor (TGFa), matrix metalloproteinases (MMPs), extracellular matrix proteins (ECM), and platelet-derived growth factors (PDGF). TAM produces several molecules that sustain malignant cell survival, modify neoplastic ECM proteins, enhance invasion and metastasis, promote the development of a newly formed vessel, and assist tumor cells in their progression. TQ potentially inhibits TAM-related expression of various factors and proteins, resulting in decreasing angiogenesis, invasion, and metastasis of TNBC.
Figure 6
Figure 6
Endoglin in the TME of TNBC. The expression of endoglin on endothelial cells is critical for promoting primary tumor growth and metastasis. Blocking endoglin in the TNBC TME with TQ exerts anti-cancer activity.
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