Review
Resveratrol for targeting the tumor microenvironment and its interactions with cancer cells

https://doi.org/10.1016/j.intimp.2021.107895Get rights and content

Highlights

  • Tumor includes a wide range of cancer and non-cancer cells that play key roles in the tumor growth.

  • CD4+ and CD8+ lymphocytes, and NK cells provide anti-tumor immunity, while macrophages, Tregs and CAFs promote tumor growth.

  • Resveratrol affect both anti-tumor and tumor-promoting cells in tumor, leading to activation of anti-tumor immunity.

  • Resveratrol can suppress hypoxia and angiogenesis through modulation of intercellular communications within tumor microenvironment.

Abstract

Tumor resistance to therapy modalities is one of the major challenges to the eradication of cancer cells and complete treatment. Tumor includes a wide range of cancer and non-cancer cells that play key roles in the proliferation of cancer cells and suppression of anti-tumor immunity. For overcoming tumor resistance to therapy, it is important to have in-depth knowledge relating to intercellular communications within the tumor microenvironment (TME). TME includes various types of immune cells such as CD4 + T lymphocytes, cytotoxic T lymphocytes (CTLs), natural killer (NK) cells, macrophages, and T regulatory cells (Tregs). Furthermore, some non-immune cells like cancer stem cells (CSCs), mesenchymal stem cells (MSCs), and cancer-associated fibroblasts (CAFs) are involved in the promotion of tumor growth. The interactions between these cells with cancer cells play a key role in tumor growth or inhibition. Resveratrol as a natural agent has shown the ability to modulate the immune system to potentiate anti-tumor immunity and also help to attenuate cancer cells and CSCs resistance. Thus, this review explains how resveratrol can modulate interactions within TME.

Introduction

Tumor resistance to anti-cancer agents is a key factor in cancer therapy. To date, several drugs and modalities have been developed to eliminate tumors with at least side effects for normal tissues. However, tumors can develop some mechanisms to resist each stress condition [1]. Each anti-cancer modality suppresses tumor progression by killing cancer cells and inhibiting their proliferation. Radiotherapy kills cancer cells through direct damage to DNA and some other vital organelles such as endothelium reticulum, mitochondria, membrane, and also inhibition of antioxidant defense following generation of heavy amounts of reactive oxygen species (ROS) [2]. Some chemotherapy drugs and also radiation can potentiate ROS production by cells through stimulation and interruption of reduction/oxidation (redox) mechanisms. Tumors use ROS as a mediator for the proliferation of cancer cells, however, heavy production of ROS can inhibit antioxidant defense and cause unrepaired damages, leading to death in exposed cells. Furthermore, induction of cell death and massive damages to cells may lead to stimulation of redox interactions and chronic overproduction of ROS [3].

In addition to radiotherapy and also classic chemotherapy drugs, targeted cancer therapy and also immunotherapy are known as sophisticated methods for the treatment of tumors. Targeted therapy is known as new chemotherapy that tries to inhibit proliferation and cancer cells and tumor growth through targeting cancer proliferating proteins, tumor growth receptors, and angiogenesis mediators [4], [5]. Immunotherapy works based on triggering immune system function against cancer cells. There are some different immunotherapy methods. These methods try to boost the activity of natural killer (NK) cells and cytotoxic CD8 + T lymphocytes (CTLs), while they attenuate the activity of immunosuppressive cells such as mesenchymal derived suppressor cells (MDSCs), regulatory T cells (Tregs), tumor-associated macrophages (TAMs) and cancer-associated fibroblasts (CAFs). Response of these cells can be modulated following radiotherapy and chemotherapy too. Using different doses or drugs may change the activity of these cells in favor or unfavor of tumor progression. Thus, modulation of cells within the tumor, either anti-tumor cells, immunosuppressive cells, and also cancer cells is vital for overcoming tumor resistance [6], [7].

In the recent decade, some methods have been suggested to modulate TME in the favor of tumor suppression via targeting of cells and communications within the tumor. For example, using hypofractionated radiotherapy can boost anti-tumor cells, while attenuating immunosuppressive cells. Furthermore, the combination of it with immunotherapy drugs such as immune checkpoint blockers has shown interesting results in pre-clinical studies and also clinical trial studies [8], [9]. Although newer drugs and technologies have provided some conditions to reduce normal tissue toxicity and boost therapeutic efficiency, yet, side effects in normal tissues and tumor regrowth remained as problems [10], [11]. For this condition, using some low tolerable adjuvants may be useful to alleviate normal tissue toxicity and also boost tumor suppression [12].

Resveratrol is known as an herbal-derived agent that has shown both protective effects for normal tissues and also modulation of cancer cell's responses to anti-cancer agents [13]. The anti-cancer effect of resveratrol has observed more than two decades ago. After that, several experimental studies have shown that resveratrol can induce cell death in various types of cancers [14], [15]. Furthermore, synergic effects of resveratrol in combination with other anti-cancer agents such as radiation, chemotherapy, hyperthermia, and immunotherapy drugs have been revealed [16], [17], [18], [19]. In this review, we aim to explain the effects of resveratrol on different cells and intercellular communication within the tumor. For this aim, we search PubMed and google scholar databases. Articles with high reputations and novelty were selected. Furthermore, we consider the date of publication and journal reputation.

Section snippets

TME and interactions within the tumor

TME includes a wide range of molecules, intercellular signals, cancer cells, cancer stem cells (CSCs), endothelial cells (ECs), dendritic cells (DCs), Tregs, MDSCs, CTLs, NK cells, macrophages including both TAMs and M1 macrophages, bone marrow mesenchymal stem cells, etc. [20], [21]. For the treatment of cancer, we need to know the function and importance of each cell and molecule within TME. This knowledge can let us decide about targeting critical cells and signaling to improve the

Resveratrol

Resveratrol (3,5,4′-trihydroxy-trans-stilbene) is an herbal-derived non-flavonoid polyphenol that was initially isolated more than 80 years ago. However, anti-cancer effects of resveratrol were observed by an experimental study in 1997 [30]. Resveratrol has shown several beneficial effects such as cardioprotective effects, modulation of metabolic diseases, protection against aging, anti-inflammatory properties, etc. [31], [32]. Resveratrol can be found and isolated from different sources. The

Targets in TME for resveratrol as alone or combination with anti-cancer modalities

Resveratrol as an anti-cancer agent has been shown that modulate several responses and signaling pathways within the tumor. As mentioned earlier, some cells within tumors help to promote cancer cell proliferation. TAMs, MDCSs, Tregs, CAFs, mesenchymal stem cells (MSCs), and also cancer cells release some factors that potentiate proliferation, invasion, and migration of cancer cells and CSCs. On the other hand, NK cells, M1 macrophages, and CTLs inhibit cancer cells [23]. Resveratrol can affect

Targeting of intercellular communications

In addition to the regulatory effects of resveratrol on immune cells, it can enhance therapeutic effects on cancer cells via modulation of intercellular communications. Resveratrol can modulate several signaling pathways in cancer cells through stimulation or suppression of some intercellular mediators such as chemokines, cytokines, miRNAs, dead signals, etc [103]. In this section, we discuss the direct regulatory effects of resveratrol on intercellular signals. These intercellular

Targeting of cancer cells

Interactions between TME and cancer cells have a key role proliferation of cancer cells, resistance to apoptosis, and tumor growth. Stimulation of cancer cell death is one of the important aims of tumor therapy [113], [114]. Some different mechanisms affect the survival of cancer cells. Apoptosis is known as the most known mechanism for killing cancer cells. However, some other mechanisms such as senescence, mitotic catastrophe, necrosis, necroptosis, autophagy, and ferroptosis can be induced

Targeting of hypoxia and angiogenesis

Hypoxia and angiogenesis are common phenomena in solid tumors that affect the function of cancer cells and other immunosuppressive or anti-tumor cells in TME [172]. Hypoxia and angiogenesis are hallmarks of TME that induce malignancy through some pathways such as epithelial-mesenchymal transition (EMT), induction of immune checkpoints to exhaust anti-tumor immunity, stimulation of survival of cancer cells, stimulation of angiogenesis, reprogramming cells in TME, etc [173], [174]. Hypoxia acts

Conclusion

Resveratrol has been shown several anti-tumor properties. However, the complete mechanisms for anti-tumor effects of resveratrol need to be more elucidated. Interactions between various types of cells in tumors play a key role in the suppression or progression of the tumor. Tumor includes both anti-tumor and tumor-promoting cells. Modulation of the interactions between cancer and non-cancer cells can be suggested for targeting the tumor. Resveratrol has been shown that modulate the interactions

Declaration of Competing Interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Acknowledgements

1. Research projects of colleges and universities in Inner Mongolia, Project Number: NJZY20113.

2. Science Research Program of Inner Mongolia University for Nationalities, Project Number: NMDYB19054.

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