Unveiling GST Family: A Critical Player in the Development and Survival of Metastatic Tumors

Giorgi Svanishvili
Anatomical Researches and Skills Centre, Tbilisi, Georgia
Correspondence to: giorgisvanishvili85@gmail.com

DOI: https://doi.org/10.70389/PJS.100035

Additional information

• Ethical approval: N/a
• Consent: N/a
• Funding: No industry funding
• Conflicts of interest: N/a
• Author contribution: Giorgi Svanishvili – Conceptualization, Writing – original draft, review and editing
• Guarantor: Giorgi Svanishvili
• Provenance and peer-review:
  Commissioned and externally peer-reviewed
• Data availability statement: N/a

Keywords:Breast cancer, Cancer metastasis, Chemotherapeutic resistance, Gene polymorphisms, Glutathione S-transferase Mu 1 (GSTM1), Glutathione S-transferase theta 1 (GSTT1), Lung cancer, Personalized cancer therapy.

Peer Review
Received: 12 September 2024
Revised: 13 November 2024
Accepted: 16 November 2024
Published: 26 November 2024

Introduction

Cancer is a complex disease defined by uncontrolled cell proliferation and division, which results in the formation of tumors. These tumors can be classified as primary or secondary. A primary tumor is the site where cancer first starts, as a result of genetic abnormalities or environmental conditions that cause cells to grow out of control. The biology of primary tumors is largely dictated by the tissue or organ from which they arise, which influences both their behavior and treatment options.¹ Secondary cancer, also known as metastatic cancer, develops when cancer cells migrate beyond the main tumor to other regions of the body. The ability to metastasize is a hallmark of malignancy and has a substantial impact on patient prognosis. Secondary tumors in new tissues or organs have the same sort of cells as the main tumor. For example, if cells from primary lung cancer move to the brain, the tumor in the brain will still contain lung cancer cells.^2,3

Metastasis is the process by which cancer cells spread from the primary tumor to invade different body parts. This multistep process includes local invasion of nearby tissues, entrance into the bloodstream or lymphatic system, survival in circulation, and eventual colonization of distant organs.^4,5 When cancer cells create secondary tumors, treatment becomes more challenging since these tumors are typically resistant to treatments that are effective for the primary tumor. Metastasis is the leading cause of cancer-related mortality, accounting for more than 90% of all cancer fatalities.⁶ While primary tumors can frequently be successfully treated with surgery, radiation, or limited therapy, the spread of cancer cells to distant organs presents a considerably more challenging clinical issue. Understanding metastasis pathways is therefore critical in developing targeted therapies that can improve outcomes for patients with advanced cancers.

Mechanisms and Steps of Metastasis Formation

Metastasis is a multi-step process that enables cancer cells to migrate from the primary tumor to distant organs. These steps include invasion, intravasation, circulation, extravasation, and colonization⁷ (Figure 1). Each phase is tightly regulated by a variety of biological signals and mechanical factors within the tumor microenvironment. Here, we outline the key steps involved in the metastatic cascade.

Invasion and Dissemination

The activation of invasion and metastasis is initiated by epigenetic factors influenced by environmental stimuli such as aging, circadian disruptions, and the tumor microenvironment. Factors like extracellular matrix (ECM) components (e.g., collagen and fibrin), ECM mechanical pressures (e.g., tension and compression), cell-cell interactions, soluble signals (e.g., growth factors and cytokines), and even the intratumoral microbiota contribute to this process. The first step in metastasis is dissemination, where cancer cells detach from the primary tumor and prepare for migration. This dissemination is preceded by chromosomal instability, which results from continuous errors in chromosome segregation during mitosis, leading to genetic mutations that promote metastatic behavior.⁸

One of the key processes in invasion is the epithelial-mesenchymal transition (EMT) (Figure 2), during which epithelial cells, which are normally immotile and tightly bound to neighboring cells and the ECM, transform into mesenchymal-like cells. This transformation enables cancer cells to become more motile and invasive, facilitating their spread.⁹ EMT is a reversible process that gives epithelial cells plasticity, which is critical for cancer progression.¹⁰ While the role of EMT in metastasis has been debated, recent research indicates that although it may not be essential for metastasis itself, it does contribute to chemoresistance, particularly in cancers such as lung and pancreatic cancer.^11–14

Intravasation

Intravasation refers to the process where cancer cells enter the bloodstream or lymphatic system, facilitating their dissemination to distant organs. Cancer cells may enter the vasculature actively or passively, depending on the tumor type, the surrounding microenvironment, and the structure of the vasculature.^15,16 Once inside the circulation, cancer cells face additional challenges to survive.

Circulation

During circulation, cancer cells are referred to as circulating tumor cells (CTCs) (Figure 3). The bloodstream presents a harsh environment, and most CTCs do not survive the journey. However, CTC clusters—groups of cancer cells that travel together—are significantly more likely to form metastases compared to single CTCs.¹⁷ Neutrophils play a role in cluster formation and help suppress immune responses, increasing the chances of CTC survival.¹⁸

CTC enrichment allows for their classification and detailed analysis, providing valuable insights into the molecular mechanisms underlying metastasis. Liquid biopsy, which involves detecting CTCs or cell-free DNA (cfDNA) in the blood, offers a non-invasive method to identify metastasis-initiating cells and assess treatment efficacy.¹⁹

Extravasation

Once CTCs reach a distant organ, they must exit the bloodstream in a process known as extravasation.² As CTCs travel through small capillaries, they may become trapped, leading to either microvascular rupture or extravasation into the surrounding tissue. Organs like the liver and bone, which have highly permeable blood vessels, are particularly susceptible to metastasis due to their structure.¹⁵ Extravasation is facilitated by interactions between cancer cells and the new microenvironment. Ligand-receptor interactions, chemokines, and nontumor cells all play a role in helping CTCs navigate and survive this stage.^16,20

Colonization

The final stage of metastasis is colonization, where cancer cells that have extravasated must establish themselves and grow in a new environment. This is often the most challenging phase, as the microenvironment in distant tissues is typically hostile to cancer cell survival.²¹ Cancer cells use several strategies to overcome these challenges. They may release tumor-derived factors and recruit bone marrow-derived cells to form a pre-metastatic niche (PMN), a supportive environment that facilitates tumor growth.^22,23 In addition, successful colonization requires the formation of a vascular network to supply nutrients and oxygen. Some cancer cells, such as breast cancer cells, can engage in vascular mimicry, forming vessel-like structures that support metastatic growth.²⁴ In certain cases, cancer cells may also exploit neuronal signaling pathways to adapt to their new environment and promote growth, further enhancing their ability to colonize distant organs.²⁵

Glutathione S-transferase Role in the Development of Metastasis

The GSTT1 gene, which encodes glutathione S-transferase theta 1 (GSTT1), has traditionally been recognized for its role in detoxification. Glutathione S-transferase (GST) enzymes help neutralize harmful substances, such as carcinogens and oxidative by-products, by binding them to glutathione (GSH) (Figure 4), a molecule essential for reducing cellular stress. After substrate activation by oxidases, glutathione is conjugated by a nucleophilic attack on the thiol group of its core cysteine.^26,27 Recent research reveals that GSTT1 plays a simultaneously unexpected and crucial role in cancer metastasis, particularly in driving the spread of tumors from the primary site to distant organs.²⁸

While GSTT1 is dispensable for the growth of primary tumors, its expression becomes critical in macrometastases, large metastatic lesions that develop in secondary sites like the lungs or liver. Within metastatic lesions, GSTT1 expression is heterogeneous: certain cells, referred to as GSTT1 High cells, show high levels of this enzyme. These cells are notable for their slow-cycling nature (they divide less frequently), making them more resistant to chemotherapy. They also exhibit features of EMT, a process through which epithelial cells (normally stationary) gain the ability to migrate and invade other tissues. Because it enables tumor cells to separate from the main tumor, infiltrate nearby tissues, and travel to distant organs, EMT is essential to metastasis. GSTT1 high cells, with their EMT features, are not only retained in metastatic lesions but are also essential for the continued dissemination of cancer cells throughout the body.²⁸

The role that GSTT1 plays in reorganizing the ECM is among the most important discoveries about this protein. The ECM is a network of chemicals and proteins that provides structural support for cells. Metastatic cancer cells must modify the ECM to suit their requirements to survive and proliferate in a new environment.²⁹ GSTT1 promotes metastasis by catalyzing the glutathionylation of fibronectin, a major structural protein in the ECM.³⁰ This process enhances the secretion of fibronectin from tumor cells and leads to its increased deposition in the ECM. A modified ECM, rich in fibronectin, supports metastatic cell survival and enables the formation of new metastatic lesions. Without this ECM remodeling, metastatic cells would struggle to establish themselves in distant organs.³⁰

The discovery of the role of GSTT1 in the tumor microenvironment is significant as it sheds light on the multifaceted nature of this enzyme. GSTT1 is known for its detoxification function, breaking down harmful compounds and protecting cells from oxidative damage. However, this study reveals that GSTT1 also plays a direct role in shaping the tumor microenvironment, creating a favorable environment for cancer cells to adapt and thrive in metastatic sites. In experiments with mouse models of pancreatic ductal adenocarcinoma and breast cancer, reducing GSTT1 expression significantly decreased the formation of metastatic lesions, almost abolishing their development. This was achieved by knocking down GSTT1 using genetic techniques like shRNA (small hairpin RNA). Conversely, when GSTT1 was overexpressed, the metastatic burden increased dramatically, confirming that GSTT1 is necessary and sufficient to drive metastasis.²⁸

Interestingly, GSTT1 was largely absent in primary tumors but highly expressed in CTCs, cells that break away from the primary tumor and travel through the bloodstream to other organs. These are the cells that are responsible for the migration and adaptation of the cells separated from the primary tumors. This suggests that GSTT1 plays a specific role in the later stages of cancer, particularly in facilitating the survival and spread of metastatic cells. One of GSTT1’s well-known functions is protecting cells from oxidative stress, a condition where cells are damaged by reactive oxygen species (ROS)—harmful molecules produced during metabolism. Normally, glutathione neutralizes these ROS, and GSTT1 helps in this detoxification process.³¹ GSTs are most commonly recognized for their ability to conjugate xenobiotics to GSH, detoxifying cellular settings; however, they may also bind nonsubstrate ligands, which have crucial cell signaling effects. Several GST isozymes from diverse classes have been found to block the action of a kinase in the MAPK pathway (a group of proteins in the cell that transmits a signal from a receptor on the cell’s surface to DNA in the nucleus) which governs cell proliferation and death, preventing the kinase from accelerating the signaling cascade.³²

Another interesting part of the GST family is Glutathione S-transferase Mu 1 (GSTM1). This gene encodes a glutathione S-transferase from the mu class. The mu class of enzymes, like GSTT1, detoxifies electrophilic molecules, such as carcinogens, drugs, environmental pollutants, and oxidative stress products, by conjugating them with glutathione. The genes that encode the mu class of enzymes are located in a gene cluster on chromosome 1p13.3 and are known to be highly polymorphic.³³ Recent studies have demonstrated a connection between GSTT1 and GSTM1 gene polymorphisms and clinical outcomes in breast cancer patients.^34,35 A comprehensive systematic review, which included 13 studies with a total of 2,311 patients, investigated the relationship between the GSTM1-null genotype and breast cancer treatment efficacy. The meta-analysis, using a random effects model, revealed a significant association between the GSTM1-null genotype and improved therapeutic results.

To explore the impact of double gene polymorphisms on breast cancer, three additional trials involving 394 patients were analyzed. A fixed-effects model indicated a notable increase in positive outcomes in patients with the GSTT1/GSTM1 double null genotype.³⁶ This observed improvement in clinical responses, including complete tumor regression, progression-free survival, and overall survival, is particularly evident during chemotherapy. The enhanced treatment efficacy is attributed to the lack of enzymatic detoxification caused by the GSTT1 and GSTM1 null genotypes, which leads to higher circulating levels of active chemotherapeutic agents. Consequently, the increased availability of these drugs results in greater cancer cell death, contributing to the superior outcomes associated with these genotypes.

In a study of 98 lung cancer patients, the GSTM1-null group had significantly higher survival time and rate than the GSTM1-present group.³⁷ It has been observed that inhibiting or reducing glutathione and/or the GST system improves treatment response rates to the popular anti-neoplastic chemotherapeutic drugs cisplatin38 and alkylating agents.³⁹ Another study intended to reveal the relationship between GST family polymorphisms (GSTM1 and GSTT1) and lung cancer outcomes. Yadong Wang et al. found that the GSTM1-null genotype was a risk factor for overall survival in individuals with lung cancer.⁴⁰

However, in the context of metastasis, the role of the GST family, particularly GSTT1, seems to go beyond simple protection from oxidative stress. Research shows that even though reducing GSTT1 levels increases oxidative stress in metastatic cells, the enzyme’s primary function in metastasis is linked to its ability to modify fibronectin and remodel the ECM.28 Interestingly, adding external sources of glutathione (such as N-acetylcysteine, or NAC) can reduce oxidative stress in cells lacking GSTT1, further emphasizing the enzyme’s dual role in managing both ROS and metastatic progression. The identification of GSTT1 as a key inducer of metastasis presents potential treatment opportunities. Targeting GSTT1 could selectively limit metastatic progression without impacting the underlying tumor, as it is important for metastasis but not for the growth of primary tumors.

Potential Usage and Therapies

GSTT1’s role in metastasis suggests several potential therapeutic strategies. Targeting GSTT1 could be particularly effective in preventing or treating metastatic disease, especially in cancers where GSTT1 is highly expressed in metastatic lesions. One approach could involve developing specific inhibitors that block GSTT1 activity, thereby hindering its role in ECM remodeling and fibronectin modification. This could potentially limit the spread of cancer cells to distant organs and improve patient outcomes. Another potential strategy is to use GSTT1 expression levels as a biomarker to identify patients at higher risk for metastatic disease. This could help in personalizing treatment plans and improving the monitoring of disease progression. Additionally, combining GSTT1-targeted therapies with existing treatments, such as chemotherapy or immunotherapy, may enhance overall efficacy by addressing multiple aspects of cancer progression and metastasis. Research into GSTT1’s interactions with other molecular pathways involved in metastasis could also uncover new therapeutic targets and strategies. For example, exploring the relationship between GSTT1 and EMT, oxidative stress, and ECM remodeling may provide further insights into how best to disrupt the metastatic process.

Limitations

Despite the promising insights into GST’s role in metastasis, there are several limitations and challenges associated with current research and therapeutic approaches. One significant limitation is the variability in GSTT1 and GSTM1 expression and activity across different cancer types and individual patients. This variability can affect the reliability of GSTT1 and GSTM1 as a universal therapeutic target. Additionally, while GSTT1/GSTM1 has been identified as crucial for metastatic progression in some studies, its role in metastasis may not be as critical in all cancer types or stages, potentially limiting the applicability of GSTT1/GSTM1-targeted therapies. Given the complexity of cancer biology, targeting a single gene or pathway may be insufficient to address the numerous aspects of metastasis formation. Since cancer cells can adapt rapidly, treatments that target the GST family may be less successful if redundant or compensatory mechanisms are present. Furthermore, to prevent negative effects on normal tissues, the toxicity and off-target effects of particular inhibitors or genetic changes must be thoroughly evaluated.

Conclusion

The study of metastasis is crucial for advancing cancer treatment, as metastasis remains the leading cause of cancer-related mortality. Understanding the mechanisms behind metastasis, including the complex processes of invasion, intravasation, circulation, extravasation, and colonization, provides valuable insights into potential therapeutic targets. The GSTT1/GSTM1 gene, traditionally known for its role in detoxification, has emerged as a significant player in cancer metastasis. Its involvement in ECM remodeling and fibronectin modification highlights its potential as a therapeutic target. However, the variability in GSTT1/GSTM1 expression and the complexity of cancer biology present challenges that need to be addressed. Future research should focus on overcoming these limitations by developing specific GSTT1/GSTM1 inhibitors, identifying patient subgroups that could benefit from GSTT1/GSTM1-targeted therapies, and integrating these approaches with existing cancer treatments.

All things considered, the discovery that the GST family plays a critical role in metastasis emphasizes the significance of continuing to explore and focus on the molecular pathways causing cancer to spread. We can improve the prognosis of patients with metastatic cancer and get closer to more efficient and individualized treatments by expanding our understanding of these mechanisms and creating efficient therapies.

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Cite this article as:
Svanishvili G. Unveiling GST Family: A Critical Player in the Development and Survival of Metastatic Tumors. Premier Journal of Science 2025;4:100035.

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