Metadherin-driven promotion of cancer stem cell phenotypes and its effect on immunity in hepatocellular carcinoma

Abstract

In this editorial we provide commentary on the article published by Wang et al, featured in the recent issue of the World Journal of Gastroenterology in 2024. We focus on the metadherin (MTDH), also known as astrocyte elevated gene-1 or lysine rich CEACAM1, and its effects on cancer stem cells (CSCs) and immunity in hepatocellular carcinoma (HCC). HCC is the most common primary liver cancer and one of the leading causes of cancer-related deaths worldwide. Most HCC cases develop in the context of liver cirrhosis. Among the pivotal mechanisms of carcinogenesis are gene mutations, dysregulation of diverse signaling pathways, epigenetic alterations, hepatitis B virus-induced hepatocarcinogenesis, chronic inflammation, impact of tumor microenvironment, oxidative stress. Over the years, extensive research has been conducted on the MTDH role in various tumor pathologies, such as lung, breast, ovarian, gastric, hepatocellular, colorectal, renal carcinoma, neuroblastoma, melanoma, and leukemias. Specifically, its involvement in tumor development processes including transformation, apoptosis evasion, angiogenesis, invasion, and metastasis via multiple signaling pathways. It has been demonstrated that knockdown or knockout of MTDH disrupt tumor development and metastasis. In addition, numerous reports have been carried out regarding the MTDH influence on HCC, demonstrating its role as a predictor of poor prognosis, aggressive tumor phenotypes prone to metastasis and recurrence, and exhibiting significant potential for therapy resistance. Finally, more studies finely investigated the influence of MTDH on CSCs. The CSCs are a small subpopulation of tumor cells that sharing traits with normal stem cells like self-renewal and differentiation abilities, alongside a high plasticity that alters their phenotype. Beyond their presumed role in tumor initiation, they can drive also disease relapse, metastasis, and resistance to chemo and radiotherapy.

Key Words: Hepatocellular carcinoma, Metadherin, Astrocyte elevated gene-1, Lysine rich CEACAM1, Cancer stem cell, Immunity

Core Tip: Metadherin (MTDH) is a protein and a predictor of poor prognosis, of aggressive tumor phenotypes prone to metastasis, recurrence, and therapy resistance in hepatocellular carcinoma (HCC). Several studies have demonstrated a correlation between MTDH and cancer stem cells, which has elevated interest in further investigating this oncogene and its impacts to a higher level. The editorial highlights the ongoing research in the HCC field, revealing the significance for future studies.

INTRODUCTION

Hepatocellular carcinoma (HCC) is the most common primary liver cancer[1] and one of the leading causes of cancer-related deaths worldwide according to GLOBOCAN database[2]. It is three times more common in men than in women[3], and holds a grater prevalence in developing countries due to a higher rate of patients infected with hepatitis B and C viruses. Despite significant advancements in prevention measures and availability of effective antiviral therapy, viral hepatitises remain a predominant risk factors. However, what has changed over the years is the impact of metabolic-associated fatty liver disease and alcohol-associated liver disease in total percentage of HCC etiology[4]. This reflects the changes in lifestyle patterns and the impact of environmental factors on human health. Consequently, it seems that these ailments will assume a leading role among risk factors in the future, eclipsing previous viral infections. Alongside these factors, a smaller proportion of cases stem from alpha-1 antitrypsin deficiency, hemochromatosis, Wilson’s disease, autoimmune hepatitis, and primary biliary cirrhosis[5]. Additionally, certain environmental factors such as tobacco smoking, intake of the fungal metabolite aflatoksin B1, and also air pollution contribute to the disease burden[6]. Therefore, when discussing HCC, we recognize it as a global health problem, owing to the widespread influence of its etiological factors and due to the poor prognosis, it carries[7]. The HCC pathophysiology is a complex and multistep process. Most cases of HCC develop in the context of liver cirrhosis[8]. Among the pivotal mechanisms of carcinogenesis are gene mutations, dysregulation of diverse signaling pathways, epigenetic alterations, hepatitis B virus-induced hepatocarcinogenesis, chronic inflammation, impact of tumor microenvironment, oxidative stress[9-11]. In this editorial we provide commentary on the manuscript published by Wang et al[12] featured in the recent issue of the World Journal of Gastroenterology.

The paper delves into the metadherin (MTDH) significance concerning stemness and immune infiltration in HCC. Due to the utilization of next-generation sequencing methods, a series of genes affecting the onset and progression of HCC have been identified. At a fundamental level, they can be categorized into two groups: Inherited and somatic mutations. Inherited mutations are widespread across the liver due to their prevalence during organ development, while somatic mutations are typically confined to individual liver lobules. Among the inherited mutations predisposing to liver diseases are C282Y/C282Y mutations of HFE, ATP7B mutations, SERPINA1, and FAH mutations[13]. These mutations are linked to conditions such as hemochromatosis, Wilson’s disease, alpha-1 antitrypsin deficiency, and glycogenosis type 1A. Based on the latest findings from the cBioPortal database[14] and the comprehensive analyses conducted by Ng et al[15], exploring the integrative proteogenomic characteristics of HCC across various causes and stages, as well as the work by Cowzer et al[16], focusing on a group of patients with advanced HCC and defining targeted molecular profiling of circulating cell-free DNA, it is evident that the most frequently mutated genes include: TERT promoter, TP53, CTNNB1, ARID1A, and TSC2. MTDH, also known as astrocyte elevated gene-1 or lysine rich CEACAM1 (LYRIC), is a protein with its gene located at human chromosome 8q22[17]. Predominantly is located on the membrane of endoplasmic reticulum, then on the cell membrane, particularly in aggressive and metastatic cells. Additionally, it can be detected within the nucleus and nucleolus, depending on the cell type and detection method employed[18]. Over the years, extensive research has been conducted on the role of this oncogene in various tumor pathologies, such as lung, breast, ovarian, gastric, hepatocellular, colorectal, renal carcinoma, neuroblastoma, melanoma, and leukemias. Specifically, its involvement in tumor development processes[18-20] including transformation, apoptosis evasion, angiogenesis, invasion, and metastasis[21] via multiple signaling pathways like particularly PI3/Akt[22-24], Wnt/b-catenin[25,26], and MAPK[27] has been investigated. It has been demonstrated that knockdown or knockout of MTDH disrupt tumor development and metastasis[28-31]. However, not all the fine action mechanisms of this oncogene are fully understood. Numerous studies have been carried out regarding the influence of MTDH on HCC[32-35], demonstrating its role as a predictor of poor prognosis, aggressive tumor phenotypes prone to metastasis and recurrence, and exhibiting significant potential for therapy resistance. Several studies have finely investigated precisely the MTDH impact on cancer stem cells (CSCs). CSCs are a small subpopulation of tumor cells that sharing traits with normal stem cells like self-renewal and differentiation abilities, alongside a high plasticity that alters their phenotype. Beyond their presumed role in tumor starting, they can drive also disease relapse, metastasis, and resistance to chemo and radiotherapy. Liang et al[36] demonstrated that epigenetic activation of TWIST1 by MTDH promotes cancer stem-like cell traits in breast cancer. Additionally, Suzuki et al[37] reported that MTDH promotes metastasis by supporting putative cancer cell properties and epithelial plasticity in pancreatic cancer. In addition, the immune cells play a critical role in both onset and development of chronic liver diseases. Considering the substantial HCC percentage arising from chronic inflammation, which involves cell death, regeneration, and consequent liver fibrosis or cirrhosis, investigating and comprehending immune system disorders and the microenvironment in general are crucial. Rumgay et al[38] provided a very clear explanation of the immune landscape of HCC. Innate immune cells involved in the processes of carcinogenesis include: Macrophages (produce IL-6 and TGF-β to promote tumor growth, IL-1, TNF-α, and IL-6 for invasion and metastasis, and TGF-β and IL-20 for silencing immune response), Kupffer cells (release anti-inflammatory cytokines and regulate antigen-presenting cells), myeloid-derived suppressor cells (silence T cell infiltration, dendritic cell function, and promote regulatory T cell expansion), neutrophils (produce oncogenic ligands and recruit regulatory T cells and macrophages for immune tolerance), dendritic cells (inhibit CD8⁺ T cells), and natural killer cells (release cytokines, particularly IFN-g). When considering the adaptive immune system in the HCC tumorigenesis processes, we note a marked decrease in the presence of CD4⁺ T cells and cytotoxic T lymphocytes, correlating with a poorer prognosis. The liver’s immunotolerant environment is sustained by interactions between liver-resident cells and peripheral leukocytes, promoted by a slight interplay of pro-inflammatory (IL-2, IL-7, IL-12, IL-15, and IFN-g) and anti-inflammatory cytokines (IL-10, IL-13, and TGF-b). Any disturbance in these processes or mechanisms leads to the HCC initiation or progression. Considering all the aforementioned information, the study conducted by Wang et al[12] appears to be very interesting, shedding light on things that were previously assumed. The authors unveil five pivotal stages in the HCC development linked to the overexpression of the MTDH gene. Firstly, there is a notable increase in MTDH gene expression within HCC tumor cells compared to healthy counterparts and adjacent tissue. Secondly, this gene exhibits a heightened presence in CSCs, marked by a positive correlation with molecular indicators of CSCs like CD133, Oct4, and Nanog, suggesting a fostering of stemness. Thirdly, there is a marked acceleration in cell migration and invasion. Fourthly, a less favorable prognosis is observed, characterized by shorter survival times. Lastly, there is a notable association with immune cell infiltration, with positive links to immature dendritic cells, T helper (Th)2 cells, memory B cells, central memory CD4 T cells, central memory CD8 T cells, natural killer T cells, activated dendritic cells, and activated CD4 T cells. Additionally, positive associations are noted with CXCL2, which stimulates the invasion and migration of HCC cells, while a negative correlation is observed with CXCL1 and CXCL12, differing from previous findings. These data collectively emphasize the relevant role of MTDH in driving tumor growth and the progression of HCC, highlighting potential therapeutic avenues. Rumgay et al[38] have provided estimates on the global burden of HCC for 2020, projecting that without intervention, the annual rate of new cases and deaths from this disease will surge by over 55% by 2040. Armed with this alarming forecast, it is imperative that we intensify our efforts, especially in designing prevention programs, addressing the root causes, ensuring timely diagnosis and treatment of early stages, and exploring avenues for research into disease progression and novel therapeutic approaches.

CONCLUSION

This study holds profound significance as it sheds light on the MTDH role in the HCC development, thereby paving way for enhanced understanding and improved strategies in preventing the migration and invasion of this carcinoma, as well as in the realm of immunotherapy. Moving forward, a next step lies in unraveling the fine mechanisms through which MTDH influences CSCs and correlates with immune infiltration, what presents a pivotal piece of the puzzle that warrants further exploration.