H. pylori-infected cy-totoxin-associated gene A (CagA) - positive GC cells exhibit the characteristics of cancer stem cells

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Abstract​

Simple Summary​

The prevalence of cancer related to the digestive system keeps rising. We examined the 2024 literature on gastric cancer. Apart from surgery, which remains the primary treatment option for gastric cancer, immunotherapy and therapeutic targeting are becoming increasingly significant in the management of this disease. Following gastric cancer surgery, a multidisciplinary approach is required, with nutritionists and psychologists playing fundamental roles.

Abstract​

Due to the high death rate associated with gastric cancer, a great deal of research has been conducted on this disease. The goal of this paper was to start a trimestral review of 2024 for the year that had just started. The scientific literature from 1 January 2024 was chosen with consideration of the the guidelines of the European Society of Medical Oncology (ESMO), which are updated with new findings but not systematically reviewed annually. We used the search term “gastric cancer” to find the most current publications in the PubMed database related to the prognosis and treatment of gastric cancer. As previously said, the only articles that satisfied the inclusion criteria were those from 2024. Articles with case reports were eliminated since they had nothing to do with our research. The treatment of gastric cancer is the focus of the majority of articles from 2024. The primary research axes include surgery and immunonutrition, immunotherapy and Helicobacter pylori, and therapeutic targets. Patients with GC may experience less psychological, social, and financial hardship if the recently identified markers discovered in circulation are better assessed and validated. This could be achieved by either including the markers in an artificial intelligence-based diagnostic score or by using them in conjunction with traditional diagnostic methods. Due to the rising death rate associated with GC, funding for research into diagnosis, prognosis, therapy, and therapeutic targets is essential.
Keywords: prognosis, treatment, gastric cancer, update, 2024

 

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1. Introduction​

The incidence of gastrointestinal cancer continues to increase, as does the age-standardized rate at diagnosis. High global variation is present, with the highest rates being detected in South America, Eastern Asia, and Central and Eastern Europe [1,2]. Globally, gastric cancer (GC) is the most common cause of cancer-related death, with the majority occurring within the first year of diagnosis. A significant predisposing factor for GC is gastric intestinal metaplasia (GIM) [3]. GC may coexist with benign disorders such as chronic pseudotumoral pancreatitis or other malignancies such as gallbladder cancer as a part of genetic predisposition (Li Fraumeni and Lynch syndrome, familial adenomatous polyposis) [1,4].

Because there is currently no effective treatment for GC and detection is often delayed, GC is still one of the most serious diseases in the world and has a poor prognosis. Many GC patients are classified as having advanced GC, with extremely short lifespans, as a result of delayed diagnosis [5]. Treatment plans for GC now include a strong emphasis on multidisciplinary team consultation. Nonetheless, a plethora of therapeutic protocols and clinical trial insights exist [6]. The majority of patients with GC have a good prognosis because personalized therapy has been implemented; however, some patients still have advanced GC with distant metastases and recurrence [7].

 

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2. Materials and Methods​

The aim of the article was to begin a systematic literature review of 2024 as a trimestral work for the year. Scientific literature was selected from 1 January 2024 while also keeping in mind the European Society of Medical Oncology (ESMO) recommendations, which are not reviewed systematically every year as a whole but with small updates being added in line with new studies. We applied the keyword “gastric cancer” to search the PubMed database for the most recent significant articles related to the prognosis and treatment of gastric cancer. As stated before, articles from the year 2024 were the only ones that met the inclusion requirements. Case report articles were excluded because they were not part of our investigation.

3. Results​

Table 1 shows the number of articles concerning specific research directions relating to gastric cancer.

Table 1​

Literature analysis for the year 2024.

​	Found Articles (Number)​
New Experimental Methods of Diagnosis​	8​
Prognosis​	15​
Treatment​	47​

 

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3.1. New Experimental Methods of Diagnosis​

From the point of view of experimental approaches, H. pylori-infected cytotoxin-associated gene A (CagA)-positive GC cells exhibit the characteristics of cancer stem cells, including enhanced expression of cluster of differentiation (CD) 44, which is a particular surface marker for cancer stem cells. In addition, they present a greater capacity to form tumor spheroids than other GC cell lines [8].

In cases of locally advanced GC, spectral computed tomography (CT) and diffusion-weighted magnetic resonance imaging (DWI) have proven to be helpful in predicting the pathologic response to neoadjuvant chemotherapy (NAC) treatment. Pathologic response was correlated with the quantitative measures of apparent diffusion coefficients and normalized iodine concentration during the delay phase; their combination showed additional benefits and was linked to patient disease-free survival [9]. Moreover, contrast-enhanced computed tomography (CE-CT) imaging can be used to distinguish stomach gastrointestinal cancers (GISTs) from gastric schwannomas (GSs). Delong’s test revealed no statistically significant differences in the prediction performance between the clinical and radiomic data models [10].

In addition, the blood levels of serum aldehyde dehydrogenase 3 family member B1 (ALDH3B1) represent a potential diagnostic biomarker for GC. Its efficacy increases when it is accompanied by the presence of carcinoembryonic antigens (CEAs) [11]. Furthermore, the preoperative C-reactive protein-to-albumin ratio is another biomarker that may have the potential to predict surgical outcomes in terms of both short- and long-term survival [12]. On the other hand, for postoperative recurrence, a useful prognostic marker is serum New York esophageal squamous cell carcinoma 1 (NY-ESO-1) antibodies, which can be detected [13].

Other markers have been evaluated in clinical practice to determine their prognostic value. By using reverse-transcription polymerase chain reaction (qRT–PCR), the levels of cytokeratin 20 (CK20) and transmembrane glycoprotein mucin 1 (MUC1) can be determined from blood samples of GC patients. Tumor size and MUC1 levels were directly correlated with CK20 levels, but the expression and prognostic value of both markers revealed no difference in disease-free survival or overall survival (OS) [14].

Fourier-transform infrared (FTIR) microscopy revealed biomacromolecular alterations during arsenic trioxide (As2O3)-induced apoptosis in the human gastric adenocarcinoma (AGS) cell line. Therefore, FTIR may be helpful in the study of apoptosis. The apoptotic effects of As2O3 on AGS cells were validated using flow cytometry data [15].

 

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3.2. Prognosis​

The OS rate of patients with advanced GC has increased as a result of well-conducted surgery involving lymph node dissection gastrectomy (15 lymph nodes), human epidermal growth factor receptor-2 (HER2), and programmed death-ligand 1 (PD-L1) immunohistochemistry, as well as the approval of new therapeutic lines [1,16,17]. Because gastric muscle fibres are mesodermal tissue, it is hypothesized that increased myogenesis in GC participates in epithelial-to-mesenchymal transition, promoting the metastatic process and poor survival. Thus, after transcriptomic analyses of GC tissue, it was revealed that myogenesis is linked to decreased cell proliferation, which increases epithelial-to-mesenchymal transition, amplifying the process of angiogenesis and proving its poor prognostic value [18].

Additionally, integrin alpha-beta6 (ITGB6) and Rac family small GTPase 1 (Rac1) are markers of poor prognosis and tumor growth in patients with GC. ITGB6 may work by targeting Rac1, as evidenced by in vitro research showing that ITGB6 and Rac1 increase the proliferation, migration, and invasion of GC cells [19]. Furthermore, patients with GC who express higher levels of integrin beta-like 1 (ITGBL1) and lower levels of fibulin-2 (FBLN2) have a negative prognosis. Through the AKT (also known as protein kinase B)/FBLN2 axis, ITGBL1 contributes to the promotion of metastasis and strengthening of GC cell resistance to anoikis [20].

 

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In contrast, the AIO-FLOT3 (Arbeitsgemeinschaft Internistische Onkologie-fluorouracil, leucovorin, oxaliplatin, and docetaxel) trial revealed a good prognosis by prospectively assessing the effectiveness of multimodal treatments for GC patients with oligometastases, such as surgical excision of primary and metastatic lesions in conjunction with chemotherapy [21].

3.2.1. Research Models​

The prognosis is determined by several independent factors, including age, surgery, chemotherapy, and the tumor-node-metastasis (TNM) staging system. In light of this, the nomogram is a model that can be used to predict both cancer-specific survival (CSS) and OS in patients with gastric signet cell carcinoma [22] and is facilitated by machine learning (ML) models available for diagnosis. Using a noninvasive method such as a radiomic-clinicopathological model of this kind may accurately predict perineural invasion (PNI) in GC patients before surgery. Patients with PNI who had GC had comparatively poor prognoses [23]. The use of imaging diagnostics is limited because 42.5% of metastatic lymph nodes in GC are of the nodular type or peripheral type. However, ML models provide good predictive power for GC lymph node metastases [24]. A subset of ML known as deep learning (DL) was developed to predict the postoperative GC patient survival rate with accuracy. The DL model outperformed the other ML models in terms of net gains at three years, according to decision curve research [25].

 

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3.2.2. Immunological Indicators​

Through type 2 (Th2) immune responses, the immune system is crucial in oncogenesis, from gastritis to metaplasia, dysplasia, and GC. A wide variety of cell types and cytokines are involved in the processes that lead to chronic inflammation and carcinogenesis, and Th2 immune responses are among the main players in this process. Specifically, the process is mediated by the activity of cytokines, such as IL-33 and IL-13, and cell types, such as mast cells, M2 macrophages, and eosinophils, which promote diffuse and chronic gastritis-dependent metaplasia [26].

Several markers have been established as potential prognostic factors in clinical research. One of them is represented by the alpha 11 integrin subunit (ITGA11), a prognostic factor associated with immunity in gastric adenocarcinoma, a factor that is crucial for modelling the tumor immune microenvironment. Both immune cell infiltration and immune checkpoint marker expression are increased in patients with gastric adenocarcinoma who have elevated ITGA11 expression [27]. The PANoptosis (a unique new form of programmed cell death) signature can predict the prognosis and immunological efficacy of GCs in addition to aiding in the identification of the features of the tumor microenvironment. In addition to having a positive prognosis, patients with a low PANoptosis-related risk score (PANS) also had low tumor purity, high microsatellite instability (MSI), high tumor mutation load (TMB), and sensitivity to immunotherapy. The PANS can help determine whether patient demographics are appropriate for a certain chemotherapeutic medication [28]. Elevated levels of CD3+ tumor-infiltrating lymphocytes (TILs) were found to be strongly correlated with better survival rates and may be used as prognostic indicators. Furthermore, Epstein–Barr virus-positive and PD-L1-positive GCs were associated with CD3+ T-cell infiltration, which could help identify targets for immunotherapy [29]. In patients with GC, the immune–metabolism signature, which is linked to the ratio of active CD4+ T cells to regulatory T (Treg) cells, can be used to evaluate treatment plans, the tumor microenvironment, and patient prognosis. When the ratio of activated CD4 T cells to Tregs was less than 1, GC was found to have a predictive adverse effect [30].

 

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3.3. Treatment​

Table 2 shows the number of articles concerning specific research directions in relation to GC treatments.

Table 2​

Literature analysis for the year 2024.

​	Found Articles (Number)​
-Immunotherapy and H. pylori​	11​
-Plant Extracts​	8​
-Chemotherapy​	5​
-Surgery and Immunonutrition​	19​
-Therapeutic Targets​	12​

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3.3.1. Immunotherapy and Helicobacter pylori (H. pylori)​

The presence of an immunological tumor center, which includes tumor-reactive chemokine ligand 13 (CXCL13) T cells, epithelial interferon-stimulated gene programs, and early immune remodelling characterized by enhanced infiltration of CD8+ T cells, is responsible for the clinical response to first-line chemoimmunotherapy for advanced GC [31]. Claudin 11 (CLDN11) and atypical chemokine receptor 3 (ACKR3), traditionally called CXCR7-positive fibroblasts, are crucial for the management of GC with peritoneal metastases [32]. A retrospective cohort study evaluated the role of neoadjuvant chemoimmunotherapy by camrelizumab + nab-paclitaxel + S−1 vs. neoadjuvant chemotherapy alone by nab-paclitaxel in 128 patients with GC. The addition of camrelizumab to chemotherapy may improve pathological response and prolong the first recurrence. Moreover, postoperative complications and side effects associated with combined therapy did not increase compared to those associated with single therapy [33].
Furthermore, the addition of immunotherapy has revealed great efficacy, with manageable levels of toxicity being observed in comparison to conventional treatment [34]. One example is pyroptosis, a proinflammatory programmed cell death mediated by an inflammasome. It has multiple effects, influencing the onset and progression of GC in distinct ways. By stimulating the secondary pyroptosis pathway, controlling the nucleotide-binding oligomerization domain-like (NOD)-like receptor family pyrin domain containing 3 (NLRP3) inflammasome, and blocking caspase-1, several pyroptosis-based treatments have been discovered to prevent GC. Consequently, pyroptosis scores can be utilized to predict the effects of immunotherapy on GC patients [35].

 

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3.3. Treatment​

Table 2 shows the number of articles concerning specific research directions in relation to GC treatments.

Table 2​

Literature analysis for the year 2024.

​	Found Articles (Number)​
-Immunotherapy and H. pylori​	11​
-Plant Extracts​	8​
-Chemotherapy​	5​
-Surgery and Immunonutrition​	19​
-Therapeutic Targets​	12​

Open in a separate window

3.3.1. Immunotherapy and Helicobacter pylori (H. pylori)​

The presence of an immunological tumor center, which includes tumor-reactive chemokine ligand 13 (CXCL13) T cells, epithelial interferon-stimulated gene programs, and early immune remodelling characterized by enhanced infiltration of CD8+ T cells, is responsible for the clinical response to first-line chemoimmunotherapy for advanced GC [31]. Claudin 11 (CLDN11) and atypical chemokine receptor 3 (ACKR3), traditionally called CXCR7-positive fibroblasts, are crucial for the management of GC with peritoneal metastases [32]. A retrospective cohort study evaluated the role of neoadjuvant chemoimmunotherapy by camrelizumab + nab-paclitaxel + S−1 vs. neoadjuvant chemotherapy alone by nab-paclitaxel in 128 patients with GC. The addition of camrelizumab to chemotherapy may improve pathological response and prolong the first recurrence. Moreover, postoperative complications and side effects associated with combined therapy did not increase compared to those associated with single therapy [33].
Furthermore, the addition of immunotherapy has revealed great efficacy, with manageable levels of toxicity being observed in comparison to conventional treatment [34]. One example is pyroptosis, a proinflammatory programmed cell death mediated by an inflammasome. It has multiple effects, influencing the onset and progression of GC in distinct ways. By stimulating the secondary pyroptosis pathway, controlling the nucleotide-binding oligomerization domain-like (NOD)-like receptor family pyrin domain containing 3 (NLRP3) inflammasome, and blocking caspase-1, several pyroptosis-based treatments have been discovered to prevent GC. Consequently, pyroptosis scores can be utilized to predict the effects of immunotherapy on GC patients [35].

It has been well established that H. pylori plays a role in the oncogenesis of GC; thus, it is strongly recommended that all patients with infection be treated. Therefore, current clinical research focuses mostly on developing strategies to prevent GC and developing treatments to combat increasing antibiotic resistance [36]. The presence of Mott cells (plasma cells that contain Russell bodies) is an independent, helpful predictor factor. Laboratory data suggest that the presence of these cells is associated with an early disease stage and a good prognosis. Thus, these cells may play a significant role in the development of H. pylori infection-related cancer [37]. The genetic diversity of H. pylori varies according to geographical location [38]. Several studies worldwide have attempted to evaluate the rate of success of first-line treatment in the pediatric population. Among the 53 patients who received treatment, the rate of eradication was only 38%. The eradication rate was below expectations, which raises many questions and underlines the importance of developing more potential medical strategies, especially through the study of antimicrobial testing [39].

One interesting point of view is that H. pylori pIRES2-DsRed-5Express-ureF DNA vaccination may be useful as an immunotherapeutic treatment in individuals with advanced GC. H. pyloriDNA vaccines elicit a change in the response from Th1 to Th2, mimicking the immunological conditions of GC patients with persistent H. pylori infection. [40].

Additional viable options for the treatment of H. pylori infections include antimicrobial peptide (AMP) hydrogels, which exhibit both efficacy and biosafety. Because of their rapid physical membrane disruption and anti-inflammatory/immunoregulatory qualities, AMP have been shown to offer special advantages over antibiotics-resistant microorganisms. AMP hydrogels offer two advantages over traditional antibiotic treatments: they eliminate the need for proton pump inhibitors throughout the treatment and quickly kill germs in the gastric juice [41].

 

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3.3.2. Possible Experimental Treatments from Plant Extracts​

Apigenin may act as an anti-GC agent, which is demonstrated by its ability to modulate multiple cancer hallmarks in GC, including cell proliferation, apoptosis, migration, inflammation, and oxidative stress [42]. Reversing stomach precancerous lesions, particularly dysplasia, was safe and effective with one pack of Moluodan, a Chinese herbal medicine, taken three times a day for a year. Greater efficacy was observed when the dose was doubled [43].

By increasing the generation of reactive oxygen species (ROS) in the mitochondria, decreasing the potential of the mitochondrial membrane, and blocking the STAT3 pathway, asarinin causes apoptosis and slows the progression of gastric precancerous lesions [44]. The programmed cell death 4 (PDCD4)-autophagy related 5 (ATG5) signalling pathway may be regulated by the ethyl acetate extract of Celastrus orbiculatus to suppress autophagy in gastric epithelial cells, thereby reversing the progression of precancerous lesions in the GC [45].

Eremia multiocellata, in combination with cisplatin, successfully decreased the migratory and invasive capacity of the GC cell line MKN45/cisplatin DDP and triggered MKN45/DDP cell apoptosis, according to the results of both in vitro and in vivo investigations [46]. With a distinct aniline–indole fused moiety, anithiactin D [1], a novel member of the 2-phenylthiazole class of natural compounds, was isolated from the marine mudflat-derived actinomycete Streptomyces sp. 10A085. It is a strong inhibitor of cancer cell motility [47].

Furthermore, silver nanoparticles (AgNPs) produced from the extract of Caralluma pauciflora may be utilized to treat GC in humans [48]. Portulaca oleracea L. (POL) may be a viable new option for the management and prevention of digestive system malignancies associated with inflammation. POL has various chemical formulas that include organic acids, terpenoids, alkaloids, flavonoids, and other types of natural substances [49].