Cancer(Basel) 2024 Jan 25;16(3):522. doi: 10.3390/cancers16030522.
Gastric cancer 의 pathogenesis 에 대한 review 입니다. H. pylori 혹은 autoimmune 이 SPEM 및 atrophic change의 중요한 원인이며, 그러한 process에 Th2 Immune responses 가 중요한 역할을 한다는 내용입니다. 하지만 그 과정에서 RAS mutation 등은 아직 모호합니다. 내용을 살펴 보겠습니다.
Figure 1. Progression from gastritis to gastric cancer. At the onset of gastric inflammation and during its progression to a chronic stage, neutrophils and Th1-associated mediators and cell types are prevalent. As chronic inflammation proceeds, multiple cell types infiltrate the gastric mucosa as part of a mixed Th1/Th2 immune response, leading to parietal cell loss and progressive chief cell transdifferentiation, with an increase in the spasmolytic peptide, TFF2, resulting in SPEM. If the chronic inflammatory insult does not subside, SPEM progresses to a more intestinalized phenotype, with the proliferation of intestinal mucus-secreting goblet-like cells, a full Th2 response and the initiation of an irreversible stage of disease, which can eventually lead to dysplasia and cancer. Abbreviations: CCNE1, Cyclin E1; CDX2, homeobox protein CDX-2; IFN, interferon; IL, interleukin; AQP5, aquaporin 5; MIST1, muscle, intestine and stomach expression 1; MUC6, mucin 6; MYC, Myc proto-oncogene protein; NK-kB, nuclear factor kappa-light-chain-enhancer of activated B cells; PD-L1, programmed death-ligand 1; SHH, sonic hedgehog; TFF2, trefoil factor 2; TP53, tumor protein P53; WFDC2, WAP four-disulfide core domain 2.
Figure 2. Th2-depenent gastric metaplasia onset and progression to SPEM. Following parietal cell loss, IL-33 is released, promoting activation and recruitment of different cell types involved in Th2 immune responses. IL-25, released by Tuft cells, also contributes, along with IL-33, to potentially induce the activation and proliferation of ILC2s. M2 macrophages and eosinophils, in turn, produce IL-13 and more IL-33, self-sustaining a feed-forward cycle, stimulating mast cell activity. The resulting downstream release of IL-13 promotes the progression to SPEM, that, in the presence of a chronic inflammatory insult, can lead to intestinal metaplasia and cancer. Abbreviations: IL, interleukin; SPEM, spasmolytic polypeptide-expressing metaplasia.
Conclusions
Increasing evidence supports Th2 immune responses and their associated cytokines to represent key players in the development of metaplasia and may serve as important targets for the treatment and prevention of gastritis and gastric metaplasia. In fact, targeting cytokines, such as IL-33, IL-25, IL-13 and IL5, is effective in modulating the downstream recruitment and activation of immune cells, such as eosinophils, M2 macrophages, mast cells, and in some instances, ILC2s, therefore can be beneficial in preventing/reducing gastritis and downstream gastric metaplasia. Moreover, taking into account the impact of chronic inflammation in promoting dysregulated tissue repair processes resulting in metaplastic events, murine models, such as SAMP mice, that develop a spontaneously occurring phenotype and more closely resemble the human setting (without chemical, immunologic, or genetic manipulation), can prove to be very useful to thoroughly dissect the contribution of specific mediators and/or cell populations prior to, and during, the progression of disease. Other models that fully develop or can be induced to progress toward gastric dysplasia and/or advanced gastric cancer will also provide the appropriate tools to further understand the pathogenesis and treatment of this devastating condition.
Simple Summary:
Gastric cancer is one of the most prevalent and deadliest neoplasms worldwide. Although significant advances have been made in recent decades to improve its treatment, an incomplete understanding of its etiology and pathogenesis still limits our ability to effectively prevent and treat gastric cancer. It is well established that the most common subtype of gastric cancer (intestinal gastric cancer) develops through a multi-step process, wherein pathologic changes in gastric cells progressively occur, ultimately leading to the development of tumors. Recent evidence suggests that, aside from environmental factors, the immune system plays a key role in the sequela from gastritis to metaplasia, dysplasia and finally, gastric cancer, primarily through type 2 immune responses. In this review, we summarize the current literature and provide an overall interpretation regarding the impact of T helper 2 (Th2) immunity on the development and progression of gastric cancer
Abstract
Gastric cancer is one of the leading causes of cancer deaths worldwide, with chronic gastritis representing the main predisposing factor initiating the cascade of events leading to metaplasia and eventually progressing to cancer. A widely accepted classification distinguishes between autoimmune and environmental atrophic gastritis, mediated, respectively, by T cells promoting the destruction of the oxyntic mucosa, and chronic H. pylori infection, which has also been identified as the major risk factor for gastric cancer. The original dogma posits Th1 immunity as a main causal factor for developing gastritis and metaplasia. Recently, however, it has become evident that Th2 immune responses play a major role in the events causing chronic inflammation leading to tumorigenesis, and in this context, many different cell types and cytokines are involved. In particular, the activity of cytokines, such as IL-33 and IL-13, and cell types, such as mast cells, M2 macrophages and eosinophils, are intertwined in the process, promoting chronic gastritis-dependent and more diffuse metaplasia. Herein, we provide an overview of the critical events driving the pathology of this disease, focusing on the most recent findings regarding the importance of Th2 immunity in gastritis and gastric metaplasia.
Keywords: IL-33; M2 macrophages; Th2 immunity; eosinophils; gastric metaplasia; intestinal metaplasia; spasmolytic polypeptide-expressing metaplasia (SPEM).
Cancer(Basel) 2024 Jan 25;16(3):522. doi: 10.3390/cancers16030522.
Gastric cancer 의 pathogenesis 에 대한 review 입니다. H. pylori 혹은 autoimmune 이 SPEM 및 atrophic change의 중요한 원인이며, 그러한 process에 Th2 Immune responses 가 중요한 역할을 한다는 내용입니다. 하지만 그 과정에서 RAS mutation 등은 아직 모호합니다. 내용을 살펴 보겠습니다.
Figure 1. Progression from gastritis to gastric cancer. At the onset of gastric inflammation and during its progression to a chronic stage, neutrophils and Th1-associated mediators and cell types are prevalent. As chronic inflammation proceeds, multiple cell types infiltrate the gastric mucosa as part of a mixed Th1/Th2 immune response, leading to parietal cell loss and progressive chief cell transdifferentiation, with an increase in the spasmolytic peptide, TFF2, resulting in SPEM. If the chronic inflammatory insult does not subside, SPEM progresses to a more intestinalized phenotype, with the proliferation of intestinal mucus-secreting goblet-like cells, a full Th2 response and the initiation of an irreversible stage of disease, which can eventually lead to dysplasia and cancer. Abbreviations: CCNE1, Cyclin E1; CDX2, homeobox protein CDX-2; IFN, interferon; IL, interleukin; AQP5, aquaporin 5; MIST1, muscle, intestine and stomach expression 1; MUC6, mucin 6; MYC, Myc proto-oncogene protein; NK-kB, nuclear factor kappa-light-chain-enhancer of activated B cells; PD-L1, programmed death-ligand 1; SHH, sonic hedgehog; TFF2, trefoil factor 2; TP53, tumor protein P53; WFDC2, WAP four-disulfide core domain 2.
Figure 2. Th2-depenent gastric metaplasia onset and progression to SPEM. Following parietal cell loss, IL-33 is released, promoting activation and recruitment of different cell types involved in Th2 immune responses. IL-25, released by Tuft cells, also contributes, along with IL-33, to potentially induce the activation and proliferation of ILC2s. M2 macrophages and eosinophils, in turn, produce IL-13 and more IL-33, self-sustaining a feed-forward cycle, stimulating mast cell activity. The resulting downstream release of IL-13 promotes the progression to SPEM, that, in the presence of a chronic inflammatory insult, can lead to intestinal metaplasia and cancer. Abbreviations: IL, interleukin; SPEM, spasmolytic polypeptide-expressing metaplasia.
Conclusions
Increasing evidence supports Th2 immune responses and their associated cytokines to represent key players in the development of metaplasia and may serve as important targets for the treatment and prevention of gastritis and gastric metaplasia. In fact, targeting cytokines, such as IL-33, IL-25, IL-13 and IL5, is effective in modulating the downstream recruitment and activation of immune cells, such as eosinophils, M2 macrophages, mast cells, and in some instances, ILC2s, therefore can be beneficial in preventing/reducing gastritis and downstream gastric metaplasia. Moreover, taking into account the impact of chronic inflammation in promoting dysregulated tissue repair processes resulting in metaplastic events, murine models, such as SAMP mice, that develop a spontaneously occurring phenotype and more closely resemble the human setting (without chemical, immunologic, or genetic manipulation), can prove to be very useful to thoroughly dissect the contribution of specific mediators and/or cell populations prior to, and during, the progression of disease. Other models that fully develop or can be induced to progress toward gastric dysplasia and/or advanced gastric cancer will also provide the appropriate tools to further understand the pathogenesis and treatment of this devastating condition.
Simple Summary:
Gastric cancer is one of the most prevalent and deadliest neoplasms worldwide. Although significant advances have been made in recent decades to improve its treatment, an incomplete understanding of its etiology and pathogenesis still limits our ability to effectively prevent and treat gastric cancer. It is well established that the most common subtype of gastric cancer (intestinal gastric cancer) develops through a multi-step process, wherein pathologic changes in gastric cells progressively occur, ultimately leading to the development of tumors. Recent evidence suggests that, aside from environmental factors, the immune system plays a key role in the sequela from gastritis to metaplasia, dysplasia and finally, gastric cancer, primarily through type 2 immune responses. In this review, we summarize the current literature and provide an overall interpretation regarding the impact of T helper 2 (Th2) immunity on the development and progression of gastric cancer
Abstract
Gastric cancer is one of the leading causes of cancer deaths worldwide, with chronic gastritis representing the main predisposing factor initiating the cascade of events leading to metaplasia and eventually progressing to cancer. A widely accepted classification distinguishes between autoimmune and environmental atrophic gastritis, mediated, respectively, by T cells promoting the destruction of the oxyntic mucosa, and chronic H. pylori infection, which has also been identified as the major risk factor for gastric cancer. The original dogma posits Th1 immunity as a main causal factor for developing gastritis and metaplasia. Recently, however, it has become evident that Th2 immune responses play a major role in the events causing chronic inflammation leading to tumorigenesis, and in this context, many different cell types and cytokines are involved. In particular, the activity of cytokines, such as IL-33 and IL-13, and cell types, such as mast cells, M2 macrophages and eosinophils, are intertwined in the process, promoting chronic gastritis-dependent and more diffuse metaplasia. Herein, we provide an overview of the critical events driving the pathology of this disease, focusing on the most recent findings regarding the importance of Th2 immunity in gastritis and gastric metaplasia.
Keywords: IL-33; M2 macrophages; Th2 immunity; eosinophils; gastric metaplasia; intestinal metaplasia; spasmolytic polypeptide-expressing metaplasia (SPEM).