Molecular pathogenesis, targeted therapies, and future perspectives for gastric cancer

Yongji Zeng; Ramon U Jin

doi:10.1016/j.semcancer.2021.12.004

. Author manuscript; available in PMC: 2026 Jan 27.

Published in final edited form as: Semin Cancer Biol. 2021 Dec 18;86(Pt 3):566–582. doi: 10.1016/j.semcancer.2021.12.004

Molecular pathogenesis, targeted therapies, and future perspectives for gastric cancer

Yongji Zeng ^a, Ramon U Jin ^b,^*

PMCID: PMC12833737 NIHMSID: NIHMS2133640 PMID: 34933124

Abstract

Gastric cancer is a major source of global cancer mortality with limited treatment options and poor patient survival. As our molecular understanding of gastric cancer improves, we are now beginning to recognize that these cancers are a heterogeneous group of diseases with incredibly unique pathogeneses and active oncogenic pathways. It is this molecular diversity and oftentimes lack of common oncogenic driver mutations that bestow the poor treatment responses that oncologists often face when treating gastric cancer. In this review, we will examine the treatments for gastric cancer including up-to-date molecularly targeted therapies and immunotherapies. We will then review the molecular subtypes of gastric cancer to highlight the diversity seen in this disease. We will then shift our discussion to basic science and gastric cancer mouse models as tools to study gastric cancer molecular heterogeneity. Furthermore, we will elaborate on a molecular process termed paligenosis and the cyclical hit model as key events during gastric cancer initiation that impart nondividing mature differentiated cells the ability to re-enter the cell cycle and accumulate disparate genomic mutations during years of chronic inflammation and injury. As our basic science understanding of gastric cancer advances, so too must our translational and clinical efforts. We will end with a discussion regarding single-cell molecular analyses and cancer organoid technologies as future translational avenues to advance our understanding of gastric cancer heterogeneity and to design precision-based gastric cancer treatments. Elucidation of interpatient and intratumor heterogeneity is the only way to advance future cancer prevention, diagnoses and treatment.

Keywords: Cancer organoids, Paligenosis, Precision oncology, Cyclical hit model, Mouse models

1. The clinical dilemma of gastric cancer

The advent of DNA sequencing technology and the “omics” revolution has heralded a new era of precision oncologic medicine [1,2]. The armamentarium for the oncologist is no longer limited to cytotoxic chemotherapies, and new more efficacious and safer molecularly targeted therapies are changing the way that we treat many solid malignancies [3–8]. While the same sequencing efforts have also characterized stomach cancer and revealed important molecular details [9,10], these new insights have not dramatically improved survival for gastric cancer patients as targeted therapies have shown only modest efficacy [11–13]. At the same time, the clinical burden of gastric cancer remains high throughout the world. In the United States for 2021, it is estimated that there will be more than 45,000 new gastric cancer cases to result in more than 26,000 deaths [14]. Worldwide, gastric cancer remains the fifth most common cancer by incidence causing the fourth-highest number of cancer-related deaths [15]. Survival for this disease also remains poor [16] as the five-year overall survival rates remain around 25% for all stages, and the five-year survival rates for gastric cancer patients diagnosed with advanced metastatic disease remain less than 5% [17]. It is clear that improved treatments for gastric cancer are needed.

We will present an overview of the current therapeutic paradigm to highlight the scarcity of molecular targeted therapies for gastric cancer [18,19]. Importantly, current gastric cancer treatments approach this disease as a single entity, and treatment strategies for gastric cancer can be divided based on either curative or palliative intent. For the former, applicable to locally advanced gastric cancers, the recommended treatment modality is based on a peri-operative multi-drug chemotherapy regimen [20–22]. Alternatively, the combination of chemotherapy and radiation [23–26] or chemotherapy alone [27–29] in the adjuvant setting after curative-intent resection has also been shown to be clinically beneficial depending on the adequacy of the surgery [30]. There is currently no evidence that targeted therapy or immunotherapy has any role in the treatment of gastric cancers for curative intent. Of note, the CheckMate 577 trial has recently shown that the addition of nivolumab, a humanized anti-programmed death 1 (PD-1) antibody improved survival among esophageal and gastroesophageal junctional cancer patients after neoadjuvant chemoradiotherapy and surgery with residual pathological disease [31]. For our discussion here we will be using the classic definition of gastric cancer along with Siewert type III gastroesophageal junctional tumors [32] given the clinical [33,34] and molecular similarities [9,35].

For advanced gastric cancers, traditional palliative intent treatment has been multi-agent cytotoxic chemotherapies [36,37]. And while clinical efficacy has been shown to increase with two and even three drug combinations, so does the side effect profile and treatment limiting toxicities [36,37]. Fortunately, given the need for efficacious and well-tolerated treatments for patients with advanced gastric cancer, targeted therapy and immunotherapy have emerged as adjuncts to traditional cytotoxic chemotherapy, Table 1. In terms of targeted therapy, there are currently only two clinically established molecular targets for advanced gastric cancer. The first is the human epidermal growth factor receptor 2 (HER2/neu or ERBB2), which is overexpressed or amplified in 10%–30% of gastric cancers [38]. To target this molecule, trastuzumab, a monoclonal antibody against HER2, was developed and has been shown in the ToGA trial to be efficacious as a frontline treatment for gastric cancer when combined with multiagent chemotherapy [39]. Multiple other HER2 targeting agents and strategies have not shown clinical efficacy [11]. It is only recently, through the DESTINY-Gastic01 trial, that an additional antibody-drug conjugate HER2 targeting drug, trastuzumab deruxtecan, has been approved as a single agent for advanced gastric cancer patients after progression on frontline treatment [40]. In addition to HER2/neu, the vascular endothelial growth factor (VEGF) signaling pathway has also emerged as a target for gastric cancer treatment. Specifically, the humanized antibody against VEGR receptor 2 (VEGFR2), ramucirumab, has been approved as a single agent [41] or in combination with paclitaxel chemotherapy [42] for patients with advanced gastric cancer after progression on frontline chemotherapy. In China, rivoceranib, an orally dosed VEGFR2 inhibitor is also approved for the treatment of advanced gastric cancer in the second-line setting [43]. Of note, targeting this VEGF signaling pathway has not been shown to be efficacious for treating gastric cancer in the frontline setting [11].

Table 1.

Targeted Therapies for Advanced Gastric Cancer. Molecular target, targeted agent, and pertinent clinical trial data including treatment strategy and clinical efficacy outcomes are presented for the major targeted therapies and immunotherapies used in advanced gastric cancer.

Molecular Target	Targeted Agent	Trial	Treatment	Clinical Efficacy Based on Primary Outcomes

HER2	Trastuzumab (Herceptin)	ToGA (Phase III) [39]	Advanced HER2 positive gastric or GEJ adenocarcinoma patients treated with firstline trastuzumab and chemotherapy (capecitabine plus cisplatin or fluorouracil plus cisplatin, n = 298) compared with chemotherapy alone (n = 296).	Median overall survival was 13.8 months in those assigned to trastuzumab plus chemotherapy compared with 11.1 months in those assigned to chemotherapy alone (hazard ratio 0.74; 95% CI 0.60–0.91; P = 0.0046).
	Trastuzumab deruxtecan (Enhertu)	DESTINY-GastricOl (Phase II) [40]	Advanced gastric or GEJ adenocarcinoma patients treated with trastuzumab deruxtecan (n = 125) compared to chemotherapy (irinotecan or paclitaxel, n = 62) after progression on at least two previous therapies.	Objective response rate was 51% in patients treated with trastuzumab deruxtecan as compared with 14% of those in the physician’s choice treatment group (P < 0.001).
VEGFR-2	Ramucirumab (Cyrmaza)	REGARD (Phase III) [41] RAINBOW (Phase III) [42]	Advanced gastric or GEJ adenocarcinoma patients treated with ramucirumab (n = 238) compared to placebo (n = 117) after progression on first-line chemotherapy. Advanced gastric or GEJ adenocarcinoma patients treated with ramucirumab and palitaxel (n = 330) compared to palitaxel (n = 335) after progression on first-line chemotherapy.	Median overall survival was 5.2 months in patients in the ramucirumab group and 3.8 months in those in the placebo group (hazard ratio 0.776; 95% CI 0.603–0.998; P = 0.047). Median overall survival was 9.9 months in patients treated with ramucirumab plus paclitaxel group compared to 7.4 months in the placebo plus paclitaxel group (hazard ratio 0.807; 95% CI 0.678–0.962; P = 0.017).
	Apatinib (Rivoceranib) *pproval in China only	Phase III Trial of Apatinib in Patients With Chemotherapy-Refractory Advanced or Metastatic Adenocarcinoma of the Stomach or Gastroesophageal Junction [43]	Advanced gastric or GEJ adenocarcinoma patients in China treated with apatinib (n = 176) compared to placebo (n = 91) after progression on at least two previous therapies.	Median overall survival was 6.5 months in the apatinib group compared with 4.7 months in the placebo group (hazard ratio 0.709; 95% CI 0.537 to 0.937; P = 0.0156).
PD-1	Pembrolizumab (Keytruda)	KEYNOTE-059 (Phase II) [46]	Advanced gastric or GEJ adenocarcinoma patients treated with pembrolizumab monotherapy (n = 259) after progression on at least two previous therapies.	Objective response rate was 11.6% in patients treated with pembrolizumab (30 of 259 patients; 95% CI 8.0%-16.1%).
		KEYNOTE-061 (Phase III) [45]	Advanced gastric or GEJ adenocarcinoma patients (combine positive score [CPS] of 1 or greater) treated with pembrolizumab (n = 196) compared to paclitaxel (n = 199) after progression on firstline chemotherapy.	Median overall survival was 9.1 months in patients treated with pembrolizumab and 8.3 months in patients treated with paclitaxel (hazard ratio 0.82; 95% CI 0.66–1.03; one-sided P = 0.0421).
		KEYNOTE-062 (Phase III) [47]	Advanced gastric or GEJ adenocarcinoma patients (combine positive score of 1 or greater) treated with firstline pembrolizumab (n = 256), pembrolizumab plus chemotherapy (cisplatin plus fluorouracil or capecitabine, n = 257), or chemotherapy (n = 250).	Pembrolizumab was noninferior to chemotherapy for median overall survival in patients with CPS ≥ 1 (10.6 vs 11.1 months; hazard ratio 0.91; 99.2% CI 0.69–1.18) and pembrolizumab prolonged median overall survival in patients with CPS ≥ 10 (17.4 vs 10.8 months; hazard ratio 0.69; 95% CI 0.49–0.97; *not statistically tested). Pembrolizumab plus chemotherapy was not superior to chemotherapy for median overall survival in patients with CPS ≥ 1 (12.5 vs 11.1 months; hazard ratio 0.85; 95% CI 0.70–1.03; P = 0.05) or CPS ≥ 10 (12.3 vs 10.8 months; hazard ratio 0.85; 95% CI 0.62–1.17; P = 0.16).
	Nivolumab (Optivo)	ATTRACTION-2 (Phase III) [49]	Advanced gastric or GEJ adenocarcinoma patients in asia treated with nivolumab monotherapy (n = 330) compared to placebo (n = 163) after progression on at least two previous therapies.	Median overall survival was 5.26 months in the nivolumab treated group and 4.14 months in the placebo treated group (hazard ratio 0.63, 95% CI 0.51–0.78; P < 0.0001).
		ATTRACTION-4 (Phase III) (Presented, unpublished) [50]	Advanced gastric or GEJ adenocarcinoma patients in asia treated with firstline nivolumab and chemotherapy (S-1 or capecitabine plus oxaliplatin, n = 362) compared to chemotherapy (n = 362).	Median progression free survival was 10.5 months in patients treated with nivolumab and chemotherapy compared to 8.3 months in patients treated with chemotherapy alone (hazard ratio 0.68; 98.51% CI 0.51–0.90; P = 0.0007). Median overall survival was 17.5 months in patients treated with nivolumab and chemotherapy compared to 17.2 months in patients treated with chemotherapy alone (hazard ratio 0.90; 95% CI 0.75–1.08; P = 0.257).
		CheckMate 032 (Phase I/II) [48]	Advanced gastric, esophageal, GEJ adenocarcinoma patients treated with nivolumab (n = 59) compared to nivolumab and ipilimumab (n = 49 with nivolumab 1 mg/kg plus ipilimumab 3 mg/ kg, n = 52 with nivolumab 3 mg/kg plus ipilimumab 1 mg/kg) after progression on first-line chemotherapy.	Objective response rates were 12% (95% CI, 5%–23%) for the nivolumab treated group, 24% (95% CI, 13%–39%) for the nivolumab 1 mg/kg and ipilimumab 3 mg/kg treated group, and 8% (95% CI, 2%–19%) for the nivolumab 3 mg/kg and ipilimumab 1 mg/kg treated group.
		CheckMate 649 (Phase III) [51]	Advanced gastric, esophageal, GEJ adenocarcinoma patients treated with firstline nivolumab and chemotherapy (capecitabine or fluorouracil plus oxaliplatin, n = 789) compared to chemotherapy only (n = 792).	Nivolumab plus chemotherapy showed statistical significant improvements in overall survival (hazard ratio 0.71; 98.4% CI 0.59–0.86; P < 0·0001) and progression free survival PFS (hazard ratio 0.68; 98% CI 0.56–0 81; P < 0·0001) versus chemotherapy alone in patients with PD-L1 CPS > 5.
Combination (HER2 and PD-1/PD-L1)	Trastuzumab and Pembrolizumab	First-line pembrolizumab and trastuzumab in HER2-positive oesophageal, gastric, or gastro-oesophageal junction cancer: an open-label, single-arm, phase II trial [52]	Advanced HER2 positive gastric, esophageal or GEJ adenocarcinoma patients treated with firstline trastuzumab, pembrolizumab, and chemotherapy (capecitabine or fluorouracil plus cisplatin or oxaliplatin, n = 37).	6 months progression free survival was 70% (26 out of 37 patients; 95% CI 54%–83%) for patients treated with trastuzumab, pembrolizumab, and chemotherapy.
		KEYNOTE-811 (Phase III) (Presented, unpublished) [53]	Advanced HER2 positive gastric or GEJ adenocarcinoma patients treated with firstline trastuzumab, pembrolizumab and chemotherapy (capecitabine plus oxaliplatin or fluorouracil plus cisplatin, n = 133) compared with trastuzumab and chemotherapy (n = 131).	Objective response rate was 74.4% for trastuzumab, pembrolizumab and chemotherapy treated patients compared to 51.9% for trastuzumab and chemotherapy treated patients (difference 22.7%; 95% CI, 11.2%–33.7%, P = 0.00006).

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In addition to targeted therapies, immunotherapies that block PD-1 to restore cancer immunosurveillance [44] have also emerged as newly approved therapies for gastric cancer. Pembrolizumab, a monoclonal antibody against PD-1, has shown clinical efficacy as monotherapy in the third-line setting (this indication was recently voluntarily withdrawn in North America) for patients whose gastric tumor demonstrates positivity for programmed cell death ligand 1 (PD-L1) combined positive score (CPS) [45,46]. Currently, there is insufficient evidence showing single agent pembrolizumab is superior to chemotherapy in the frontline setting [47]. Nivolumab is another monoclonal antibody targeting PD-1. Similar to pembrolizumab, single agent nivolumab has been shown to be efficacious in patients with advanced gastric adenocarcinoma after progression on standard chemotherapy with approvals for use in this setting in Japan [48,49]. Recently, nivolumab has demonstrated efficacy in the frontline setting when combined with multi-agent chemotherapy based on the ATTRACTION-4 [50] and CheckMate 649 [51] trials. Finally, there are encouraging data regarding the possible combination of immunotherapy and targeted therapy as potential future treatment strategies including recent clinical data with the combination of pembrolizumab with trastuzumab [52,53].

In summary, we have detailed here the current treatment strategies including approved targeted therapies and immunotherapies for advanced gastric cancer. Despite our continued molecular characterization and understanding of gastric cancer, there are currently no targeted agents that have shown single agent frontline efficacy for gastric cancers. In fact, most of these novel treatments are still used in combination with traditional cytotoxic chemotherapies. While these agents described above have improved our treatment of gastric cancer patients, why has our basic science understanding of this disease not more fully translated to new efficacious treatments as in other solid tumor malignancies? The answer lies in the fact that current treatments for gastric cancers approach this disease as a homogeneous disease. Whereas, in reality, gastric cancers constitute a diverse number of diseases with separate molecular characteristics that we will explore in detail in the next section.

2. The molecular characterization of gastric cancers

Gastric cancers have traditionally been categorized based on tumor histology by Lauren classification (diffuse or intestinal types) or World Health Organization (WHO) classification (papillary, tubular, mucinous, or poorly cohesive types) [54,55]. Recently, the molecular profiling of gastric and gastroesophageal junctional adenocarcinomas has revealed distinct molecular and clinical characteristics. These advancements in sequencing have expanded our understanding of basic gastric cancer biology and the heterogeneity that is inherent to this disease. There have been several major efforts to this end for gastric cancer; work from the ‘Singapore-Duke’ study [56], the Asian Cancer Research Group (ACRG) study [57], and The Cancer Genome Atlas (TCGA) group [9], have provided the basis for the molecular classification of gastric cancer. Here we will discuss the results of these efforts and detail the unique molecular heterogeneity of gastric cancer, Table 2. Of note, besides the ‘Singapore-Duke’, the ACRG, and TCGA gastric cancer molecular classifications, there are numerous other gastric cancer molecular classification efforts that we will not review here [58,59].

Table 2.

The Molecular Characterization of Gastric Cancer. Major molecular subgroup classifications are shown based on the the Singapore-Duke’, the Asian Cancer Research Group (ACRG), and The Cancer Genome Atlas (TCGA) group studies with highlighted key molecular and clinical characteritics. Novel mouse models are displayed for several TCGA subgroups.

					Mesenchymal	Proliferative	Metabolic

“SINGAPORE–DUKE” Study Classification ⁵³	Molecular Characteristics				- Low frequency of TP53 mutations; - Few copy number alterations; - KEGG pathways: Focal Adhesion and ECM Receptor Interaction; - GO pathways: Cell Adhesion, Cell Motility, and Angiogenesis - Activation of the Epithelial-Mesenchymal Transition and Cancer Stem Cell pathways; - Hypermethylation	- High frequency of TP53 mutations; - High copy number alterations; - KEGG pathways: Cell Cycle and DNA Replication; - GO pathways: M phase and Mitotic Cell Cycle; - Activation of E2F, MYC and RAS pathways; - Genes amplified: CCNE1, MYC, ERBB2, and KRAS; - Hypomethylation	- Low frequency of TP53 mutations; - KEGG pathways: Metabolic processes; - GO pathways: Digestion and Secretion (“normal gastric mucosa gene expression”); - Activation of Spasmolytic-Polypeptide-Expressing Metaplasia (SPEM) pathway
“SINGAPORE–DUKE” Study Classification ⁵³	Clinical Characteristics				- Mostly Lauren Diffuse histology type; - High histologic grade; - Potential Benefit from PI3K-PTEN-mTOR pathway inhibitors	- Mostly Lauren Intestinal histology type; - Low histologic grade; - Worse disease-free survival based on multivariate analysis	- No histologic correlation; - Beneficial effect of 5-FU treatment after surgery
		MSS/TP53+	MSI		MSS/EMT	MSS/TP53−
ASIAN CANCER RESEARCH GROUP Classification ⁵⁴	Molecular Characteristics	- Intact TP53 activity signature; - High prevalence of mutations in APC, ARID1A, KRAS, PIK3CA, and SMAD4;	- Hypermutation in KRAS, ALK, ARID1A, and genes in the PI3K-PTEN-mTOR pathway; - Loss of MLH1 by RNA expression; - Elevated DNA methylation signature; - Overexpression of PD-L1; - T cell infiltrate		- Lower number of mutation events; - Loss of CDH1 by RNA expression; - Epithelial-to-Mesenchymal Transition gene expression signature	- Most common subtype; - Loss of TP53 activity signature; - Highest frequency of TP53 mutations with low frequency of other mutations; - Highest genomic instability index with recurrent amplifications in ERBB2, EGFR, CCNE1, CCND1, MDM2, ROBO2, GATA6 and MYC;
ASIAN CANCER RESEARCH GROUP Classification ⁵⁴	Clinical Characteristics	- Associated with EBV infection; - Intermediate patient survival	- Tumors predominantly located in the antrum; - Early-stage disease; - Mostly Lauren Intestinal histology type; - Best patient survival; - Low recurrence rate with preferential liver only metastases		- Significantly younger patient median age; - Late-stage disease; - Mostly Lauren Diffuse histology type; - Worst patient survival; - High recurrence rate with preferential peritoneal seeding	- Mostly Lauren Intestinal histology type; - Intermediate patient survival; - Preferential liver only metastases
		EBV	MSI	HM-SNV ⁵⁷	GS	CIN
The CANCER GENOME ATLAS Classification ⁹	Molecular Characteristics	- EBV-CpG Island Methylator Phenotype; - DNA hypermethylation (CDKN2A silencing); - Frequent mutations in PI3KCA, ARID1A, and BCOR; - PD-L1/2 Overexpression; - JAK2, CD274 and PDCD1LG2 amplifications; - CD8+ T cell infiltrate and IFN-γ immune signature	- Gastric-CpG Island Methylator Phenotype; - Hypermutation including mutations in TP53, MSH6, EGFR, KRAS, BAX, CASPASE5, PLK1, BLM, HLA-B, B2M, E2F, RNF43, AGO2, PIK3CA, and MLK3; - Hypermethylation of MLH1 promoter (MLH1 silencing); - Mitotic and DNA pathway enrichment; - CD8+ T cell infiltrate	- POLE mutations; - Hypermutation; - Heterogeneity in immune signature expression	- Frequent CDH1, RHOA, and ARID1A mutations, and CLDN18– ARHGAP fusions; - Cell Adhesion and Angiogenesis pathways enriched with increased Epithelial - Mesenchymal Transition signature; - B cell, CD4+ T cell and macrophage immune infiltrates	- Most common subtype; - Frequent mutations in TP53, cell-cycle mediator genes (CCNE1, CCND1, and CDK6), and β-catenin pathway genes (APC and CTNNB1); - Recurrent amplifications of various receptor tyrosine kinase signaling pathway genes (ERBB2, EGFR, FGFR2, ERBB3, MET, KRAS, NRAS, and VEGFA); - Loss of Heterozygosity (LOH); - T cell exclusion and high levels of CD68+ macrophages
	Clinical Characteristics	- Occurs predominantly in the fundus and body; - Male patient predominance; - Best prognosis in patients with resectable disease; - Potential benefit from anti-PD-1 antibodies and JAK2 inhibitors	- Occurs predominantly in the antrum; - Older age predominance (median age 72 years); - Lack of benefit from adjuvant chemotherapy; - Best benefit from anti-PD-1 antibodies	- May benefit from agents that enhance NK cell activity	- Occurs predominantly in the distal stomach; - Younger age predominance (median age 59 years); - Mostly Lauren Diffuse histology type; - Worst prognosis in patients with resectable disease; - Lack of benefit from chemotherapy; - May benefit from FAK inhibition, ROS1 inhibition, and immunotherapy	- Occurs predominantly in the GEJ/cardia; - Mostly Lauren Intestinal histology type; - Associated with H. pylori infection; - Greatest benefit from adjuvant chemotherapy; - Potential benefit from targeting receptor tyrosine kinase signaling pathways (e.g., ERBB2 and VEGFR); - Potential lack of benefit from anti-PD-1 antibodies
	Novel Mouse Models ²²³				GS-Wnt Model: Anxa10-CreERT2;Cdh1^fl/fl;Kras^G12D/+; Apc^fl/fl GS-TGFB Model: Anxa10-CreERT2;Cdh1^fl/fl; Kras^G12D/+;Smad4^fl/fl	CIN Model: Anxa10-CreERT2; Kras^G12D/+;Tp53^R172H/+;Smad4^fl/fl

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The ‘Singapore-Duke’ study identified three major molecular subtypes of gastric cancer based on gene expression patterns from a selection of 248 Singapore stomach tumors and an additional 70 independent gastric cancer sample set [56]. Through this analysis, gastric adenocarcinomas were subclassified into 1) a proliferative subtype with a high number of TP53 mutations, genomic instability, and DNA hypomethylation; 2) a metabolic subtype with “normal” gastric mucosa gene expression profile (including MUC5AC, TFF2, MUC6, GIF, ATP4A, ATP4B, and CHGA; Gene Ontology terms “digestion” and “secretion”); and 3) an epithelial-mesenchymal transition (EMT) subtype (termed ‘mesenchymal’) with rare TP53 mutations, decreased CDH1 expression, and increased undifferentiated cell markers [56,58]. Interestingly, the proliferative subtype associates strongly with Lauren intestinal type histology, and the mesenchymal subtype displays mostly Lauren diffuse type histology [56]. When analyzed for patient survival metrics, the authors found no significant survival differences amongst the subgroups. However, the authors did show that response to treatment differed significantly among the subtypes. The proliferative subtype displayed the least sensitivity to 5-fluorouracil (5-FU) chemotherapy likely due to high frequency of TP53 mutations [60–62], the metabolic subtype was more sensitive to treatment with 5-FU chemotherapy possibly due to low frequency of TP53 mutations, and the mesenchymal subgroup responded particularly well to inhibition of the phosphatidylinositol-3-kinase (PI3K) pathway in part due to increased “cancer stem cell” signature mediated activation of this pathway [63].

Next, the Asian Cancer Research Group (ACRG) performed gene expression profiling, genome-wide copy number microarrays, and targeted gene sequencing on 300 gastric cancers [57]. Based on these studies, the ACRG classified the gastric tumors in their cohort into four subtypes: microsatellite instability (MSI), microsatellite stable (MSS)/EMT, MSS/TP53+, or MSS/TP53−. The ACRG first showed that these molecular subtypes associated with unique patient clinical characteristics; the MSI subtype had early-stage tumors located in the antrum with intestinal histology, MSS/EMT subtype consisted of significantly younger patients, and MSS/TP53+ tumors were more likely to be Epstein-Barr virus (EBV) associated. In contrast to the ‘Singapore-Duke’ study, patient survival differed among the ACRG subtypes. The MSI subtype had the best patient survival, followed by MSS/TP53+ and MSS/TP53− groups. The MSS/EMT gastric cancers showed the worst prognosis and survival metrics. Through genomic sequencing, the authors found that the MSI gastric cancers displayed hypermutation with frequent mutations in KRAS, ALK, ARID1A, and additional genes in the PI3K signaling pathway. The MSS/EMT group had a relatively low number of somatic alterations. The MSS/TP53− group was enriched in TP53 mutations resulting in high genomic instability and genomic amplifications in ERBB2, EGFR, CCNE1, CCND1, MDM2, ROBO2, GATA6, and MYC. Finally, the MSS/TP53+ group displayed genomic stability but harbored a higher number of mutations in APC, ARID1A, KRAS, PIK3CA, and SMAD4. Interestingly, the authors noted that the MSS/TP53+ subgroup was associated with EBV infection, but found no molecular association with H. pylori infection. Together, the ‘Singapore-Duke’ and the ACRG studies not only have revealed unique molecular differences among gastric cancers, but also raise the possibility that molecular characterization may be used to prospectively predict patient treatment responses and survival.

In 2014, The Cancer Genome Atlas group performed a comprehensive molecular study of 295 primary gastric adenocarcinomas including detailed DNA, RNA, and protein analyses [9]. Through this work, they concluded that gastric cancer could be divided into four distinct entities: Epstein–Barr virus (EBV), Microsatellite instability (MSI), genomically stable (GS) and chromosomal instability (CIN) subtypes [9]. Of note, in 2018, Liu et al. analyzed 462 cases of upper GI adenocarcinomas that had molecular data available from the TCGA core platforms and categorized an additional rare small subset of hypermutated (non-MSI) tumors as a hypermutated single-nucleotide variants (HM-SNV) subtype [64]. Here, we will detail each major TCGA molecular subtype.

Epstein-Barr virus infection is clearly associated with the development of gastric cancers [65,66], and EBV-associated gastric carcinomas account for about 10% of gastric adenocarcinomas worldwide [67]. EBV-associated gastric cancers can be detected in a variety of ways including in situ hybridization via Epstein-Barr virus-encoded small RNA assays [68,69]. Accordingly, the TCGA found a distinct molecular subgroup of EBV-positive tumors that occur mostly in the fundus and body of the stomach with a male predominance [9]. The most significant molecular feature of EBV-positive tumors is its extreme CpG island methylator phenotype (CIMP) characterized by extensive hypermethylation (i.e., inactivation) of various cancer-related genes’ promoter region CpG islands [70–72]. For example, CDKN2A promoter hypermethylation can be detected in 81.6% of EBV-positive tumors [73], and is a key molecular characteristic for these gastric cancers [74]. In addition, EBV-positive tumors also demonstrate frequent somatic mutations in PIK3CA, ARID1A, and BCOR [9,75,76], which may be leveraged for future drug development [10]. Importantly, 80% of EBV-positive gastric cancers have non-silent PIK3CA mutations that result in the activation of the PI3K-AKT signaling pathway [9,75, 77–79]. Clinically, EBV-associated gastric cancers display the best prognosis among the TCGA subtypes [80–83]. The better prognosis of EBV-positive tumors may be due to the increased viral mediated immune response resulting in downregulation of cancer cell metabolic activity [81,84]. In addition, histologic subclassification and tumor-infiltrating lymphocytes (TILs) can be used to further predict recurrence-free survival (RFS) and disease-free survival (DFS) for patients with EBV-positive tumors [85]. CD8 + T lymphocytes are the major immune cells to target tumors during cancer progression [86], and accordingly, increased CD8 + T lymphocytes infiltration is often found in EBV-positive tumors [10,87]. Amplification of CD274 or interferon-gamma (IFN-γ) mediated signaling via activation of IRF3 has been shown to cause PD-L1 overexpression [88]. Moreover, EBV-positive gastric cancers also demonstrate amplifications of JAK2 and PDCD1LG2 (PD-L2) [9]. Thus, patients with EBV-positive tumors may preferentially benefit from anti-PD-1 therapy and JAK pathway inhibition [9,65]. Furthermore, preferential responses to immunotherapy may be a more general principle for all EBV-positive tumors [89–92].

MSI is a molecular phenotype described by the TCGA that is caused by impaired DNA mismatch repair (MMR) function [93,94], and readily identifiable clinically via immunohistochemistry or molecular analyses [68]. MSI gastric cancers have the unique molecular feature of hypermutation, and specifically there are several genes most commonly mutated including TP53, MSH6, EGFR, KRAS, BAX, CASPASE5, PLK1, BLM, HLA-B, B2M, E2F, RNF43, AGO2, PIK3CA, and MLK3 [9,95–99]. These genes are involved in a variety of cellular processes such as signal transduction, transcriptional regulation, cell cycle progression/regulation, DNA integrity maintenance, chromatin remodeling, and apoptosis [100]. In detail, PIK3CA mutations demonstrate a strong association with MSI status [101], and TCGA molecular analyses reported PIK3CA gene mutations in 42% of the MSI gastric cancer tumors [9]. Lynch syndrome, a hereditary cancer predisposition syndrome caused by MMR-related germline gene mutations, is involved in about 15% of microsatellite instability-high (MSI-H) gastroesophageal cancers [10,102,103]. MSI gastric cancers demonstrate favorable survival outcomes compared to microsatellite stable tumors, again likely due to immunosurveillance with high infiltrating levels of CD8 + T cells [10, 100,104,105]. Furthermore, MSI gastric cancers also display frequent alterations in the major histocompatibility complex class I genes (e.g., B2M and HLA-B), resulting in the HLA class 1 complex expression loss and immune-surveillance escape [100]. MSI-H gastroesophageal cancers feature dense lymphocyte infiltration with a widespread increased expression of immune-checkpoint proteins including PD-L1 [104,106, 107]. MSI-H tumors demonstrated worse clinical response towards cytotoxic chemotherapy, but importantly, improved durable responses to immune checkpoint inhibitors (ICIs) [100,107,108], due to the increased CD8 + T cell infiltration and higher PD-L1 and IFN-γ protein expression levels [105,109–111]. This has been confirmed in clinical trials as MSI status and tumor mutational burden (a surrogate marker for hypermutation) are now routinely used clinically to determine the utility of immunotherapy for many cancers [112–115].

Gastric and gastroesophageal cancers lacking the molecular characteristics associated with any of the other subtypes are classified as genomically stable (GS) [9]. For example, other TCGA subtypes demonstrate mitotic network upregulation, such as increased mRNA levels of AURKA, AURKB, E2F, FOXM1, PLK1, and MYC activation targets, but the GS subtype uniquely does not [9]. These GS gastric tumors often arise in the distal stomach, are enriched for the diffuse histological variant, and frequently harbor CDH1 and RHOA mutations and fusions involving RHO-family GTPase-activating proteins (e.g., CLDN18-ARH-GAP26 fusions) [9,116–119]. Consequently, these molecular aberrancies are associated with an increased epithelial-to-mesenchymal transition molecular signature [9,116–119]. RHOA regulates the formation of actin stress fibers during EMT [120,121], and CDH1 encodes the E-cadherin (E-cad) protein, which is critical for normal epithelial cell-cell adhesion [120–122]. CLDN18-ARHGAP26 fusions lead to CLDN18 loss and ARHGAP26 gain-of-function, which impairs gastric cellular epithelial barrier properties and results in EMT phenotypes [118]. In addition, the GS subtype gastric cancers display poor prognosis [10,81], and are often refractory to chemotherapy (especially in the adjuvant setting) due to their increased mesenchymal characteristics [10,81,123]. However, the GS subtype and its recurrent mutations may potentially benefit from targeted therapeutic strategies including FAK inhibition for those with tumors harboring RHOA mutations [124] and inhibition of ROS1 for patients with CDH1 mutations [10,125]. Interestingly, GS tumors also demonstrate high levels of B cells, CD4 + T cells, and tumor-associated macrophages with the development of ectopic immune cell aggregations termed tertiary lymphoid structures (TLS) [126,127] possibly making these cancers promising candidates for immunotherapy [126].

The final TCGA subgroup of gastric cancers is the chromosomal instability (CIN) subtype. These CIN gastric cancers are the most common molecular subtype, found in at least 50% of gastric cancers, and they are associated with Lauren intestinal-type histology classification [128]. CIN gastric cancers are preferentially located at the gastroesophageal junction and proximal cardiac region of the stomach [9,10]. There exists heterogeneity in this subgroup of gastric cancers in of itself, and CIN gastric cancers may be a compilation of an even more molecularly heterogeneous group of tumors [68]. CIN gastric cancers display marked aneuploidy determined by large chromosome-level abnormalities amplifications [9,97] resulting in upregulation of many various growth factor signaling pathways [10]. CIN gastric cancers also display loss of heterozygosity (LOH) and genomic deletions leading to loss of tumor suppressor gene function [129,130]. In fact, high-levels of LOH are correlated with CIN associated intestinal or mixed-typed histology gastric cancers [131,132]. Determination of CIN gastric cancer subtype is difficult and requires oftentimes molecular analyses as there are no easily assayable biomarkers [68]. Many current additional diagnostic methods have been proposed to identify CIN gastric cancers including comparative genomic hybridization, single nucleotide polymorphism array, micronuclei counting, karyotyping, LOH analysis, and fluorescent in situ hybridization [133]. However, none of these methods are the optimal clinical diagnostic tools [68], and further work is needed to further define and diagnose CIN gastric cancers.

Despite their heterogeneity, CIN gastric cancers do display certain common molecular characteristics that include TP53 mutation enrichment [9]; recurrent amplifications of various receptor tyrosine kinase signaling pathway genes (ERBB2, EGFR, FGFR2, ERBB3, MET, KRAS, NRAS, and VEGFA); mutations in cell-cycle mediator genes (CCNE1, CCND1, and CDK6); β-catenin pathway (APC and CTNNB1) loss-of-function mutations; and COSMIC signature 17 with common AA > AC nucleotide transversions [9,10,97,134,135]. Additional common molecular pathways induced by CIN tumors are being elucidated including the presence of double-stranded DNA in the cytosol and activation of the cGAS-STING anti-viral pathway [136], and changes in cellular physiology including autophagy and protein stress response pathways to tolerate aneuploidy [137]. Furthering the understanding of these pathways may allow the development of simplified IHC based, clinically applicable biomarkers. In terms of prognostic significance of the CIN subtype, studies have found that it has an intermediate prognosis (worse than the EBV subtype but better than the GS subtype), but with variability that is likely due to its greater intragroup heterogeneity [81]. Furthermore, the CIN subtype displayed the greatest benefit from adjuvant chemotherapy [81]. In addition, Derks et al. demonstrated that more than 50% of all CIN tumors exhibit T cell exclusion and high levels of CD68+ macrophages [126]. The associations of increased MYC activity and CCNE1 amplification with immune-poor CIN gastric cancer may shed light on immune evasion mechanisms [126]. As discussed above, many of these shared CIN molecular pathways have been therapeutically targeted [9–11,134,138]. For example, trastuzumab and trastuzumab deruxtecan have activity in those CIN gastric cancers with overexpression of ERBB2 [39,40], and the VEGFR2 targeting antibody ramucirumab has efficacy in those CIN gastric cancers with VEGFA gene amplifications [41,42].

This particular subtype of gastric cancer is also highly correlated with Helicobacter pylori infection, and the chromosomal instability may be a direct consequence of this pathogen [139]. Zhang et al. examined the mutational signature of 1703 gastric tumor tissue samples [140]. The H. pylori-positive group of gastric cancers displayed unique mutational signatures shared with the CIN molecular subtype [140]. Mechanistically, it is known that H. pylori infection affects the DNA damage response and impairs DNA repair in epithelial cells [141]. Specifically, H. pylori strains with the cag pathogenicity island (PAI) that produce the cytotoxin-associated gene A (CagA) are thought to induce more severe gastric epithelial damage and are more strongly associated with gastric cancer development [142–145]. H. pylori induces genomic damage through cag PAI mediated suppression of DNA damage response pathways [146,147], and other potential cag PAI independent mechanisms [148,149]. In particular, H. pylori infection is thought to dysregulate TP53 function through multiple mechanisms including increased frequency of TP53 mutations [150,151], increased MDM2 mediated TP53 feedback loop [152], and alteration of TP53 isoform expression [153]. Direct DNA damage and impaired DNA repair response due to H. pylori infection, ultimately result in genomic translocations and amplifications by breakage-fusion-bridge cycles (i.e., chromosomal instability) [154–156]. Interestingly, certain telomere-proximal, actively transcribed regions demonstrate the most susceptibility to DNA damage induced by H. pylori, and these same genomic aberrations in susceptible genomic regions can be found in H. pylori associated gastric cancers as well [146].

Here we have detailed the molecular and clinical characteristics of the major molecular gastric cancer subgroups. There is still much work to be done to bridge the gaps between the basic and clinical understanding of these subgroups, and this will be critical given the future clinical translatability of gastric cancer molecular subtypes. Current molecular gene mutational profiling and gene expression based categorization are too cumbersome and time consuming to be clinically applicable. Immunohistochemical based tests that can serve as faithful biomarkers are needed and studies have started to develop algorithms based on histology and immunohistochemistry markers to approximate the molecular subtypes of gastric cancer [157–160], but these methodologies need to be validated by larger studies.

As a whole, it is clear that stomach cancer is comprised of different unique diseases each with its own pathogenesis. Gastric cancers oftentimes lack “early” oncogenic drivers such as KRAS mutations in pancreatic adenocarcinoma [161,162] and APC mutations in colorectal cancers [163]. Molecular subgroups have not been included in gastric cancer clinical decision making as gastric adenocarcinomas are still viewed as a common clinical entity. This monochromatic view of a complex disease is likely the reason why our translational efforts in gastric cancer have resulted in few new targeted agents with only modest clinical benefit (e.g., improvements in overall survival measured in weeks to months). To facilitate future clinical translational efforts, we need improved preclinical models of gastric cancer to study and elucidate the pathophysiological and developmental origins of gastric cancer molecular heterogeneity.

3. Imurine models of gastric cancer

Mus Musculus represents one of the best in vivo models to study carcinogenesis [164]. However, a challenge for gastric cancer mouse models is our theme of heterogeneity and the lack of unified oncogene driver mutations found in gastric cancers (especially for the most common CIN molecular subgroup). Unlike pancreatic adenocarcinoma mouse models in which two or three mutations can be targeted to specific pancreatic cell lineages to model human pancreas carcinogenesis [165,166], such simplicity is not available for gastric cancer mouse models [167–169]. A detailed review of these models is beyond the scope of this work and has been covered previously [167–169]. Our intention here is to highlight the progression of murine models of gastric cancer as this advancement has directly fueled our basic and translational understanding of gastric cancer. In this section we will highlight several mouse models available for gastric cancer research including chemical/infectious models, transgenic models, site-specific recombinase systems, and more recent human TCGA-based models.

To start, chemical agent and infectious-based mouse models were developed to recapitulate the pathogenesis of human stomach cancers. These models display differing tumor phenotypes with distinct tumorigenesis mechanisms. Specifically, we will elaborate on chemical carcinogenesis with N-methyl-N-nitrosourea (MNU) and pathogen-based carcinogenesis with Helicobacter infection models. The MNU model relies on a highly potent gastric carcinogen exposure for 30–50 weeks to induce adenocarcinoma formation in the glandular stomach [170–174]. The exact mechanism of MNU induced gastric tumorigenesis is still unclear [168], but this model has allowed researchers to elucidate many potential basic science pathways involved in gastric cancer formation [175–182]. After H. pylori was identified as a type I carcinogen and H. pylori infection was deemed to be the greatest risk for developing gastric cancer [139], researchers started to develop Helicobacter infection based gastric cancer mouse models. The H. felis, [183] and mouse-adapted H. pylori strains (e.g., Sydney strain, SS1) [184] infection models were developed as feasible means to study the progression from gastritis to adenocarcinoma as mice are resistant to human H. pylori colonization [185,186]. Chronic infection with H. felis results in inflammation, atrophy, and invasive adenocarcinoma [187]. Murine models utilizing H. pylori SS1 develop dysplasia after chronic infection [184], but only develop adenocarcinomas when the cag pathogenicity island is introduced, CagA-positive H. pylori SS1 (PMSS1) [188]. These animal models have been crucial in allowing researchers to understand the role of dietary exposure, inflammation, and infection on gastric carcinogenesis [167].

Transgenic mouse models were introduced to allow researchers in the gastric cancer field more precise control over the tumor initiating events. The INS-GAS transgenic mice were designed to excessively express the gastric hormone, gastrin, under control of the insulin promoter [189,190]. These mice develop gastric atrophy, dysplasia, and gastric cancer [167]. However, this process is exacerbated when combined with chronic Helicobacter infection as invasive gastric adenocarcinomas appear in these mice under 12 months of age [189,190]. Genetic knockout of trefoil factor 1, a protein with tumor suppressor role, in mice (Tff1^−/−) demonstrates a progression from hyperplasia to antral intramucosal carcinoma within five months in 30 percent of the mice [191] with increased mucosal inflammation through the activation of NF-κB [192] and COX2 signaling pathways [193]. The H/K-ATPase: IL-1β mice were designed to allow increased expression of the pro-inflammatory cytokine, IL-1β, in a stomach-specific manner under the control of the parietal cell specific H/K-ATPase promoter [194]. These mice develop gastric atrophy and metaplasia, and by 18 months of age, 30% of these mice progress to gastric cancer [194]. The inflammatory mechanisms of gastric carcinogenesis and the role of the microenvironment have been explored using these mice [195,196]. The next transgenic murine model we will touch upon is the gp130^F/F mice, in which a mutation in the IL-6 receptor β-chain, gp130, results in upregulation of STAT signaling [197,198]. These mice develop gastric adenomas quickly by 3 months of age, but rarely do these tumors progress to invasive cancers [197,198]. A similar STAT signaling inflammation mediated model of gastric carcinogenesis has been shown for Nfkb1^–/– mice with 95% developing gastric tumors by 18 months of age with the majority of these tumors displaying evidence of invasion [199,200]. Finally, oncogenic Kras^V12D has been expressed under the keratin 19 (K19) promoter, which itself is expressed in the gastric isthmal neck zone [201]. Inflammation, metaplasia, dysplasia, and gastric adenocarcinomas form in one-third of the mice by 16 months of age [202]. These transgenic and genetic knockout mouse models have proven to be insightful tools, but they are often limited due to their additional tissue non-specific phenotypes [168]. For example, the INS-GAS and Tff1^−/− mouse models have well documented intestinal phenotypes [191,203,204]. In addition, these transgenic and genetic knockout mouse models by themselves rarely demonstrated the aggressiveness and metastatic gastric adenocarcinoma phenotypes seen in the human disease [167].

To increase the specificity (i.e., targeting of genetic changes only in gastric cell lineages) and biological relevance of murine models of gastric cancer, researchers have turned to use site-specific recombinase, in particular, Cre recombinase technology to develop new gastric cancer mouse models [168,205]. Researchers have crossed K19-Cre^ERT knock-in mice with Lox-Stop-Lox-Kras^G12D mice to allow inducible conditional expression of oncogenic K-ras in the K19 expressing cell lineages resulting in hyperplasia, metaplasias and adenomas in the stomach (but also in the oral cavity, colon, and lung) [206]. Other models make use of the intestinal and gastric antral Villin-Cre line and a more stomach specific Foxa3-Cre to delete the tumor suppressor, Krüppel-like factor 4 (Klf4) by crossing with Klf4^fl/fl mice [182]. The authors showed that loss of Klf4 results in metaplastic changes in the gastric antrum that develop into tumors in 29% of these mice by 80 weeks of age, a process that is accelerated with MNU treatment [182]. The applicability of these early “site-specific” mouse models of gastric cancer is also limited due to the lack of unique stomach-specific promoters [167–169]. To this end, researchers have evaluated many gastrointestinal tissue stem/progenitor genetic markers such as Tff1, Bmi1, Lrig1, Lgr5, Hopx, Sox2, and Sox9 [207–213] in an attempt to identify a better gene promoter to drive Cre-recombinase expression specifically in gastric cell lineages. However, the results for these markers have failed to identify the “perfect” gastric cell lineage marker as each marker exhibits potential extra-gastric expression. For example, Tff1-CreERT2 mice were designed as a stomach specific (corpus and antral) inducible Cre recombinase that forms gastritis, metaplasia and gastric adenomas when crossed with Kras^LSL–G12D (tumors in 30% of mice after 9 months) and Braf^LSLV600E (tumors in 66% of mice after 8 months) mice in a STAT4 dependent manner [207]. However, the Tff1-Cre transgenic mouse (not Tff1-CreERT2 mice) also showed recombination detectable in Brunner glands, cecum, and proximal colon in addition to the stomach suggesting the non-stomach specific nature of this gene promoter [214]. Interestingly, using this Tff1-Cre mouse, researchers found that activation of oncogenic K-ras or deletion of Pten resulted in the development of atrophy and spasmolytic polypeptide expressing metaplasia (SPEM) or pseudopyloric metaplasia without evidence of dysplasia even at 12 months of age [214]. Furthermore, the use of Tff1-Cre to delete Cdh1 resulted in columnar epithelial loss and replacement with squamous epithelium [214].

More recently with the elucidation of the molecular subtypes of human gastric cancer, genetic mouse models have been designed to recapitulate the molecular characteristics of the human disease rather than previous candidate gene approaches. The Bass lab developed a genetic mouse model of genomically stable diffuse gastric cancer through overexpression of mutant Rhoa^Y42C in combination with loss of Cdh1 (common genomic events in GS gastric cancers as discussed above) using an inducible Mist1-CreERT2 allele [124]. Of note, MIST1 is expressed in specific gastric cell lineages including gastric chief cells [215–217], but also in the pancreas [218], salivary glands [219], and plasma cells [220]. Histologically signet-ring tumors formed in most mice 14 months after Cre recombinase induction [124]. In addition, the authors developed an organoid based xenograft system to induce in vitro recombination and show that these genetically altered organoids recapitulated many key aspects of the human disease including peritoneal carcinomatosis and ascites formation when orthotopically transplanted into the gastric wall of nude recipient mice [124]. The same researchers also developed a model for the CIN gastric cancer subtype using Mist1-CreERT2 and Lgr5-CreERT2 to drive conditional deletion of Tp53 and subsequent carcinogen (deoxycholate bile acid and MNU) exposure [221]. They showed that these mice formed dysplastic lesions in vivo, and organoids derived from these mice exhibited key features of CIN gastric cancer pathogenesis including genome doubling events and transcriptional upregulation of cell cycle and stem cell related pathways [221]. Again, it should be noted that neither of these genes are stomach specific with MIST1 expression discussed above, and LGR5 expression shown also in intestines [222]. This work has demonstrated the importance of gene-environment interactions in gastric carcinogenesis and is a novel murine model to study early molecular events of CIN gastric cancer formation.

The Stange lab has sought to further effectively recapitulate the human TCGA subgroups by developing a novel stomach and pan-gastric cell-type inducible Cre mouse line. Using bioinformatic data from murine gene expression databases, the authors found the Annexin A10 (Anxa10) gene to have a stomach-specific expression pattern in all gastric cell lineages [223]. Interestingly, in humans, ANXA10 is also expressed in duodenal Brunner’s glands, the urothelium, and certain pancreatobiliary cancers [224]. Utilizing a tamoxifen-inducible Cre recombinase within the Anxa10 gene locus, Seidlitz et al. generated several stomach-specific cancer mouse models: a CIN mouse model (Anxa10-CreERT2; Kras^G12D/+; Tp53^R172H/+; Smad4^fl/fl) and two models for the genomically stable subtype (GS-TGFB, Anxa10-CreERT2; Cdh1^fl/fl; Kras^G12D/+; Smad4^fl/fl, GS-Wnt, Anxa10-CreERT2; Cdh1^fl/fl; Kras^G12D/+; Apc^fl/fl) [223]. For the CIN mouse model, the authors sought to genetically recapitulate the three most common altered molecular pathways exhibited by the human subtype [129,223]. After tamoxifen administration and Cre recombinase activation, in gastric cells expressing Anxa10, there would be concomitant activation of oncogenic Kras^G12D mutant, expression of pathogenic mutant Tp53^R172H, and Smad4 deletion. These mice develop gastric dysplasia within 2–3 weeks and early gastric cancer formation within 2–8 weeks that were histologically similar to human intestinal-type gastric cancer. Subsequently, subserosa invasive cancers form within 8–10 weeks, and these mice progress to advanced disease with lung and liver metastases after 10 weeks. Interestingly, the authors also show that this mouse model mirrors many aspects of the human pre-cancerous progression from SPEM to intestinal metaplasia, and that proliferating chief cells (i.e., cells that undergo paligenosis, see below) can be found in these early pre-cancerous lesions. For the GS-TGFB mouse model, the authors genetically combined loss of Cdh1 with activation of oncogenic Kras^G12D and Smad4 deletion. After Anxa10 Cre recombinase activation with tamoxifen, early signet ring cell containing cancerous lesions developed within one week, progressed to more locally advanced disease over the next 16 weeks, and finally resulted in metastatic disease in the lungs and peritoneum after 16 weeks. Similar to the CIN mouse model above, proliferating cells expressing chief cell markers were found in these tumors. Finally, for the GS-Wnt mouse model, the authors combined loss of Cdh1 with activation of oncogenic Kras^G12D and Apc loss. Early in these mice, dysplasia developed with proliferating cells expressing chief cell markers as well as persistent parietal cells (i.e., lack of oxyntic atrophy). The gastric tumors that later developed exhibited maximum invasion to the submucosa, and adenomatous serrated tooth-like structures histologically. Furthermore, in vitro organoids derived from the tumors of these three mouse models showed differential responses to treatment. For example, organoids derived from the CIN model were more refractory to epidermal growth factor receptor (EGFR) pathway inhibition with the MEK1/2 inhibitor, trametinib, and more responsive to docetaxel chemotherapy compared to the GS models.

The development and continued evolution of animal models of gastric cancer has allowed further understanding of the basic biology underlying this disease. While these different mouse models of human gastric cancer display important features of the human tumors there are key differences. For example, human gastric cancer tumorigenesis (CIN molecular subtype) is a process that involves years of injury/inflammation with induction of early TP53 mutations resulting in later chromosomal amplifications and activation of receptor tyrosine kinase pathways. These mouse models [223] do not recapitulate the same molecular sequence of events, but rather rely on concomitant activation of genetic oncogenic “drivers”. In addition, questions remain about the ultimate faithfulness and clinical translatability of these models. How are the immune/stromal components of these mouse models? How well do these mouse models respond to standard of care chemotherapy treatment in vivo? Do these tumors express the same predictive biomarkers and response to targeted treatment? Further collaborations between basic scientists and clinical physicians working on gastric cancer will fuel future improvements in our ability to model gastric cancers using animal models. In addition, further “omics” based comprehensive analyses, lineage tracing cell-of-origin studies, and microenvironment investigations will continue to uncover the underlying mechanisms of human gastric cancer development and progression. Specifically, improvements in animal modeling have uniquely enabled novel insights to be made into the early molecular events during gastric cancer formation. Next, we will describe one newly emerging molecular process to view and understand the development of gastric cancers.

4. Paligenosis: a novel lens to view gastric cancer

On a tissue level, the stomach exhibits marked cellular plasticity [225–227]. Spasmolytic polypeptide expressing metaplasia or pseudopyloric metaplasia is generally thought to be a reversible, regenerative response to injury of gastric glands to chronic inflammation and damage usually induced by H. pylori infection [215,228–230]. This process is often termed “atrophy”, as acid-secreting parietal cells die, and mature chief cells in the base of the gland become metaplastic [215,228–234]. In patients infected with chronic H. pylori, the stomach undergoes continued SPEM that may be accompanied by less-reversible intestinal-type metaplasia [228–230]. It is thought that continued infection and inflammation leads to a progression of SPEM to intestinal metaplasia, and to dysplasia and cancer; a process termed the “Correa pathway” [235–237]. Here, we will discuss the emerging evidence that the molecular basis for the tissue plasticity of the stomach may contribute to inflammation and injury induced cancer risk.

Recent work has shown that many differentiated cells such as chief cells in the stomach and pancreatic acinar cells use an evolutionarily conserved program termed paligenosis to reprogram their metabolism and readopt a progenitor state as a reparative response to injury [238–241]. This process of inherent tissue plasticity is likely to be important for an even broader range of differentiated cells including those in the lung [242,243], kidney [244], intestine [245–247], liver [248,249], and skin [250,251]. The potential universality of a paligenotic injury response [241,252,253] has also been demonstrated during neurite regeneration after axotomy in the murine dorsal root ganglion, regeneration after limb amputation in the amphibian axolotl, and gut stem cell recruiting oxidative stress injury for Drosophila melanogaster [238]. At its core, paligenosis is a fundamental cellular and molecular process that explains how cells previously thought to be nondividing can become proliferative again. The molecular regulation of this conserved cellular regeneration program has recently been elucidated. As with any conserved cellular process, paligenosis is comprised of distinct stages with carefully regulated intervening checkpoints: Stage 1 involves autodegradation of differentiated cellular architecture; Stage 2 necessitates upregulating of progenitor-associated or metaplasia-associated gene expression; and Stage 3 results in cell cycle re-entry [238,239,254], Fig. 1A. After these differentiated cells divide through paligenosis, it is thought that they may “redifferentiate” though the molecular details of these steps are still yet unclear. As a whole, the process of paligenosis allows tissue healing following injury as differentiated cells are able to divide and initiate repair [239]. Specifically, upon inflammation and injury in the stomach, zymogenic chief cells that normally have abundant mTORC1 activity to drive zymogen production, decrease mTORC1 activity and massively upregulate lysosomes/autophagosomes (i.e., autophagy) to completely repurpose cellular architecture and metabolism [216]. In addition, at this initial Stage 1 phase, activating transcription factor 3 (Atf3) is induced to transcriptionally activate lysosomal trafficking genes such as Rab7b and facilitate autodegradation [255]. Loss of Atf3, results in a failure to increase RAB7-positive autophagic and lysosomal vesicles and eventual cell death due to “failed” paligenosis progression [255]. Subsequently, after Stage I, damage and progenitor associated metaplastic genes such as Sox9 and Cd44 are upregulated and mTORC1 is reactivated in preparation for cell cycle re-entry [239]. As mentioned before, this process has multiple exquisitely regulated checkpoints centered around this biphasic mTORC1 signaling. For example, blocking the reemergence of mTORC1 signaling during Stage II to Stage III transition still allows induction of autophagy and metaplastic genes (Stage I and Stage II), but prevents cell cycle re-entry at S-phase (Stage III) [239], Fig. 1B. In addition, two highly conserved genes, DNA damage-induced transcript 4 (DDIT4) and interferon-related developmental regulator 1 (IFRD1), have been found to increase during paligenosis as key regulators of this process [238]. Increasing DDIT4 initially suppresses mTORC1 during Stage I to allow autodegradation. As cells progress through Stage I, DDIT4 decreases and TP53 becomes activated to continue mTORC1 suppression to maintain cell quiescence. Later in paligenosis, increased IFRD1 suppresses TP53 activity to allow mTORC1 reactivation and cell cycle entry. Of note, Ddit4^−/− cells never suppress mTORC1 and bypass the later IFRD1-TP53 proliferation checkpoint resulting in less cell death and increased proliferation, whereas Ifrd1^−/− cells do not complete paligenosis due to persistent TP53 mediated prevention of mTORC1 reactivation resulting in more cell death and less proliferation [238]. Together, DDIT4 and IFRD1 cooperate to allow only “healthy” cells to re-enter the cell cycle. They are the safety mechanisms built into this regenerative process to minimize the risk of cancer development while still permitting normal tissue healing.

On a cellular level, unregulated (i.e., “unlicensed”) paligenosis increases cancer risk over time, Fig. 1C. In the stomach, this may allow mature chief cells to aberrantly re-enter the cell cycle during chronic inflammation induced injury [225]. This unlicensed plasticity permits chief cells to undergo cycles of de-differentiation and re-differentiation with each entry into the cell cycle increasing the risk of cancer-predisposing mutational accumulation [225]. On the other hand, during transient periods of redifferentiation, these increasing mutational signatures may be “hidden” within these seemingly normal differentiated chief cells evading cancer immunosurveillance [256]. These cancer cells-of-origin may acquire mutations over the years or decades of the cells’ lifespan accumulating with little effect until the cells acquire certain key changes and become trapped in a proliferative and more embryonic-like state [225,228,239,257,258]. Once redifferentiation is blocked, dysplastic oncogenic clones emerge may in a process that leads to carcinogenesis. This we term “the cyclical hit model” [225,259], Fig. 1D. The initial events that may lead to the emergence of these pathogenic clones may involve disfunction of key regulators of paligenosis, such as DDIT4, IFDR1 or TP53. The oncogenic consequences of unlicensed paligenosis have been clearly demonstrated [260]. As discussed, Ddit4^−/− chief cells never suppress initial mTORC1 activity. This results in inappropriate cell cycle entry of chief cells harboring potential DNA mutations. After multiple cycles of unregulated paligenosis with concomitant carcinogen exposure, these Ddit4^−/− mice had increased rates of spontaneous gastric tumorigenesis [260]. Clearly, unlicensed paligenosis affords differentiated cells the potential to divide in an unregulated manner, and it becomes immediately clear why under these circumstances, dysplasia and cancer may develop from chronic inflammation-induced areas of metaplasia [225,259,260]. The emergence of these unlicensed pathogenic clones harboring heterogeneous somatic mutational burdens can give rise to cancer sporadically and at potentially different chronologic times. Thus, the gastric cancers that arise may be genomically and phenotypically heterogeneous. The cyclical hit model explains, incorporates, and unifies key molecular features of gastric cancer (in particular the CIN subtype) discussed earlier including the occurrence of early TP53 mutations, molecular and clonal heterogeneity, and subsequent activation of multiple oncogenic pathways. Many studies using animal models and high-resolution genomic and transcriptomic analyses of metaplastic and cancerous tissues have demonstrated a critical role for SPEM lineages as precursor lesions for gastric cancer [216,231,261–263]. However, there are studies that support a gastric cancer cell-of-origin higher in the gastric gland [264–266]. The chief cell centric model is certainly not the only model for the origin of gastric metaplasia or cancer, nor is there reason to believe there is only one route to gastric tumorigenesis.

Paligenosis and the cyclical hit model lie at the nexus of basic science and clinical medicine. Continued elucidation of the pathways involved in the stages of paligenosis will undoubtedly further our fundamental understanding of the stomach and the cellular origins of gastric cancer. More importantly, understanding the origins of gastric cancer through the perspective of paligenosis and the cyclical hit model allows new avenues for diagnosis and treatment. Developing assays to determine and identify cells that have undergone cycles of paligenosis or have started to display unlicensed paligenosis may clue into cells that are at risk for neoplastic progression. In addition, elucidation of genes specific to paligenosis will allow the development of specific “biomarkers” that indicate when this process is occurring akin to the markers we have now for other fundamental cellular processes like apoptosis. Leveraging our understanding of paligenosis may become a route for chemoprevention to prevent the formation of gastric cancer. We may be able to “re-differentiate” cells at risk for cancer development in an effort to block further unlicensed cycles of paligenosis and prevent them from re-entering the cell cycle. In addition, tumors that arise via aberrant paligenosis may continue to exhibit an abnormal paligenotic response to stress. Eventual treatment in the form of chemotherapy or radiation may be interpreted by these tumor cells to be a paligenosis-inducing injury or stress. In response, the cancer cells may exploit paligenosis as a survival pathway to proliferate and survive these treatments. Targeting paligenosis might be a promising adjunct strategy for cancer treatment especially as paligenosis does not occur during normal organ homeostasis, and it is not a process used by the normal constitutively active organ stem cells. Undoubtedly, these are exciting avenues for future lines of translational investigation as we learn more about the emerging concept of paligenosis.

5. Future perspectus

Here we have detailed the molecular pathogenesis of gastric cancer in an attempt to explain why targeting specific pathways has been such a difficult translational task for this disease. The key to overcoming these hurdles will be continued elucidation of the interpatient and intrapatient heterogeneity that exists in gastric cancer. In other words, we must appreciate that each tumor may contain unique mixed populations of cancer cells that may respond differently to treatment. To start, we must increase the resolution by which we are able to molecularly characterize cancer. Continued genomic analyses have now integrated over 2,600 sequenced genomes from 38 differing tumor types [267], and established a pan-cancer DNA mutational “roadmap”. Specifically, for gastric cancer (especially for the most common CIN molecular subtype), the findings corroborate previous findings of TP53 mutations frequently occurring as an early event with chromosomal alterations occurring later as subclonal events as discussed above. However, our understanding of cancer must advance towards single cell resolution. The advent of single-cell “omics” now allows important insights towards this goal of fully understanding cancer heterogeneity [268]. The use of whole-genome and exome sequencing of single-cell nuclei has enabled investigators to detail the mutational clonal diversity of single cells within a breast cancer tumor mass [269] and also compare the genomic makeup of the primary colorectal cancer tumor cells compared to metastatic tumor cells and adjacent normal cells [270].

In addition to genomic profiling cancers at single cell resolution, detailed single-cell transcriptome analyses have also been performed in an attempt to further elucidate the heterogeneity of cancers. Several studies have laid the foundation for a single-cell transcriptomic map of the normal upper gastrointestinal tract [271]. Building upon this, recent work has used single-cell RNA sequencing to study gastric cancer. In a study by Zhang et al., the authors assessed the single cell transcriptomic profile from 9 primary gastric adenocarcinomas and were able to identify unique expression profile subgroups [272]. Importantly, they also identified the molecular characteristics of these intratumor subgroups including assignment of “differentiation degrees” within the tumors of these gastric cancers as a means to explain interpatient and intrapatient responses to treatment and prognosis. The power of single-cell transcriptomics has also been applied to the stroma to elucidate the tumor microenvironment of gastric cancer [273]. Analyzing tumor cells from seven gastric cancer patients and one patient with gastric intestinal metaplasia, Sathe et al. used single-cell RNA sequencing to detail the tumor microenvironment including unique molecular characteristics of tumor-associated stromal and immune cells, T cell exhaustion mechanisms among cytotoxic T cells, and distinct intercellular signaling pathways within the tumor microenvironment. More recently, several studies have used this technology to study the molecular changes that occur between primary gastric cancer and metastases including those to the lymph nodes [274] and to the peritoneum [275]. These above-detailed studies rely on the input of single cell suspensions, which in of itself results in certain transcriptional changes and loss of spatial resolution. However, new spatial transcriptomic platforms have been able to closely match the resolution power of single-cell RNA sequencing technology, while still maintaining tissue spatial relationships as a means to study gastric cancer tumor heterogeneity [276], and specifically the importance of recognizing this intratumor diversity as these diverse regions differ in the targetable genomic and transcriptomic molecular profiles.

The functional determinants of gastric cancer development and pathogenesis are not limited to the genome or transcriptome. Epigenomic changes are now recognized as important mechanisms for gastric cancer carcinogenesis including changes in DNA methylation, histone modification (methylation and acetylation markers) and non-coding RNAs [277] with analyses to describe these processes being developed at the single cell resolution [278] as well as single-cell chromatin accessibility assays [279]. In addition, advancements in mass spectrometry have also enabled the possibility of single cell metabolomics and proteomics of human tissues [280]. With these seemingly unlimited expansive layers of data describing the cellular composition of tumors, there also needs equal advancements in our ability to integrate and interpret these complex data sets [280–283]. Continued integration of these data sets into meaningful translation and clinically applicable information will be an additional important future target. The goal of these studies is to parse through the tumor to ultimately find targetable pathways and be able to predict resistance mechanisms in an effort to improve treatment for individual cancer patients. How can we use the data gathered from these high resolution “omics” methods to prospectively predict patient response to treatment?

Organoids are an established model system to study cancer biology [284–288], and human-derived organoid “biobanks” have been generated for many GI cancers that faithfully reproduce key aspects of and reflect the heterogeneity of the original tumor enabling characterization of molecular pathways of carcinogenesis, genetic modification for disease modeling, and drug screening to predict treatment efficacy and resistance [289,290]. Specifically, for gastric cancer, Seidlitz et al. established a biobank of twenty gastric cancer organoids with appropriate genomic, transcriptomic, and histologic characterization [291]. The authors show that these established gastric cancer organoids have differing responses to five standard chemotherapies as well as targeted therapies including trastuzumab for ERBB2 mutations and palbociclib for CDKN2A mutations. In a similar set of experiments, Steele et al. characterized seven human gastric cancer organoid lines and demonstrated a correlation between organoid treatment response and in vivo patient response to standard chemotherapies [292]. Cancer organoids have also been used to demonstrate important genotype-phenotype correlations (e.g., mutations in CHD1 and TP53 correlate with Wnt pathway independence) that may uncover new targetable pathways for gastric cancer treatment [293]. In addition, Yan et al. established a more expanded gastric cancer organoid biobank comprised of 63 organoids derived from 34 patients [294]. They performed genomic, transcriptomic, and histologic characterization of their organoids to detail similarities with the actual in vivo tumors [294]. Their gastric cancer organoid system was shown as an important tool to recapitulate intra-tumoral heterogeneity and model tumor clonal evolution. Importantly, Yan et al. were able to demonstrate concordance of organoid and in vivo treatment response to chemotherapy and targeted therapy, and perform a 37 anticancer drug screen to assay for large-scale cancer treatment sensitivity. Finally, several groups have demonstrated the utility of patient-derived cancer organoids to study the tumor microenvironment and response to immunotherapy in gastric cancers using advanced air-liquid interface or immune cell co-culture techniques [295–297].

Recently, studies have demonstrated the translatable application of cancer organoids as a tool to potentially prospectively predict cancer patient treatment response. Ganesh et al. established a biobank of 65 rectal cancer organoids and showed that the organoids ex vivo and when transplanted into transplanted in mouse rectums faithfully recapitulates in vivo patient responses to both chemotherapy and radiation treatments [298]. Yao et al. similarly derived rectal cancer organoids from 80 patients and directly compared organoid responses to the actual patient responses to radiation, 5-FU, and irinotecan [299]. The authors found that these cancer organoids were able to predict patient clinical outcomes with 78% sensitivity, 92% specificity, and 84% accuracy. More recent studies have begun to integrate cancer organoids prospectively into clinical oncology. The Tumor Organoids: feasibility to predict sensitivity to treatment in cancer patients (TUMOROID) study was a prospective observational trial to study the ability of colon cancer organoids to predict patient chemotherapy response [300]. The study was able to predict patient responses to single agent irinotecan and combination irinotecan chemotherapy with 80% and 83%, respectively with timely turnaround times of 2–3 weeks. The culmination of this work has been the Selecting Cancer Patients for Treatment Using Tumor Organoids (SENSOR) trial in which organoids were used to predict and guide patients with investigational agents [301]. This innovative trial generated 31 organoid lines from 54 enrolled advanced colorectal cancer patients prior to their last standard of care treatment. The authors were able to perform drug screening on 25 of the organoid lines against an 8 targeted therapy panel: vistusertib to block mTOR signaling, capivasertib to block AKT signaling, selumetinib to block MEK signaling, gefitinib to block EGFR signaling, palbociclib to inhibit CDK4/6 signaling, axitinib to block VEGFR signaling, gedatolisib to block PI3K/mTOR signaling, and glasdegib to block SMO signaling. Based on their organoids responses, three patients were treated with vistusertib and three additional patients were treated with capivasertib. However, none of these selected patients had predicted clinical responses. This trial demonstrates the future challenges in cancer organoid integration into clinical oncology, mainly, the ability to generate these organoids in a timely and efficient manner while the patient maintains good treatment tolerability and, most importantly, the ability to objectively decide and select pathways to test and target.

6. Conclusions

Clearly, the advancement of single cell genomics, transcriptomics, and protein analyses will enable unprecedented insight into the intra- and interpatient heterogeneity of gastric cancers. Human-derived organoid culture techniques will also enable unique experimental potential to explore and exploit this heterogeneity. However, new challenges remain. How do we interpret and integrate in a timely manner the big data that results from these advanced single cell studies? How do we also improve the prospective potential for organoid treatment screening? The answer lies in combining the resolution and precision of single cell “omics” with the functional potential of organoids. In other words, using single cell “omics” to determine the pathways and molecular vulnerabilities of the cancer, while using functional organoid drug screens to determine the best combination of drugs and compounds to block those signaling pathways. Clearly, when appropriately selected there is clinical efficacy to a molecularly targeted approach for gastric cancer [302]. Overall, we must progress beyond thinking about gastric cancers as a singular entity and disease. We must recognize that each gastric cancer is uniquely different, and every line of treatment should be tailored based on the individual features of that patient’s cancer. Only with patient-oriented precision oncology treatments can we truly improve survival for gastric cancers.

Acknowledgements

RUJ: Department of DefenseW81XWH-20-PRCRP-CDA, American Society of Clinical Oncology (ASCO)2021YIA-8674301298, and NIH NCIU54 CA163060.

Footnotes

Declaration of Competing Interest

The authors report no declarations of interest.

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Molecular pathogenesis, targeted therapies, and future perspectives for gastric cancer

Yongji Zeng

Ramon U Jin

Abstract

1. The clinical dilemma of gastric cancer

Table 1.

2. The molecular characterization of gastric cancers

Table 2.

3. Imurine models of gastric cancer

4. Paligenosis: a novel lens to view gastric cancer

Fig. 1. Paligenosis and The Clinical Hit Model for Gastric Carcinogenesis.

5. Future perspectus

6. Conclusions

Acknowledgements

Footnotes

References

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PERMALINK

Molecular pathogenesis, targeted therapies, and future perspectives for gastric cancer

Yongji Zeng

Ramon U Jin

Abstract

1. The clinical dilemma of gastric cancer

Table 1.

2. The molecular characterization of gastric cancers

Table 2.

3. Imurine models of gastric cancer

4. Paligenosis: a novel lens to view gastric cancer

Fig. 1. Paligenosis and The Clinical Hit Model for Gastric Carcinogenesis.

5. Future perspectus

6. Conclusions

Acknowledgements

Footnotes

References

ACTIONS

PERMALINK

RESOURCES

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