Advances in molecular mechanism of gastric cancer peritoneal metastasis

Table 1 Incidence of peritoneal metastasis in major abdominal and gynecological cancers

Type of cancer	Incidence of peritoneal metastases	Ref.
Ovarian cancer	> 75%	[187]
Gastric cancer	33%-66%	[188,189]
Colorectal cancer	5%-15%	[190]
Liver cancer	2%-18%	[191]
Pancreatic cancer	10%	[192]

This table summarizes the widely reported frequency of peritoneal metastasis in different primary tumor types, highlighting that ovarian and gastric cancers exhibit the highest tropism for the peritoneum.

Table 2 Key genetic mutations and their signaling pathways in gastric cancer peritoneal metastasis

Gene	Alteration type	Affected pathway	Function	Clinical implication
CDH1	Deletion mutations	Cell adhesion and LGN	Randomization of cell division direction and increased invasiveness	Potential targeting direction for cell division
TP53	Deletion mutations	p53 signaling and apoptosis	Loss of cell cycle control and apoptosis	ctDNA TP53 mutation predicts poor response to chemotherapy
ARID1A	Deletion mutations	mTOR/SOX9	Enhanced migration and invasion	Potential target for mTOR inhibitors
NF2/RASA1	Deletion mutations	Wnt and YAP	Increased tumor stemness and metastatic capacity	Synthetic lethality with combined Bcl-2 and YAP inhibitors
ERBB2/ERBB3	Activating mutation	-	Enhanced TMB, CD8+ T cell infiltration, and TME immunological activity	Predict response to chemoimmunotherapy

This table summarizes the major genetic alterations implicated in gastric cancer peritoneal metastasis, their affected signaling pathways, functional consequences, and clinical implications. It highlights mutations that guide patient stratification, predict treatment response, or represent potential therapeutic targets. LGN: Leu-Gly-Asn repeat-enriched protein; ctDNA: Circulating tumor DNA; mTOR: Mammalian target of rapamycin; SOX9: SRY box 9; TMB: Tumor mutation burden.

Table 3 Summary of key molecules and signaling pathways driving epithelial-mesenchymal transition and extracellular matrix remodeling in gastric cancer peritoneal metastasis

Category	Key molecule/pathway	Mechanism of action	Functional	Clinical potential
EMT drivers	CST1	Stabilizes GPX4 to inhibit ferroptosis; upregulates N-cadherin/Snail, downregulates E-cadherin	Synergistically drives EMT and tumor invasion	Prognostic biomarker and combination targeting strategy
	BGN/FAP/STAT3 loop	BGN binds TLR2/4 on mesothelial cells → NF-κB activation → mesothelial-to-CAF transition; CAFs secrete FAP → forms positive feedback loop	Continuous EMT activation	Prediction of biomarkers and therapeutic targets
	APOC2/CD36	Activates PI3K/AKT/mTOR pathway via CD36 receptor	Upregulates mesenchymal markers and MMPs	Therapeutic target
	CD44/STAT3	Signaling integration platform cooperating with STAT3	Initiates EMT transcriptional reprogramming	Therapeutic target
ECM remodeling	MMPs	Degrade ECM barrier and release matrix-bound growth factors	Promote invasion and metastasis	Prognostic biomarkers
	LOX	Catalyzes collagen crosslinking → increased matrix stiffness; remote pre-conditioning of metastatic niche	Promotes invasion, EMT, and immunosuppression	Prognostic biomarker and therapeutic target
EMT-ECM crosstalk	FERMT2/SOX2/FN1	Stabilizes SOX2 → activates FN1 transcription → guides fibronectin matrix remodeling	Promotes tumor cells survival, invasion, and metastasis	Therapeutic target
	GRP94/YAP/TEAD1	Upregulates IL6 expression → activates YAP/TEAD1 pathway	Anoikis resistance; promotes migration and invasion	Therapeutic target
	CTSL, macrophage-derived	Degrades ECM components; promotes M2 macrophage polarization	Promotes EMT and invasion	Dual-effect target
	Exosomal miR-106a	Delivered to mesothelial cells → activates TGF-β signaling → induces MMT	Disrupts peritoneal integrity; establishes pre-metastatic niche	Diagnostic/prognostic biomarker and therapeutic target

This table catalogs the major molecular regulators of epithelial-mesenchymal transition and extracellular matrix remodeling in gastric cancer peritoneal metastasis. It summarizes their mechanisms of action, functional consequences, and translational potential. EMT: Epithelial-mesenchymal transition; CST1: Cystatin SN; GPX4: Glutathione peroxidase 4; BGN: Biglycan; FAP: Fibronectin attachment protein; STAT3: Signal transducer and activator of transcription 3; TLR2/4: Toll-like receptor 2/4; NF-κB: Nuclear factor-kappa B; CAF: Cancer-associated fibroblast; APOC2: Apolipoprotein C2; PI3K: Phosphatidylinositide 3-kinase; AKT: Protein kinase B; mTOR: Mammalian target of rapamycin; MMPs: Matrix metalloproteinases; ECM: Extracellular matrix; LOX: Lysyl oxidase; FERMT2: Fermitin family homolog-2; SOX2: SRY box 2; FN1: Fibronectin 1; GRP94: Glucose-regulated protein 94; TEAD1: TEA domain transcription factor 1; CTSL: Cathepsin L; TGF: Transforming growth factor; MMT: Mesothelial-mesenchymal transition.

Table 4 Tumor microenvironment components in gastric cancer peritoneal metastasis: Functions, interactions, and therapeutic opportunities

TME component	Subset/key factor	Mechanisms	Key interactions	Potential therapeutic targets
CAFs	General CAFs	Immunosuppression; tumor survival/stemness; angiogenesis; invasion	Interact with tumor cells, immune cells, and endothelial cells	FAP inhibitors; IL-6R antibody
	apCAFs (CD74+, HLA-DRA+)	Antigen-presenting function	Spatially enriched around tertiary lymphoid structures	Prognostic biomarker; predict immunotherapy response
	myCAFs (GDF15-driven)	Form dense physical barrier; impede CD8+ T cell infiltration	Interact with tumor cells	Target GDF15 to relieve immune exclusion
TAMs	M2-like TAMs	Immunosuppression; angiogenesis; ECM remodeling	Interact with tumor cells, immune cells, CAFs and endothelial cells	TAM reprogramming (anti-DKK1, anti-IL10, anti-POU1F1)
	CTSL+ TAMs	Establish pre-metastatic microenvironment; mediate tumor cell “homing”	Dynamic lineage transition to C1Q+ TAMs	Target CTSL
	C1Q+ TAMs	Drive proliferation, immune evasion, therapeutic resistance	Dynamic lineage transition from C1Q+TAMs	C1 inhibitor
	SPP1+ TAMs	Immunosuppression	Interact with THBS2+ CAFs	C3aR antagonists
	VCAN+ TAM	Angiogenesis, immunosuppression and chemotherapy resistance	-	Target VCAN
Adipocytes	-	Secrete CXCL2 → AKT-HIF1α-VEGFA axis (angiogenesis); LAMC1 drives preadipocyte differentiation → releases free fatty acids (metabolic reprogramming); NSUN2/ORAI2 activates PI3K-AKT (proliferation/migration)	Interact with tumor cells	Omentectomy; serum LAMC1 as biomarker; urinary CXCL2 as biomarker; FAO inhibitors
Angiogenesis	VEGF/VEGFR; ESM1/c-Met; CAF-derived HGF	VEGF/VEGFR primary pathway; ESM1 activates MAPK → HIF-1α/VEGFA/MMP-9; CAF-derived HGF promotes multiple vascular patterns	-	Anti-VEGF/VEGFR (bevacizumab, ramucirumab); ESM1 antibody; c-Met inhibitors; HGF inhibitors PI3K/MEK/ERK inhibitors

This table summarizes the key components of the tumor microenvironment in gastric cancer peritoneal metastasis, including cancer-associated fibroblasts, tumor-associated macrophages, angiogenic factors, and adipocytes. It highlights their pro-tumor mechanisms, intercellular interactions, and potential therapeutic targets for clinical translation. TME: Tumor microenvironment; CAFs: Cancer-associated fibroblasts; TAMs: Tumor-associated macrophages; FAP: Fibronectin attachment protein; IL-6R: Interleukin-6 receptor; apCAFs: Antigen-presenting cancer-associated fibroblasts; GDF-15: Growth differentiation factor 15; DKK1: Dickkopf-1; IL10: Interleukin-10; POU1F1: POU class 1 homeobox1; CTSL: Cathepsin L; SPP1: Secreted phosphoprotein 1; THBS2: Thrombospondin 2; VCAN: Versican; CXCL2: C-X-C motif chemokine ligand 2; FAO: Fatty acid oxidation; AKT: Protein kinase B; HIF1α: Hypoxia-inducible factor 1alpha; VEGFA: Vascular endothelial growth factor A; LAMC1: Laminin gamma 1; NSUN1: NOL1/NOP2/sun family; PI3K: Phosphatidylinositide 3-kinase; VEGF: Vascular endothelial growth factor; VEGFR: Vascular endothelial growth factor receptor; ESM1: Endothelial cell-specific molecule 1; HGF: Hepatocyte growth factor; MAPK: Mitogen-activated protein kinase; MMP-9: Matrix metallopeptidase 9.

Table 5 Summary of non-coding RNAs involved in gastric cancer peritoneal metastasis

ncRNA	Location	Association with GC	Targeted genes and pathways	Application
CircPTBP3[140]	Plasma with GC, peritoneal metastasis and cell lines	Promote MMT	SGK1	Diagnostic and therapeutic, potential
lncRNA BDNF-AS[150]	Primary and peritoneal metastatic GC tissue	Inhibit ferroptosis	FBXW7	Prognosis and therapeutic, potential
lncRNA SEMA3B-AS1[193]	Primary and peritoneal metastatic GC tissue	Promote ubiquitination	FBXW7	Tumor suppressor
lncRNA-PMAN[92]	Peritoneal metastatic GC tissue	Inhibit ferroptosis	SLC7A11	Prognosis and therapeutic, potential
LINC00924[148]	GC cells	Lipid metabolism remodeling	Mnk2	Potential therapeutic effector
lncRNA CASC15[194]	Primary and peritoneal metastatic GC tissue	Promote EMT	JNK and p38	Predicting recurrence
lncRNA SNHG12[195]	Extracellular vesicles	Promote HPMC apoptosis and MMT	MAPK/ERK	Potential therapeutic target
lncRNA CTSLP4[196]	GC tissue	Suppress MMT	Snail	Tumor suppressor
lncRNA CCAT1[197]	GC tissue	Promote proliferation and metastasis	Bmi-1	Potential therapeutic target
lncRNA-HOXA11[198]	GC cells	Promote MMT	PDGF BB and TGF β1	Potential therapeutic target
miR-193a-3p[128]	Primary and peritoneal metastatic	Promote proliferation and metastasis	LAMC1	Tumor suppressor
miR-466[199]	GC tissue	Inhibit proliferation, migration and invasion	Unknown	Tumor suppressor
has-let-7 g-3p and has-miR-10395-3p[200]	Samples from peritoneal lavage	Promote metastasis and chemotherapy resistance	Unknown	Predicting peritoneal metastasis and the efficacy of chemotherapy
miR-106a[75]	Exosome	Promote MMT	Smad7 and TIMP2	Potential therapeutic target
miR-136[201]	GC tissue	Inhibit migration and invasion	HOXC10	Tumor suppressor
miR-493[202]	Exosome	Promote chemotherapy resistance	MAD2 L1	Predicting the efficacy of chemotherapy
miR-214[203]	GC cells	Promote proliferation, migration and invasion	PTEN	Potential therapeutic target
miR-21-5p[141]	Exosome	Promote MMT	SMAD7	Potential therapeutic target
miR-106a[204]	Exosome	Promote MMT	SMAD7	Potential therapeutic target
miR-22[143]	GC tissue	Inhibit ECM remodeling and EMT	MMP14 and Snail	Tumor suppressor
miR-30a[205]	GC tissue	Inhibit migration	FAPα	Tumor suppressor
miR-93-5p[142]	GC tissue	Promote proliferation, migration and invasion	IFNAR1	Potential therapeutic target
miR-544[206]	Extracellular vesicles	Promote migration and invasion	PLZF	Potential diagnostic and therapeutic targets
miR-196a-5p[207]	Exosome	Promote MMT	FBXO45	Potential therapeutic target
miR-199a-3p[208]	Primary and peritoneal metastatic GC tissue	Promote EMT	DDR2	Potential therapeutic target
miR-338-3p[209]	GC tissue	Inhibit migration	PTP1B	Tumor suppressor
miR-370[210]	GC tissue	Promote EMT	UQCRC2	Potential therapeutic target

This table catalogs the diverse functions of circular RNAs, long non-coding RNAs, and microRNAs in gastric cancer peritoneal metastasis. It details their cellular or exosomal location, associated mechanisms (e.g., promoting mesothelial-mesenchymal transition, inhibiting ferroptosis), targeted genes/pathways, and their potential applications as diagnostic biomarkers or therapeutic targets. ncRNA: Non-coding RNA; GC: Gastric cancer; circRNAs: Circular RNAs; MMT: Mesothelial-mesenchymal transition; SGK1: Serum and glucocorticoid-regulated kinase 1; lncRNAs: Long non-coding RNAs; BDNF: Brain-derived neurotrophic factor; miRNAs: MicroRNAs; EMT: Epithelial-mesenchymal transition; JNK: Jun N-terminal kinase; HPMC: Human peritoneal mesothelial cell; MAPK: Mitogen-activated protein kinase; PDGF BB: Platelet-derived growth factor-BB; TGF: Transforming growth factor; LAMC1: Laminin gamma 1; TIMP2: Tissue inhibitor of metalloproteinases 2; HOXC10: Homeodomain-containing gene 10; PTEN: Phosphatase and tensin homolog; MMP14: Matrix metallopeptidase 14; FAPα: Fibroblast activation protein alpha; IFNAR1: Interferon (alpha and beta) receptor 1; PLZF: Promyelocytic leukemia zinc finger protein; DDR2: Discoidin domain receptor 2; PTP1B: Protein tyrosine phosphatase 1B; UQCRC2: Ubiquinol-cytochrome c reductase core protein 2.

Table 6 Key pathways and mechanisms in metabolic reprogramming in gastric cancer peritoneal metastasis

Metabolic pathway	Key molecule/enzyme	Mechanism of action	Functional	Clinical potential
Glycolysis (Warburg effect)	PKM2	Accelerated glucose metabolism; translocates to nucleus as co-activator	Promotes proliferation, invasion, metastasis	Target PKM2 (PKM2 inhibitors or PKM2 activators)
	LINC00589	Regulates alternative splicing of pyruvate kinase pre-mRNA toward PKM2 isoform	Drives Warburg effect	LINC00589 delivery via PMSNs
Lipid metabolism	FASN	Accelerated fatty acid anabolism	Promote proliferation, survival, and metastasis	FASN inhibitors
	PI3K-AKT-mTORC1	Upregulates monounsaturated fatty acid synthesis; inhibits phospholipid peroxidation	Confers ferroptosis resistance	mTORC1 inhibitor combined with ferroptosis inducer
	LINC00924/hnRNPC/Mnk2	Regulates alternative splicing of Mnk2 → inhibits p38 MAPK → activates PPARα	Enhances fatty acid oxidation and uptake	PPARα inhibitors
Amino acid metabolism	Glutamine	Converted to glutamate → enters TCA cycle; regulates redox status and signal transduction	Promotes proliferation, invasion, metastasis	Glutaminase inhibitors
Neural-tumor crosstalk	Mitochondrial transfer	Neurons donate functional mitochondria to tumor cells via intercellular transfer	Enhances oxidative phosphorylation; provides bioenergetic support for metastasis	Chemical denervation

This table summarizes the core metabolic pathways involved in gastric cancer peritoneal metastasis: Glycolysis, lipid metabolism, and amino acid metabolism. It highlights key enzymes, mechanisms of action, functional consequences, and therapeutic opportunities. PKM2: Pyruvate kinase M2; PMSNs: Polyethyleneimine-modified mesoporous silica nanoparticles; FASN: Fatty acid synthase; PI3K: Phosphatidylinositide 3-kinase; AKT: Protein kinase B; mTORC1: Mechanistic target of rapamycin complex 1; MAPK: Mitogen-activated protein kinase; PPARα: Peroxisome proliferator-activated receptor alpha; TCA: Tricarboxylic acid.