Peritoneal Metastasis Mechanisms in Gastric Cancer

Peritoneal metastasis in gastric cancer arises when tumour cells detach from the primary gastric lesion, survive in the ascitic fluid and adhere to the peritoneal lining. Key steps include loss of cell–cell adhesion through downregulation of E-cadherin, acquisition of motile phenotypes via epithelial-mesenchymal transition and remodelling of the extracellular matrix by matrix metalloproteinases. Detached cells interact with mesothelial cells, inducing local fibrosis and creating a niche supportive of tumour cell implantation. Hypoxia within the peritoneal microenvironment triggers autophagy in mesothelial and cancer cells, upregulates factors such as VEGFA and fibronectin and promotes angiogenesis, facilitating persistent colonisation. In certain peritoneal milky spots, a hypoxic niche fosters a cancer stem-like cell population, enhancing self-renewal and resistance to therapy. Integrin-mediated adhesion, cytokine signalling (for example, TGF-β and IL-17A) and crosstalk with the mesothelial stroma drive progressive invasion of peritoneal organs. The resulting vascularisation and stromal fibrosis impede effective drug delivery, contributing to poor prognosis. Recent advances in preclinical modelling and molecular dissection of these pathways have begun to inform novel therapeutic strategies aimed at interrupting peritoneal dissemination and improving patient survival.

Research from Nature Portfolio

A foundational orthotopic mouse model has been established in which luciferase-tagged gastric cancer cells are injected into the gastric subserosa, enabling real-time monitoring of tumour invasion and peritoneal dissemination. Three cell lines with distinct invasive profiles recapitulate human heterogeneity: one remains non-metastatic, a second exhibits moderate spread, and a third demonstrates rapid peritoneal colonisation. This model has proved invaluable for assessing anti-invasive and anti-metastatic compounds in a physiologically relevant setting, illuminating how specific genetic backgrounds influence peritoneal tropism and offering a robust platform for preclinical evaluation of targeted therapies.

Peritoneal Metastasis Mechanisms in Gastric Cancer publication trend

The graph below shows the total number of articles in peritoneal metastasis mechanisms in gastric cancer across all publications each year (not limited to Nature Index journals).

Technical terms

Peritoneal metastasis: Spread of gastric cancer cells to the lining of the abdominal cavity, forming secondary implants.

Mesothelial cells: Specialized epithelial cells that line the peritoneum and interact dynamically with invading tumour cells.

Extracellular matrix: A complex network of proteins and glycoproteins that provides structural support and signalling cues in tissues.

Angiogenesis: Formation of new blood vessels from pre-existing vasculature, essential for nutrient supply to metastases.

Epithelial-mesenchymal transition (EMT): A process by which epithelial cells acquire mesenchymal properties, increasing motility and invasiveness.

References

1. An orthotopic mouse model of gastric cancer invasion and metastasis. Scientific Reports (2018).
2. FN1 mRNA 3'-UTR supersedes traditional fibronectin 1 in facilitating the invasion and metastasis of gastric cancer through the FN1 3'-UTR-let-7i-5p-THBS1 axis. Theranostics (2023).
3. ESM1 Interacts with c-Met to Promote Gastric Cancer Peritoneal Metastasis by Inducing Angiogenesis. Cancers (2023).
4. Hypoxia-autophagy axis induces VEGFA by peritoneal mesothelial cells to promote gastric cancer peritoneal metastasis through an integrin α5-fibronectin pathway. Journal of Experimental & Clinical Cancer Research (2020).
5. Peritoneal Milky Spots Serve as a Hypoxic Niche and Favor Gastric Cancer Stem/Progenitor Cell Peritoneal Dissemination Through Hypoxia‐Inducible Factor 1α. Stem Cells (2014).
6. Induction of gastric cancer cell adhesion through transforming growth factor-beta1-mediated peritoneal fibrosis. Journal of Experimental & Clinical Cancer Research (2010).
7. Interleukin-17A derived from mast cells contributes to fibrosis in gastric cancer with peritoneal dissemination. Gastric Cancer (2020).