Why Gastric Cancer Spreads Across the Abdomen: The Biology of Peritoneal Metastasis

Gastric cancer does not always spread through the bloodstream. In many patients with advanced disease, cancer cells move directly into the abdominal cavity and establish metastases across the peritoneum.

This pattern, known as peritoneal metastasis in gastric cancer, is one of the most difficult forms of disease to detect and treat. It develops through a complex sequence of events involving tumor-cell shedding, survival in peritoneal fluid, attachment to the mesothelial surface, and interaction with a highly supportive local microenvironment.

Understanding how gastric cancer spreads across the abdomen helps explain why peritoneal disease behaves differently from other metastatic sites – and why earlier detection and more effective treatment remain major challenges in GI oncology.

How Does Gastric Cancer Reach the Peritoneal Cavity?

Gastric cancer can spread directly into the peritoneal cavity once the primary tumor grows through the stomach wall and reaches the serosal surface. At that point, cancer cells can detach and enter the abdomen without first passing through the bloodstream. (Kanda and Kodera, 2016; Sun et al., 2017).

These free cancer cells are carried by peritoneal fluid and can reach surfaces throughout the abdominal cavity. From there, they must survive outside their original tissue, attach to the peritoneum, invade beneath the mesothelial lining, and establish new metastatic deposits. (Kanda and Kodera, 2016).

The risk is highest in locally advanced tumors, particularly those with serosal invasion. Diffuse-type gastric cancer, signet-ring cell carcinoma, linitis plastica, advanced T and N stage, and larger infiltrative tumors are also associated with a greater likelihood of peritoneal metastasis. (Thomassen et al., 2014).

This direct route of spread helps explain why the peritoneum is such a characteristic metastatic site in advanced gastric cancer.

How Do Gastric Cancer Cells Survive and Spread Through Peritoneal Fluid?

Once gastric cancer cells detach into the abdominal cavity, they lose the normal attachment signals provided by surrounding tissue. Ordinarily, this would trigger anoikis, a form of programmed cell death caused by detachment from the extracellular matrix. Cancer cells that develop resistance to anoikis are more likely to survive during peritoneal dissemination. (Kanda and Kodera, 2016; Kang and Kim, 2022).

Cells may circulate individually or form multicellular clusters or spheroids, which provide cell-to-cell contact and improve survival under stressful conditions.

Malignant ascites can further support this process. It contains cytokines, growth factors, extracellular vesicles, and tumor-derived exosomes that influence tumor-cell behavior. Exosomes isolated from gastric cancer–associated ascites have been shown to promote invasive and EMT-related programs. (Hu et al., 2019; Chen et al., 2021).

The ability to remain viable while suspended in peritoneal fluid is therefore a critical step between release from the primary tumor and implantation elsewhere in the abdomen.

How Do Gastric Cancer Cells Attach to and Invade the Peritoneum?

After reaching the peritoneal surface, cancer cells must first attach to the mesothelial layer. Adhesion molecules such as CD44 and integrins help tumor cells interact with mesothelial cells and components of the underlying extracellular matrix. (Kanda and Kodera, 2016; Kang and Kim, 2022).

Inflammatory and tumor-derived signals can also alter the mesothelial barrier. Cytokines including TGF-β and TNF-αcan promote mesothelial retraction and expose the basement membrane, making the surface more permissive to invasion.

Once attached, tumor cells begin to penetrate beneath the mesothelium. Matrix metalloproteinases, including MMP-9, degrade extracellular-matrix components and facilitate invasion into subperitoneal tissue. TNF-α can also stimulate mesothelial cells to produce MMP-9, further supporting this process. (Oku et al., 2018).

Certain areas of the peritoneum, including lymphatic structures known as milky spots, may provide particularly favorable sites for implantation and early metastatic growth. (Sun et al., 2017).

Peritoneal implantation is therefore an active multistep process rather than simple deposition of tumor cells on an abdominal surface.

What Makes the Peritoneal Microenvironment Favor Metastatic Growth?

Once gastric cancer cells establish contact with the peritoneum, they can begin to reshape the surrounding tissue into an environment that supports further growth. (Yao et al., 2020).

Malignant ascites contains growth factors, cytokines, extracellular vesicles, and other signals that support tumor-cell survival and communication. Cancer-derived exosomes can also modify mesothelial cells, fibroblasts, and immune cells and contribute to formation of a metastatic niche. (Chen et al., 2021).

Stromal cells are central to this process. Cancer-associated fibroblasts, mesothelial cells, endothelial cells, and macrophages remodel the extracellular matrix and support angiogenesis. Peritoneal macrophages, for example, can produce EGF and VEGF, promoting tumor growth and new blood-vessel formation. (Song et al., 2019).

The immune environment can also become increasingly suppressive. Tumor-associated macrophages, regulatory T cells, myeloid-derived suppressor cells, hypoxia, and inflammatory signaling can weaken T-cell and NK-cell activity. (Yao et al., 2020).

The relationship becomes self-reinforcing: gastric cancer cells reshape the peritoneal environment, while the altered peritoneum provides the signals needed for metastatic deposits to survive and expand.

Why Is Peritoneal Metastasis in Gastric Cancer So Difficult to Treat?

Peritoneal metastasis is difficult to treat because disease is often diffuse and biologically aggressive, with numerous small implants distributed across the abdominal cavity.

Drug delivery is another challenge. Peritoneal deposits often have irregular vascular supply, and the plasma–peritoneal barrier can limit exposure to intravenously administered chemotherapy. This has driven interest in treatments delivered directly into the abdominal cavity. (Kitayama et al., 2018).

Clinical complications can further restrict treatment. Malignant ascites, bowel obstruction, pain, malnutrition, and declining performance status may reduce a patient’s ability to tolerate intensive systemic therapy or major surgery. (Khan and Johnston, 2022).

Systemic therapy remains the main treatment backbone for metastatic gastric cancer. Cytoreductive surgery, HIPEC, repeated intraperitoneal chemotherapy, and PIPAC have been investigated as additional strategies, mainly in carefully selected patients and specialized centers. (Lordick et al., 2022; Manzanedo et al., 2023).

Importantly, the phase III GASTRIPEC-I trial did not demonstrate an overall-survival benefit from adding HIPEC to cytoreductive surgery, highlighting the uncertainty around which patients benefit most from this approach. (Rau et al., 2024).

The challenge therefore reflects both the biology and distribution of the disease: peritoneal metastases can spread widely while remaining difficult to reach with systemic treatment or remove completely.

Can Peritoneal Metastasis Be Detected Earlier or Prevented?

Early detection remains difficult because very small peritoneal deposits may not be visible on routine CT or other cross-sectional imaging.

For patients with resectable gastric cancer who are at meaningful risk of peritoneal spread, staging laparoscopy with peritoneal washings for cytology can identify small-volume or microscopic disease that imaging may miss. This is particularly relevant in patients being considered for perioperative chemotherapy. (Lordick et al., 2022).

Positive peritoneal cytology can indicate microscopic dissemination even when no visible implants are present and can substantially change staging and treatment planning.

Preventing peritoneal metastasis is more difficult. There is currently no established strategy that reliably prevents peritoneal spread. Perioperative systemic therapy remains the standard approach for appropriate locally advanced gastric cancers, while prophylactic or adjuvant intraperitoneal treatments such as HIPEC continue to be studied in high-risk patients. (Manzanedo et al., 2023).

For now, the most practical strategy is to identify patients at increased risk, use staging laparoscopy when appropriate, and continue investigating treatments aimed at eliminating microscopic peritoneal disease before established metastases develop.