Gastric Cancer Cells and Fibroblasts Locked in a Deadly Mutual Promotion Loop

Scirrhous gastric cancer is among the most feared forms of stomach malignancy, distinguished by rapid infiltration of cancer cells through the stomach wall accompanied by extensive fibrosis of the supporting stroma. Patients with this subtype fare significantly worse than those with other gastric cancers, largely because the tumor spreads early and aggressively before it is detected. A new study published in BMC Cancer by Takashi Sakuma, Masakazu Yashiro, Kiyoshi Maeda and colleagues at Osaka Metropolitan University Graduate School of Medicine has now uncovered a molecular handshake between scirrhous gastric cancer cells and the cancer-associated fibroblasts that surround them, revealing how two cell types in the tumor microenvironment actively fuel each other’s invasive behavior through a reciprocal signaling circuit.

The research team set out to understand how scirrhous gastric cancer cells and cancer-associated fibroblasts, or CAFs, communicate within the tumor microenvironment and how that communication drives progressive invasion. Using four pairs of CAFs and normal fibroblasts derived from patients, together with three gastric cancer cell lines, the investigators combined RNA sequencing with functional assays to identify molecular markers that distinguish the activated fibroblasts of the tumor stroma from their normal counterparts. Their in silico analysis pointed to stanniocalcin-1, a secreted glycoprotein previously implicated in tissue remodeling and stress responses, as a reliable marker of the cancer-associated fibroblast phenotype.

Laboratory measurements confirmed the significance of this finding. The mRNA expression of stanniocalcin-1 in CAFs was significantly higher than in normal fibroblasts, and, critically, the expression was significantly upregulated when the fibroblasts were exposed to the supernatant, or conditioned medium, of OCUM-12 cells, a scirrhous gastric cancer cell line. This observation demonstrated that something released by the aggressive cancer cells could reprogram the fibroblasts to produce more of this secreted protein, suggesting a directed molecular dialogue rather than random stromal activation.

Functional testing then revealed the consequences of this dialogue. Stanniocalcin-1 secreted by the CAFs was associated with increased invasion activity of the scirrhous gastric cancer cells and with the induction of epithelial-mesenchymal transition, the developmental program by which epithelial cancer cells lose their cell-cell adhesion properties and gain migratory, invasive characteristics. Morphologic analysis of the cancer cells exposed to CAF-conditioned medium showed the characteristic spindle-like shape changes of EMT, confirming that the fibroblast-derived signal was not merely a bystander effect but a driver of the invasive phenotype.

The investigators then turned their attention to what the cancer cells were contributing to this exchange. Their candidate was mesotrypsin, a trypsinogen isoform encoded by the PRSS3 gene, which is known to be expressed in aggressive pancreatic and other gastrointestinal malignancies. Mesotrypsin released from OCUM-12 cells was found to activate protease-activated receptor 2, or PAR-2, a cell surface receptor that responds to proteolytic cleavage by trypsin-like enzymes. When mesotrypsin cleaved PAR-2 on the surface of the fibroblasts, it triggered an intracellular signaling cascade through the signal transducer and activator of transcription 3, or STAT-3, pathway, which in turn upregulated stanniocalcin-1 expression in the CAFs.

What makes this discovery particularly striking is the reciprocal nature of the interaction. The investigators found that PRSS3/mesotrypsin expression in the cancer cells was itself upregulated by stanniocalcin-1, completing a positive feedback loop. Cancer cells secrete mesotrypsin, which activates PAR-2 on fibroblasts, which activates STAT-3, which increases stanniocalcin-1 production, which feeds back to the cancer cells to increase mesotrypsin expression, which then further stimulates the fibroblasts. Each round of this mutual amplification strengthens the invasive behavior of the cancer cells and deepens the activated state of the stromal fibroblasts, creating a self-reinforcing engine of tumor progression.

The clinical relevance of this circuit was underscored by survival analysis of gastric cancer patients. The investigators found that high mesotrypsin expression contributed to significantly poorer survival in gastric cancer patients, linking the molecular mechanism identified in vitro to patient outcomes. This finding suggests that mesotrypsin expression levels could serve as a prognostic biomarker, helping clinicians identify patients whose tumors have engaged this aggressive stromal interaction program and who may require more intensive treatment strategies.

From a therapeutic perspective, the identification of the PAR-2/STAT-3/stanniocalcin-1 axis in CAFs and the reciprocal PRSS3/mesotrypsin signal from cancer cells opens multiple potential intervention points. Blocking PAR-2 activation, inhibiting STAT-3 signaling, neutralizing stanniocalcin-1, or suppressing mesotrypsin activity could each disrupt the feedback loop at a different stage. Because the loop requires both partners to sustain itself, targeting either side could potentially collapse the entire mutual promotion circuit, offering a strategy that conventional chemotherapy directed solely at cancer cells cannot achieve.

The study also contributes to a broader shift in cancer research toward understanding the tumor microenvironment as an active participant in disease progression rather than a passive scaffold. Scirrhous gastric cancer, with its dense fibrotic stroma, represents an extreme example of this principle, where the stromal compartment is not merely abundant but functionally indispensable to the invasive phenotype. By demonstrating that cancer cells and fibroblasts engage in a specific, targetable molecular dialogue, the Osaka Metropolitan University team has provided a mechanistic framework that may explain why this subtype is so relentlessly invasive and has identified a promising direction for the development of stroma-directed therapies for one of the most challenging malignancies in oncology.

Subject of Research: PRSS3/mesotrypsin from scirrhous gastric cancer cells and stanniocalcin-1 from cancer-associated fibroblasts mutually promote invasion activity

Article Title: PRSS3/mesotrypsin from scirrhous gastric cancer cells and stanniocalcin-1 from cancer-associated fibroblasts mutually promote invasion activity

Article References: Sakuma, T., Gao, H., Ma, D., Sano, T., Imanishi, D., Fan, C., Nishikubo, H., Yamamoto, Y., Kasashima, H., Yashiro, M., & Maeda, K. (2026). PRSS3/mesotrypsin from scirrhous gastric cancer cells and stanniocalcin-1 from cancer-associated fibroblasts mutually promote invasion activity. BMC Cancer. https://doi.org/10.1186/s12885-026-16988-y

Image Credits: AI Generated

DOI: 10.1186/s12885-026-16988-y

Keywords: PRSS3, mesotrypsin, scirrhous, gastric, cancer, cells, stanniocalcin-1, cancer-associated, fibroblasts, mutually, promote, invasion