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Host sphingosine kinase 1 worsens pancreatic cancer peritoneal carcinomatosis
Hiroaki Aoki1, Masayo Aoki1, Eriko Katsuta2
1Division of Surgical Oncology, Department of Surgery, Virginia Commonwealth University School of Medicine and Massey Cancer Center, Richmond, Virginia.
Background:
There are no effective treatments for pancreatic cancer peritoneal carcinomatosis (PC) or cancer dissemination in abdominal cavity. Sphingosine-1-phosphate (S1P), a bioactive lipid mediator produced by sphingosine kinases (SphK1 and SphK2), plays critical roles in cancer progression. We reported that SphK1, but not SphK2, is responsible for S1P export from breast cancer cells and recently discovered that S1P is linked to inflammation and cancer in colitis-associated cancer progression. Given the fact that inflammation is known to be essential for the establishment and progression of PC, we hypothesized that SphK1 in the host animals is involved in progression of pancreatic cancer PC.
Methods:
Murine pancreatic adenocarcinoma panc02-luc cells were intraperitoneally injected into wildtype or SphK1 knockout (KO) mice to generate a syngeneic PC model. Cell proliferation and apoptosis were determined by Ki67 and TUNEL staining, respectively.
Results:
All the animals developed panc02-luc PC. SphK1 KO mice developed significantly less tumor burden, less total tumor weight, and fewer number of PC nodules at 14 d after implantation. Histologically, less inflammatory cell infiltration and less cancer cell proliferation were observed in the tumors. There was no difference in apoptosis.
Conclusions:
Our results raise an intriguing possibility that S1P generated by SphK1 in the host promotes pancreatic cancer PC progression by stimulation of proliferation of cancer cells.
Insights
Sphingosine kinase 1 (SphK1) in host animals promotes pancreatic cancer progression. Inhibiting SphK1 in mice reduced tumor growth and spread, suggesting SphK1 as a therapeutic target for pancreatic cancer peritoneal carcinomatosis.
Area of Science:
- Oncology
- Cancer Biology
- Immunology
Background:
- Pancreatic cancer peritoneal carcinomatosis (PC) lacks effective treatments.
- Sphingosine-1-phosphate (S1P) is a lipid mediator involved in cancer progression.
- Inflammation is crucial for PC development and progression.
Purpose of the Study:
- To investigate the role of Sphingosine kinase 1 (SphK1) in host animals in pancreatic cancer progression.
- To test the hypothesis that host SphK1 promotes pancreatic cancer peritoneal carcinomatosis.
Main Methods:
- A syngeneic pancreatic cancer model was established by injecting panc02-luc cells into wildtype or SphK1 knockout (KO) mice.
- Tumor burden, nodule number, and weight were assessed.
- Cancer cell proliferation and apoptosis were evaluated using Ki67 and TUNEL staining, respectively.
Main Results:
- SphK1 KO mice exhibited significantly reduced tumor burden, total tumor weight, and fewer PC nodules compared to wildtype mice.
- Histological analysis revealed decreased inflammatory cell infiltration and cancer cell proliferation in tumors of SphK1 KO mice.
- No significant difference in apoptosis was observed between the groups.
Conclusions:
- Host SphK1 plays a critical role in promoting pancreatic cancer progression.
- S1P generated by host SphK1 may stimulate cancer cell proliferation, contributing to PC.
- Targeting SphK1 presents a potential therapeutic strategy for pancreatic cancer peritoneal carcinomatosis.
