Host sphingosine kinase 1 worsens pancreatic cancer peritoneal carcinomatosis.
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.



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.



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.



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.
Division of Surgical Oncology, Department of Surgery, Virginia Commonwealth University School of Medicine and Massey Cancer Center, Richmond, Virginia.
Hiroaki
H
Aoki
Division of Surgical Oncology, Department of Surgery, Virginia Commonwealth University School of Medicine and Massey Cancer Center, Richmond, Virginia.
Masayo
M
Aoki
Division of Surgical Oncology, Department of Surgery, Virginia Commonwealth University School of Medicine and Massey Cancer Center, Richmond, Virginia; Breast Surgery, Roswell Park Cancer Institute, Buffalo, New York.
Eriko
E
Katsuta
Division of Surgical Oncology, Department of Surgery, Virginia Commonwealth University School of Medicine and Massey Cancer Center, Richmond, Virginia.
Rajesh
R
Ramanathan
Department of Pathology, Virginia Commonwealth University School of Medicine and Massey Cancer Center, Richmond, Virginia.
Michael O
MO
Idowu
Department of Biochemistry & Molecular Biology, Virginia Commonwealth University School of Medicine and Massey Cancer Center, Richmond, Virginia.
Sarah
S
Spiegel
Division of Surgical Oncology, Department of Surgery, Virginia Commonwealth University School of Medicine and Massey Cancer Center, Richmond, Virginia; Breast Surgery, Roswell Park Cancer Institute, Buffalo, New York. Electronic address: kazuaki.takabe@roswellpark.org.
Kazuaki
K
Takabe
D000230:Adenocarcinoma / Q000201:enzymology / Q000401:mortality / Q000473:pathology / Q000556:secondary*; D000818:Animals; D017209:Apoptosis; D014408:Biomarkers, Tumor / Q000172:deficiency / Q000378:metabolism*; D049109:Cell Proliferation; D020287:In Situ Nick-End Labeling; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009368:Neoplasm Transplantation; D010190:Pancreatic Neoplasms / Q000201:enzymology / Q000401:mortality / Q000473:pathology*; D010534:Peritoneal Neoplasms / Q000201:enzymology / Q000401:mortality / Q000473:pathology / Q000556:secondary*; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000172:deficiency / Q000378:metabolism*; D047368:Tumor Burden; D000099157:Sphingosine Kinase
D014408:Biomarkers, Tumor; D017853:Phosphotransferases (Alcohol Group Acceptor); D000099157:Sphingosine Kinase
Animal; Carcinomatosis; Dissemination; Mouse; Pancreatic cancer; Peritoneal; S1P; SphK1; Sphingosine kinase; Sphingosine-1-phosphate
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