Aoki Hiroaki, Aoki Masayo, Katsuta Eriko, Ramanathan Rajesh, Idowu Michael O, Spiegel Sarah, Takabe Kazuaki
Division of Surgical Oncology, Department of Surgery, Virginia Commonwealth University School of Medicine and Massey Cancer Center, Richmond, Virginia.
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.
J Surg Res. 2016 Oct;205(2):510-517. doi: 10.1016/j.jss.2016.05.034. Epub 2016 Jul 9.
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.
目前尚无有效的治疗方法来治疗胰腺癌腹膜转移（PC）或腹腔内癌症播散。鞘氨醇-1-磷酸（S1P）是一种由鞘氨醇激酶（SphK1和SphK2）产生的生物活性脂质介质，在癌症进展中起关键作用。我们报道SphK1而非SphK2负责乳腺癌细胞中S1P的输出，并且最近发现S1P与结肠炎相关癌症进展中的炎症和癌症有关。鉴于炎症已知对PC的发生和进展至关重要，我们推测宿主动物中的SphK1参与胰腺癌PC的进展。
将小鼠胰腺腺癌panc02-luc细胞腹腔注射到野生型或SphK1基因敲除（KO）小鼠中，以建立同基因PC模型。分别通过Ki67和TUNEL染色测定细胞增殖和凋亡。
所有动物均发生了panc02-luc PC。在植入后14天，SphK1 KO小鼠的肿瘤负荷明显减轻，总肿瘤重量减轻，PC结节数量减少。组织学上，肿瘤中观察到较少的炎性细胞浸润和较少的癌细胞增殖。凋亡方面无差异。
我们的结果提出了一种有趣的可能性，即宿主中SphK1产生的S1P通过刺激癌细胞增殖促进胰腺癌PC进展。
