Abstract 195: CD44v9 expression in clinical pancreatic cancer and the gemcitabine plus sulfasalazine therapy against chemoresistant pancreatic cancer murine model
Authors: Kurokawa Tomohiro , Oda Tatsuya , Inagaki Yuki , Miyamoto Ryoichi , Akashi Yoshimasa , Ohkohchi Nobuhiro 
Published: May 2015

Objective: Chemoresistance associating CD44-positive cancer stem cells may presents a crucial problem in treating pancreatic cancer. Among the various isoforms of CD44, valiant 9 (CD44v9) have revealed especially implicated in tumor growth, invasion, and metastasis. Interaction of CD44v9 with the cystine transporter subunit xCT provide the ability of cancer cells to defend themselves against reactive oxygen species, mediating chemoresistance. Sulfasalazine (SSZ), which is a specific inhibitor of xCT-mediated cystine transport,could be a new therapeutic weapon fight against cancer stem cells.

However, the extent of this remains unclear, suggesting the need for a histological evaluation of CD44v9 expression in clinical pancreatic cancer and the anti-tumor effect on pancreatic cancer of SSZ. Therefore,

In this study, we analyze the expression of CD44v9 in a pancreatic cancer surgical specimen and examine the anti-tumor effect of SSZ and altered expression of CD44v9 by administration of GEM (GEM) with tumorgrafts.

Methods:

Experiment 1: A total of 70 clinical primary ductal adenocarcinoma of the pancreas were applied for immunohistochemical evaluation of CD44v9 expression. Randomly picked up 10 fields for each cases were analyzed for intensity of membrane staining and the percentage of stained cancer cells per field, followed by summing the scores using our own scoring system.

Experiment 2: Three lines of created tumorgrafts from clinical pancreatic cancer. We administered GEM to the tumorgrafts and also scored the clinical specimens’ immunohistochemical evaluation by CD44v9. In addition, using one line, we divided the mice into two groups, a GEM group and a GEM + SSZ group, and repeated as above to determine the effect on GEM of SSZ.

Results:

Experiment 1: There was no correlation for prognosis. It was found that CD44v9-positive cells are present in high numbers.

Experiment 2: In 1 line, which increased CD44v9-positive cell after GEM treatment,the GEM group showed tumor regression of 85% and the GEM+SSZ group showed tumor regression of 90%.

Discussion: Result in Experiment 1 is reasonable, therefore, to consider the significance of the treatment target CD44vv9 as likely to be very high. Further, there was one line of tumorgrafts used, but not all percentages of CD44v9-positive cells increased markedly by GEM administration. This suggests the possibility that CD44v9 may be regarded as a marker of GEM resistance. In addition, a small but insignificant tumor regression effect on GEM of SSZ was found.

We present evidence that for pancreatic cancer as well as other carcinomas, CD44v9-positive cells may be regarded as one of the markers of chemo resistance. Furthermore, since SSZ shows the antitumor effects of plus for GEM, we suggest that SSZ treatment is a possibility for a new treatment option.

Citation Format: Tomohiro Kurokawa, Tatsuya Oda, Yuki Inagaki, Ryoichi Miyamoto, Yoshimasa Akashi, Nobuhiro Ohkohchi. CD44v9 expression in clinical pancreatic cancer and the gemcitabine plus sulfasalazine therapy against chemoresistant pancreatic cancer murine model. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 195. doi:10.1158/1538-7445.AM2014-195