Abstract 2023: Cellular senescence, represented by expression of caveolin-1, in cancer-associated fibroblasts promotes tumor Invasion in pancreatic cancer cellular
Authors: Yamao Takanobu , Yamashita Yo-ichi , Yamamura Kensuke , Umezaki Naoki , Itoyama Rumi , Nakao Yosuke , Yusa Toshihiko , Miyata Tatsunori , Nakagawa Shigeki , Okabe Hirohisa , Imai Katsunori , Hayashi Hiromitsu , Chikamoto Akira , Ishiko Takatoshi , Baba Hideo 
Published: August 2019

Background: The role of cellular senescence of cancer associated fibroblasts (CAFs) in the development of cancer is controversial. In this study, we investigated how senescence of CAFs, represented by Caveolin-1 (CAV1) expression, affects tumor progression in pancreatic cancers (PC).

Methods: We used CAV1 expression to monitor cellular senescence, because CAV1 has been reported to play a major role in cellular senescence. A total 157 consecutive patients with PC underwent curative resections between January 2004 and December 2017 were enrolled. Patients were divided into two groups according to CAV1 expression in CAFs (high and low CAV1, measured by immunohistochemistry). We investigated the relationship between the CAV1 expression in CAFs and the patients’ clinicopathological characteristics, including survival. We also established ten CAFs cell lines using PC clinical samples and and evaluated the relationship between CAV1

and senescence marker expression, such as p21 and p53. We chose high CAV1 CAFs to knock down CAV1 expression using siRNA. Finally, we cultured a PC cell line (MIAPaCa-2) with CAFs-conditioned medium (CM) to evaluate the effect of cellular senescence in CAFs on proliferation and invasion of PC cell lines.

Results: The high CAV1 group counts of 49 patients (31%), and the low CAV1 group counts of 110 patients (69%). As for patients’ clinicopatholoical factors, the serum levels of CA19-9 (p=0.024) and pathological T factor stage (T0,1/T2,3,4) (p=0.014), defined by Japan Pancreas Society as the “General Rules for the Study of Pancreatic Cancer” were significantly higher in the high CAV1 group. The high CAV1 group had significantly worse outcomes in overall (log-rank p=0.0062) and disease-free survivals (log-rank p=0.0018). Multivariate analysis revealed that high CAV1 group was the independent prognostic factors for OS (p=0.043) and DFS (p=0.018). In coculture assays using CAFs-CM

and MIAPaCa-2 cells, we found that knockdown of CAV1 in CAFs negatively affected the invasion of the PC cells compared to that with si control (p&lt;0.0001).

Conclusion: The present results suggest that, in PC, CAV1 expression in CAFs is associated with patients’ poor prognosis and the downregulation of CAV1 in CAFs reduces the invasive ability of PC cells. Therefore, CAV1 of CAFs might be a new target for the treatment of PC.

Citation Format: Takanobu Yamao, Yo-ichi Yamashita, Kensuke Yamamura, Naoki Umezaki, Rumi Itoyama, Yosuke Nakao, Toshihiko Yusa, Tatsunori Miyata, Shigeki Nakagawa, Hirohisa Okabe, Katsunori Imai, Hiromitsu Hayashi, Akira Chikamoto, Takatoshi Ishiko, Hideo Baba. Cellular senescence, represented by expression of caveolin-1, in cancer-associated fibroblasts promotes tumor Invasion in pancreatic cancer cellular [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 2023.