Vitamin D Supplementation is a Promising Therapy for Pancreatic Ductal Adenocarcinoma in Conjunction with Current Chemoradiation Therapy

Yosuke Mukai, Daisaku Yamada, Hidetoshi Eguchi, Yoshifumi Iwagami, Tadafumi Asaoka, Takehiro Noda, Koichi Kawamoto, Kunihito Gotoh, Shogo Kobayashi, Yutaka Takeda, Masahiro Tanemura, Masaki Mori, Yuichiro Doki

Research output: Contribution to journalArticle

4 Citations (Scopus)

Abstract

Background: The cancer-associated fibroblasts (CAFs) in pancreatic ductal adenocarcinoma (PDAC) are well known to play a dominant role in distant metastasis. Nevertheless, the effect on CAFs with current chemoradiation therapies remains uncertain. Objective: This study aimed to reveal the role of CAFs under current chemoradiation therapy (CRT) and investigate the factors regulating CAFs. Methods: α-SMA-positive cells in 86 resected PDAC specimens with/without preoperative CRT were evaluated by immunohistochemistry. Various factors, including the plasma levels of vitamin D, were investigated for association with the number of CAFs or distant metastasis-free survival (DMFS). Human pancreatic satellite cells (hPSCs) extracted from clinical specimens were used to validate the factors. Results: All PDAC samples contained CAFs but the number varied widely. Multivariate analysis for DMFS indicated a larger number of CAFs was a significant risk factor. Univariate analysis for the number of CAFs identified two clinical factors: preoperative CRT and lower plasma levels of vitamin D. In subgroup analysis, the higher plasma level of vitamin D was a dominant factor for longer DMFS in PDAC patients after preoperative CRT. These results were validated by using extracted hPSCs. Irradiation activated stromal cells into CAFs facilitating malignant characteristics of PDAC and the change was inhibited by vitamin D supplementation in vitro. Conclusion: In conjunction with established current therapies, vitamin D supplementation may be an effective treatment for PDAC patients by inactivating CAFs.

Original languageEnglish
Pages (from-to)1868-1879
Number of pages12
JournalAnnals of Surgical Oncology
Volume25
Issue number7
DOIs
Publication statusPublished - Jul 1 2018
Externally publishedYes

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Vitamin D
Adenocarcinoma
Neoplasm Metastasis
Therapeutics
Survival
Cancer-Associated Fibroblasts
Stromal Cells
Multivariate Analysis
Immunohistochemistry

All Science Journal Classification (ASJC) codes

  • Surgery
  • Oncology

Cite this

Vitamin D Supplementation is a Promising Therapy for Pancreatic Ductal Adenocarcinoma in Conjunction with Current Chemoradiation Therapy. / Mukai, Yosuke; Yamada, Daisaku; Eguchi, Hidetoshi; Iwagami, Yoshifumi; Asaoka, Tadafumi; Noda, Takehiro; Kawamoto, Koichi; Gotoh, Kunihito; Kobayashi, Shogo; Takeda, Yutaka; Tanemura, Masahiro; Mori, Masaki; Doki, Yuichiro.

In: Annals of Surgical Oncology, Vol. 25, No. 7, 01.07.2018, p. 1868-1879.

Research output: Contribution to journalArticle

Mukai, Y, Yamada, D, Eguchi, H, Iwagami, Y, Asaoka, T, Noda, T, Kawamoto, K, Gotoh, K, Kobayashi, S, Takeda, Y, Tanemura, M, Mori, M & Doki, Y 2018, 'Vitamin D Supplementation is a Promising Therapy for Pancreatic Ductal Adenocarcinoma in Conjunction with Current Chemoradiation Therapy', Annals of Surgical Oncology, vol. 25, no. 7, pp. 1868-1879. https://doi.org/10.1245/s10434-018-6431-8
Mukai, Yosuke ; Yamada, Daisaku ; Eguchi, Hidetoshi ; Iwagami, Yoshifumi ; Asaoka, Tadafumi ; Noda, Takehiro ; Kawamoto, Koichi ; Gotoh, Kunihito ; Kobayashi, Shogo ; Takeda, Yutaka ; Tanemura, Masahiro ; Mori, Masaki ; Doki, Yuichiro. / Vitamin D Supplementation is a Promising Therapy for Pancreatic Ductal Adenocarcinoma in Conjunction with Current Chemoradiation Therapy. In: Annals of Surgical Oncology. 2018 ; Vol. 25, No. 7. pp. 1868-1879.
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AU - Mukai, Yosuke

AU - Yamada, Daisaku

AU - Eguchi, Hidetoshi

AU - Iwagami, Yoshifumi

AU - Asaoka, Tadafumi

AU - Noda, Takehiro

AU - Kawamoto, Koichi

AU - Gotoh, Kunihito

AU - Kobayashi, Shogo

AU - Takeda, Yutaka

AU - Tanemura, Masahiro

AU - Mori, Masaki

AU - Doki, Yuichiro

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AB - Background: The cancer-associated fibroblasts (CAFs) in pancreatic ductal adenocarcinoma (PDAC) are well known to play a dominant role in distant metastasis. Nevertheless, the effect on CAFs with current chemoradiation therapies remains uncertain. Objective: This study aimed to reveal the role of CAFs under current chemoradiation therapy (CRT) and investigate the factors regulating CAFs. Methods: α-SMA-positive cells in 86 resected PDAC specimens with/without preoperative CRT were evaluated by immunohistochemistry. Various factors, including the plasma levels of vitamin D, were investigated for association with the number of CAFs or distant metastasis-free survival (DMFS). Human pancreatic satellite cells (hPSCs) extracted from clinical specimens were used to validate the factors. Results: All PDAC samples contained CAFs but the number varied widely. Multivariate analysis for DMFS indicated a larger number of CAFs was a significant risk factor. Univariate analysis for the number of CAFs identified two clinical factors: preoperative CRT and lower plasma levels of vitamin D. In subgroup analysis, the higher plasma level of vitamin D was a dominant factor for longer DMFS in PDAC patients after preoperative CRT. These results were validated by using extracted hPSCs. Irradiation activated stromal cells into CAFs facilitating malignant characteristics of PDAC and the change was inhibited by vitamin D supplementation in vitro. Conclusion: In conjunction with established current therapies, vitamin D supplementation may be an effective treatment for PDAC patients by inactivating CAFs.

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