Abstract
Activation of vitamin D receptor (VDR) in cancer-associated fibroblasts (CAFs) has been implicated in hesitating tumor progression and chemoresistance of several human malignancies. Yet, the role of VDR in CAF-induced chemotherapy resistance of gastric cancer (GC) cells remains elusive. In this study we first conducted immunohistochemistry analysis on tissue microarrays including 88 pairs of GC and normal mucosa samples, and provided clinical evidence that VDR was mainly expressed in gastric mucous cells but almost invisible in CAFs, and VDR expression was negatively correlated with malignant clinical phenotype and advanced stages, low VDR expression confers to poor overall survival rate of patients with GC. In a co-culture system of primary CAFs and cancer cells, we showed that treatment of HGC-27 and AGS GC cells with VDR ligand calcipotriol (Cal, 500 nM) significantly inhibited CAF-induced oxaliplatin resistance. By using RNA-sequencing and Human Cytokine Antibody Array, we demonstrated that IL-8 secretion from CAFs induced oxaliplatin resistance via activating the PI3K/AKT pathway in GC, whereas Cal treatment greatly attenuated the tumor-supportive effect of CAF-derived IL-8 on GC cells. Taken together, this study verifies the specific localization of VDR in GC tissues and demonstrates that activation of VDR abrogates CAF-derived IL-8-mediated oxaliplatin resistance in GC via blocking PI3K/Akt signaling, suggesting vitamin D supplementation as a potential strategy of enhancing the anti-tumor effect of chemotherapy in GC.
Similar content being viewed by others
Log in or create a free account to read this content
Gain free access to this article, as well as selected content from this journal and more on nature.com
or
Data availability
All data generated and described in this article are available from the corresponding author on reasonable request.
References
Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A, et al. Global Cancer Statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2021;71:209–49.
Smyth EC, Nilsson M, Grabsch HI, van Grieken NCT, Lordick F. Gastric cancer. Lancet. 2020;396:635–48.
Ajani JA, D’Amico TA, Bentrem DJ, Chao J, Cooke D, Corvera C, et al. Gastric Cancer, Version 2.2022, NCCN Clinical Practice Guidelines in Oncology. J Natl Compr Canc Netw. 2022;20:167–92.
Biagioni A, Skalamera I, Peri S, Schiavone N, Cianchi F, Giommoni E, et al. Update on gastric cancer treatments and gene therapies. Cancer Metastasis Rev. 2019;38:537–48.
Hanahan D, Coussens LM. Accessories to the crime: functions of cells recruited to the tumor microenvironment. Cancer Cell. 2012;21:309–22.
Park D, Sahai E, Rullan A. SnapShot: cancer-associated fibroblasts. Cell. 2020;181:486.
Chen X, Song E. Turning foes to friends: targeting cancer-associated fibroblasts. Nat Rev Drug Discov. 2019;18:99–115.
Kobayashi H, Enomoto A, Woods SL, Burt AD, Takahashi M, Worthley DL. Cancer-associated fibroblasts in gastrointestinal cancer. Nat Rev Gastroenterol Hepatol. 2019;16:282–95.
Oya Y, Hayakawa Y, Koike K. Tumor microenvironment in gastric cancers. Cancer Sci. 2020;111:2696–707.
Zhai J, Shen J, Xie G, Wu J, He M, Gao L, et al. Cancer-associated fibroblasts-derived IL-8 mediates resistance to cisplatin in human gastric cancer. Cancer Lett. 2019;454:37–43.
Ji Z, Tian W, Gao W, Zang R, Wang H, Yang G. Cancer-associated fibroblast-derived interleukin-8 promotes ovarian cancer cell stemness and malignancy through the notch3-mediated signaling. Front Cell Dev Biol. 2021;9:684505.
Chen C, Zhang R, Ma L, Li Q, Zhao YL, Zhang GJ, et al. Neuropilin-1 is up-regulated by cancer-associated fibroblast-secreted IL-8 and associated with cell proliferation of gallbladder cancer. J Cell Mol Med. 2020;24:12608–18.
Morita M, Okuyama M, Akutsu T, Ohdaira H, Suzuki Y, Urashima M. Vitamin D supplementation regulates postoperative serum levels of PD-L1 in patients with digestive tract cancer and improves survivals in the highest quintile of PD-L1: a post Hoc analysis of the AMATERASU randomized controlled trial. Nutrients. 2021;13:1987.
Chandler PD, Chen WY, Ajala ON, Hazra A, Cook N, Bubes V, et al. Effect of vitamin D3 supplements on development of advanced cancer: a secondary analysis of the VITAL randomized clinical trial. JAMA Netw Open. 2020;3:e2025850.
Yuan C, Ng K. Vitamin D supplementation: a potential therapeutic agent for metastatic colorectal cancer. Br J Cancer. 2020;123:1205–6.
Sherman MH, Yu RT, Engle DD, Ding N, Atkins AR, Tiriac H, et al. Vitamin D receptor-mediated stromal reprogramming suppresses pancreatitis and enhances pancreatic cancer therapy. Cell. 2014;159:80–93.
Ferrer-Mayorga G, Gomez-Lopez G, Barbachano A, Fernandez-Barral A, Pena C, Pisano DG, et al. Vitamin D receptor expression and associated gene signature in tumour stromal fibroblasts predict clinical outcome in colorectal cancer. Gut. 2017;66:1449–62.
Wen Y, Da M, Zhang Y, Peng L, Yao J, Duan Y. Alterations in vitamin D signaling pathway in gastric cancer progression: a study of vitamin D receptor expression in human normal, premalignant, and malignant gastric tissue. Int J Clin Exp Pathol. 2015;8:13176–84.
Chen LW, Chang LC, Hua CC, Cheng TC, Lee CC. Comparing the expressions of Vitamin D receptor, cell proliferation, and apoptosis in gastric mucosa with gastritis, intestinal metaplasia, or adenocarcinoma change. Front Med (Lausanne). 2021;8:766061.
Sun H, Chang J, Ye M, Weng W, Zhang M, Ni S, et al. GCNT4 is associated with prognosis and suppress cell proliferation in gastric cancer. OncoTargets Ther. 2020;13:8601–13.
Sun H, Ni SJ, Ye M, Weng W, Zhang Q, Zhang M, et al. Hedgehog interacting protein 1 is a prognostic marker and suppresses cell metastasis in gastric cancer. J Cancer. 2018;9:4642–9.
Dottermusch M, Krüger S, Behrens HM, Halske C, Röcken C. Expression of the potential therapeutic target claudin-18.2 is frequently decreased in gastric cancer: results from a large Caucasian cohort study. Virchows Arch. 2019;475:563–71.
Francescone R, Barbosa Vendramini-Costa D, Franco-Barraza J, Wagner J, Muir A, Lau AN, et al. Netrin G1 promotes pancreatic tumorigenesis through cancer-associated fibroblast-driven nutritional support and immunosuppression. Cancer Discov. 2021;11:446–79.
Heichler C, Scheibe K, Schmied A, Geppert CI, Schmid B, Wirtz S, et al. STAT3 activation through IL-6/IL-11 in cancer-associated fibroblasts promotes colorectal tumour development and correlates with poor prognosis. Gut. 2020;69:1269–82.
Jin Z, Lu Y, Wu X, Pan T, Yu Z, Hou J, et al. The cross-talk between tumor cells and activated fibroblasts mediated by lactate/BDNF/TrkB signaling promotes acquired resistance to anlotinib in human gastric cancer. Redox Biol. 2021;46:102076.
Johansson H, Spadola G, Tosti G, Mandala M, Minisini AM, Queirolo P, et al. Vitamin D supplementation and disease-free survival in stage II melanoma: a randomized placebo controlled trial. Nutrients. 2021;13:1931.
Chung I, Wong MK, Flynn G, Yu WD, Johnson CS, Trump DL. Differential antiproliferative effects of calcitriol on tumor-derived and matrigel-derived endothelial cells. Cancer Res. 2006;66:8565–73.
Min D, Lv XB, Wang X, Zhang B, Meng W, Yu F, et al. Downregulation of miR-302c and miR-520c by 1,25(OH)2D3 treatment enhances the susceptibility of tumour cells to natural killer cell-mediated cytotoxicity. Br J Cancer. 2013;109:723–30.
Kong F, Li L, Wang G, Deng X, Li Z, Kong X. VDR signaling inhibits cancer-associated-fibroblasts’ release of exosomal miR-10a-5p and limits their supportive effects on pancreatic cancer cells. Gut. 2019;68:950–1.
Li Q, Li Y, Jiang H, Xiao Z, Wu X, Zhang H, et al. Vitamin D suppressed gastric cancer cell growth through downregulating CD44 expression in vitro and in vivo. Nutrition. 2021;91-92:111413.
Chang S, Gao Z, Yang Y, He K, Wang X, Wang L, et al. miR-99b-3p is induced by vitamin D3 and contributes to its antiproliferative effects in gastric cancer cells by targeting HoxD3. Biol Chem. 2019; 400:1079–86
Chang S, Gao L, Yang Y, Tong D, Guo B, Liu L, et al. miR-145 mediates the antiproliferative and gene regulatory effects of vitamin D3 by directly targeting E2F3 in gastric cancer cells. Oncotarget. 2015;6:7675–85.
Bao A, Li Y, Tong Y, Zheng H, Wu W, Wei C. Tumor-suppressive effects of 1, 25-dihydroxyvitamin D3 in gastric cancer cells. Hepatogastroenterology. 2013;60:943–8.
Shany S, Sigal-Batikoff I, Lamprecht S. Vitamin D and myofibroblasts in fibrosis and cancer: at cross-purposes with TGF-beta/SMAD signaling. Anticancer Res. 2016;36:6225–34.
Anbil S, Pigula M, Huang HC, Mallidi S, Broekgaarden M, Baglo Y, et al. Vitamin D receptor activation and photodynamic priming enables durable low-dose chemotherapy. Mol Cancer Ther. 2020;19:1308–19.
Bussard KM, Mutkus L, Stumpf K, Gomez-Manzano C, Marini FC. Tumor-associated stromal cells as key contributors to the tumor microenvironment. Breast Cancer Res. 2016;18:84.
Bae WJ, Ahn JM, Byeon HE, Kim S, Lee D. PTPRD-inactivation-induced CXCL8 promotes angiogenesis and metastasis in gastric cancer and is inhibited by metformin. J Exp Clin Cancer Res. 2019;38:484.
Fang T, Lv H, Lv G, Li T, Wang C, Han Q, et al. Tumor-derived exosomal miR-1247-3p induces cancer-associated fibroblast activation to foster lung metastasis of liver cancer. Nat Commun. 2018;9:191.
Acknowledgements
This work was supported by National Natural Science Foundation of China (81972249, 82172702, 81902430), Shanghai Clinical Science and Technology Innovation Project of Municipal Hospital (SHDC12020102), Clinical Research Project of Shanghai Shenkang Hospital Development Center (SHDC2020CR4068), Natural Science Foundation of Shanghai (21ZR1414900, 22ZR1413000), Artificial Intelligence Medical Hospital Cooperation Project of Xuhui District (2021-017), Shanghai Science and Technology Development Fund (19MC1911000), Shanghai Municipal Key Clinical Specialty (shslczdzk01301), Shanghai “Rising Stars of Medical Talents” Youth Development Program Youth Medical Talents – Specialist Program (SHWSRS(2020)_087).
Author information
Authors and Affiliations
Contributions
MDX, ZXZ, YQZ and HS conceived the study, performed the literature search and bioinformatics analysis, and prepared the figures. ZQC, JJC, XinW, CT, ZQC, SJN, WWW, MZ, DH, LW and XuW helped with data collection, analysis, and interpretation. YF, MDX and WQS wrote and revised the manuscript. All authors read and approved the final manuscript.
Corresponding authors
Ethics declarations
Competing interests
The authors declare no competing interests.
Rights and permissions
About this article
Cite this article
Zhao, Zx., Zhang, Yq., Sun, H. et al. Calcipotriol abrogates cancer-associated fibroblast-derived IL-8-mediated oxaliplatin resistance in gastric cancer cells via blocking PI3K/Akt signaling. Acta Pharmacol Sin 44, 178–188 (2023). https://doi.org/10.1038/s41401-022-00927-1
Revised:
Accepted:
Published:
Issue date:
DOI: https://doi.org/10.1038/s41401-022-00927-1
Keywords
This article is cited by
-
Cancer-associated fibroblasts as therapeutic targets for cancer: advances, challenges, and future prospects
Journal of Biomedical Science (2025)
-
PDPN+LTBP1+ cancer-associated fibroblasts induce a liver pre-metastatic niche in gastric cancer via PDPN/YAP/LTBP1 and CCL11/CCR3 axis
Cell Communication and Signaling (2025)
-
In-depth insight into tumor-infiltrating stromal cells linked to tertiary lymphoid structures and their prospective function in cancer immunotherapy
Experimental Hematology & Oncology (2025)
-
The fibroinflammatory response in cancer
Nature Reviews Cancer (2025)
-
Deciphering the dual role of autophagy in gastric cancer and gastroesophageal junction cancer: from tumor suppression to cancer progression
Discover Oncology (2025)
