Metronomic chemotherapy remodel cancer‑associated fibroblasts to decrease chemoresistance of gastric cancer in nude mice

  • Authors:
    • Chao Wang
    • Wenqi Xi
    • Jinling Jiang
    • Jun Ji
    • Yingyan Yu
    • Zhenggang Zhu
    • Jun Zhang
  • View Affiliations

  • Published online on: October 16, 2017     https://doi.org/10.3892/ol.2017.7197
  • Pages: 7903-7909
Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )
Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )


Abstract

The present study aimed to evaluate whether capecitabine or 5‑fluorouracil (5‑Fu) chemotherapy with the metronomic pattern may cause significant chemoresistance compared with the traditional pattern, and whether CAFs are involved in drug resistance. SGC‑7901 cells were subcutaneously injected into the nude mice, and the mice were divided into five groups: The control group, intraperitoneally injected with normal saline; the 5‑Fu conventional dose group [5‑Fu maximum tolerated dose (MTD) group], intraperitoneally injected with 50 mg/kg, twice per week for 2 weeks, with an 1‑week discontinuation for 6 weeks; the capecitabine conventional dose group (capecitabine MTD group), intragastric 500 mg/kg, twice per week for 2 weeks, with a 1‑week discontinuation for 6 weeks; the 5‑Fu metronomic group [5‑Fu low‑dose metronomic (LDM) group], intraperitoneally injected with 15 mg/kg, twice a week for 6 weeks; and the capecitabine metronomic group (capecitabine LDM group), intragastric administration at 200 mg/kg, twice a week for 6 weeks. The chemotherapy resistance markers [glutathione transferase Pi (GSTP) and multidrug resistance protein 1 (MDR1)] were detected by immunohistochemical staining (IHC), and the association of the expression of these markers with the chemotherapy administration patterns was analyzed. Vascular endothelial growth factor (VEGF) and the cancer‑associated fibroblast (CAF) marker α‑smooth muscle actin were also examined by IHC to illustrate the possible mechanism of chemoresistance. The expression of GSTP and MDR1 in the MTD groups was significantly higher compared with those of the LDM groups (P<0.01). Furthermore, the number of CAFs and the level of VEGF in the MTD groups were significantly higher compared with those of the LDM groups (P<0.05). The low dose metronomic chemotherapy did not increase the risk of chemoresistance compared with the conventional dose traditional chemotherapy in terms of capecitabine or 5‑Fu, the increasing amount of CAFs in the microenvironment of cancer cell following therapy may protect cell from capecitabine or 5‑Fu via producing VEGF to increase vascularization.

References

1 

Torre LA, Bray F, Siegel RL, Ferlay J, Lortet-Tieulent J and Jemal A: Global cancer statistics, 2012. CA Cancer J Clin. 65:87–108. 2015. View Article : Google Scholar : PubMed/NCBI

2 

Fujitani K: Overview of adjuvant and neoadjuvant therapy for resectable gastric cancer in the East. Dig Surg. 30:119–129. 2013. View Article : Google Scholar : PubMed/NCBI

3 

Bang YJ, Kim YW, Yang HK, Chung HC, Park YK, Lee KH, Lee KW, Kim YH, Noh SI, Cho JY, et al: Adjuvant capecitabine and oxaliplatin for gastric cancer after D2 gastrectomy (CLASSIC): A phase 3 open-label, randomised controlled trial. Lancet. 379:315–321. 2012. View Article : Google Scholar : PubMed/NCBI

4 

Nakajima T, Kinoshita T, Nashimoto A, Sairenji M, Yamaguchi T, Sakamoto J, Fujiya T, Inada T, Sasako M and Ohashi Y: National Surgical Adjuvant Study of Gastric Cancer Group: Randomized controlled trial of adjuvant uracil-tegafur versus surgery alone for serosa-negative, locally advanced gastric cancer. Br J Surg. 94:1468–1476. 2007. View Article : Google Scholar : PubMed/NCBI

5 

Sasako M, Sakuramoto S, Katai H, Kinoshita T, Furukawa H, Yamaguchi T, Nashimoto A, Fujii M, Nakajima T and Ohashi Y: Five-year outcomes of a randomized phase III trial comparing adjuvant chemotherapy with S-1 versus surgery alone in stage II or III gastric cancer. J Clin Oncol. 29:4387–4393. 2011. View Article : Google Scholar : PubMed/NCBI

6 

Banys-Paluchowski M, Schütz F, Ruckhäberle E, Krawczyk N and Fehm T: Metronomic chemotherapy for metastatic breast cancer - a systematic review of the literature. Geburtshilfe Frauenheilkd. 76:525–534. 2016. View Article : Google Scholar : PubMed/NCBI

7 

Pasquier E, Kavallaris M and André N: Metronomic chemotherapy: New rationale for new directions. Nat Rev Clin Oncol. 7:455–465. 2010. View Article : Google Scholar : PubMed/NCBI

8 

Shi H, Jiang J, Ji J, Shi M, Cai Q, Chen X, Yu Y, Liu B, Zhu Z and Zhang J: Anti-angiogenesis participates in antitumor effects of metronomic capecitabine on colon cancer. Cancer Lett. 349:128–135. 2014. View Article : Google Scholar : PubMed/NCBI

9 

Yuan F, Shi H, Ji J, Cai Q, Chen X, Yu Y, Liu B, Zhu Z and Zhang J: Capecitabine metronomic chemotherapy inhibits the proliferation of gastric cancer cells through anti-angiogenesis. Oncol Rep. 33:1753–1762. 2015. View Article : Google Scholar : PubMed/NCBI

10 

Browder T, Butterfield CE, Kräling BM, Shi B, Marshall B, O'Reilly MS and Folkman J: Antiangiogenic scheduling of chemotherapy improves efficacy against experimental drug-resistant cancer. Cancer Res. 60:1878–1886. 2000.PubMed/NCBI

11 

Wang W, McLeod HL, Cassidy J and Collie-Duguid ES: Mechanisms of acquired chemoresistance to 5-fluorouracil and tomudex: Thymidylate synthase dependent and independent networks. Cancer Chemother Pharmacol. 59:839–845. 2007. View Article : Google Scholar : PubMed/NCBI

12 

Li J, Guan J, Long X, Wang Y and Xiang X: mir-1-mediated paracrine effect of cancer-associated fibroblasts on lung cancer cell proliferation and chemoresistance. Oncol Rep. 35:3523–3531. 2016. View Article : Google Scholar : PubMed/NCBI

13 

Shintani Y, Fujiwara A, Kimura T, Kawamura T, Funaki S, Minami M and Okumura M: IL-6 secreted from cancer associated fibroblasts mediates chemoresistance in NSCLC by increasing epithelial-mesenchymal transition signaling. J Thorac Oncol. 11:1482–1492. 2016. View Article : Google Scholar : PubMed/NCBI

14 

Lotti F, Jarrar AM, Pai RK, Hitomi M, Lathia J, Mace A, Gantt GA Jr, Sukhdeo K, DeVecchio J, Vasanji A, et al: Chemotherapy activates cancer-associated fibroblasts to maintain colorectal cancer-initiating cells by IL-17A. J Exp Med. 210:2851–2872. 2013. View Article : Google Scholar : PubMed/NCBI

15 

Tanaka K, Miyata H, Sugimura K, Fukuda S, Kanemura T, Yamashita K, Miyazaki Y, Takahashi T, Kurokawa Y, Yamasaki M, et al: miR-27 is associated with chemoresistance in esophageal cancer through transformation of normal fibroblasts to cancer-associated fibroblasts. Carcinogenesis. 36:894–903. 2015. View Article : Google Scholar : PubMed/NCBI

16 

Amornsupak K, Insawang T, Thuwajit P, O-Charoenrat P, Eccles SA and Thuwajit C: Cancer-associated fibroblasts induce high mobility group box 1 and contribute to resistance to doxorubicin in breast cancer cells. BMC Cancer. 14:9552014. View Article : Google Scholar : PubMed/NCBI

17 

Shen L, Shan YS, Hu HM, Price TJ, Sirohi B, Yeh KH, Yang YH, Sano T, Yang HK, Zhang X, et al: Management of gastric cancer in Asia: Resource-stratified guidelines. Lancet Oncol. 14:e535–e547. 2013. View Article : Google Scholar : PubMed/NCBI

18 

Zhao W, Chen R, Zhao M, Li L, Fan L and Che XM: High glucose promotes gastric cancer chemoresistance in vivo and in vitro. Mol Med Rep. 12:843–850. 2015. View Article : Google Scholar : PubMed/NCBI

19 

Longley DB and Johnston PG: Molecular mechanisms of drug resistance. J Pathol. 205:275–292. 2005. View Article : Google Scholar : PubMed/NCBI

20 

Geng M, Wang L, Chen X, Cao R and Li P: The association between chemosensitivity and Pgp, GST-π and Topo II expression in gastric cancer. Diagn Pathol. 8:1982013. View Article : Google Scholar : PubMed/NCBI

21 

Verset L, Tommelein J, Lopez Moles X, Decaestecker C, Boterberg T, De Vlieghere E, Salmon I, Mareel M, Bracke M, De Wever O and Demetter P: Impact of neoadjuvant therapy on cancer-associated fibroblasts in rectal cancer. Radiother Oncol. 116:449–454. 2015. View Article : Google Scholar : PubMed/NCBI

22 

Yan H, Guo BY and Zhang S: Cancer-associated fibroblasts attenuate Cisplatin-induced apoptosis in ovarian cancer cells by promoting STAT3 signaling. Biochem Biophys Res Commun. 470:947–954. 2016. View Article : Google Scholar : PubMed/NCBI

23 

Steinbichler TB, Metzler V, Pritz C, Riechelmann H and Dudas J: Tumor-associated fibroblast-conditioned medium induces CDDP resistance in HNSCC cells. Oncotarget. 7:2508–2518. 2016. View Article : Google Scholar : PubMed/NCBI

24 

Hara M, Nagasaki T, Shiga K and Takeyama H: Suppression of cancer-associated fibroblasts and endothelial cells by itraconazole in bevacizumab-resistant gastrointestinal cancer. Anticancer Res. 36:169–177. 2016.PubMed/NCBI

25 

Salnikov AV, Heldin NE, Stuhr LB, Wiig H, Gerber H, Reed RK and Rubin K: Inhibition of carcinoma cell-derived VEGF reduces inflammatory characteristics in xenograft carcinoma. Int J Cancer. 119:2795–2802. 2006. View Article : Google Scholar : PubMed/NCBI

26 

Zhang J and Liu J: Tumor stroma as targets for cancer therapy. Pharmacol Ther. 137:200–215. 2013. View Article : Google Scholar : PubMed/NCBI

27 

Franco OE, Shaw AK, Strand DW and Hayward SW: Cancer associated fibroblasts in cancer pathogenesis. Semin Cell Dev Biol. 21:33–39. 2010. View Article : Google Scholar : PubMed/NCBI

28 

Yan Y, Wang LF and Wang RF: Role of cancer-associated fibroblasts in invasion and metastasis of gastric cancer. World J Gastroenterol. 21:9717–9726. 2015. View Article : Google Scholar : PubMed/NCBI

29 

Rudin CM, Brahmer JR, Juergens RA, Hann CL, Ettinger DS, Sebree R, Smith R, Aftab BT, Huang P and Liu JO: Phase 2 study of pemetrexed and itraconazole as second-line therapy for metastatic nonsquamous non-small-cell lung cancer. J Thorac Oncol. 8:619–623. 2013. View Article : Google Scholar : PubMed/NCBI

Related Articles

Journal Cover

December 2017
Volume 14 Issue 6

Print ISSN: 1792-1074
Online ISSN:1792-1082

Sign up for eToc alerts

Recommend to Library

Copy and paste a formatted citation
APA
Wang, C., Xi, W., Jiang, J., Ji, J., Yu, Y., Zhu, Z., & Zhang, J. (2017). Metronomic chemotherapy remodel cancer‑associated fibroblasts to decrease chemoresistance of gastric cancer in nude mice. Oncology Letters, 14, 7903-7909. https://doi.org/10.3892/ol.2017.7197
MLA
Wang, C., Xi, W., Jiang, J., Ji, J., Yu, Y., Zhu, Z., Zhang, J."Metronomic chemotherapy remodel cancer‑associated fibroblasts to decrease chemoresistance of gastric cancer in nude mice". Oncology Letters 14.6 (2017): 7903-7909.
Chicago
Wang, C., Xi, W., Jiang, J., Ji, J., Yu, Y., Zhu, Z., Zhang, J."Metronomic chemotherapy remodel cancer‑associated fibroblasts to decrease chemoresistance of gastric cancer in nude mice". Oncology Letters 14, no. 6 (2017): 7903-7909. https://doi.org/10.3892/ol.2017.7197