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Cancer-associated fibroblasts contribute to cancer metastasis and apoptosis resistance in human ovarian cancer via paracrine SDF-1α

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Abstract

Background

Cancer-associated fibroblasts (CAFs), one of the main members of stromal cells in tumor microenvironment are proposed to play a central role in promoting tumor metastasis. It is unclear whether and how CAFs mediates tumor metastasis or chemoresistance in human ovarian cancer.

Methods

CAFs were extracted from human ovarian cancer tissues (OCs) of patients with different kinds of histological types.

Results

We found that CAFs showed more aggressive potency than those tumor cells, both of which were isolated from the same ovarian cancer specimen. Moreover, when co-cultured with CAFs, cell migration abilities of ovarian cancer cells (SKOV3, OVCAR3 and HEY) were significantly increased. Next, we preliminarily detected a higher CAFs density in sections of metastatic lesions than those in primary tumor site of primary OCs clinically. However, no significant difference of stromal derived factors-1α (SDF-1α) production from CAFs was found between primary and metastatic lesions. Additionally, in contrast with tumor cells, CAFs exhibited obvious apoptosis resistance when treated with cisplatin. Furthermore, we found that cisplatin-induced cytotoxicity and apoptosis were significantly inhibited by co-cultured with recombinant human SDF-1α in SKOV3 in a time and dose-dependent manner, and this effect was suppressed by the CXCR4 antagonist AMD3100.

Conclusions

CAFs might be involved in the malignant metastasis in human ovarian cancer through promoting cell migration in tumor cells. And their resistance to cytotoxic agents might be mediated by paracrine SDF-1α/CXCR4 signaling in ovarian cancer.

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Data availability

The data generated or analyzed during the current study are available from the corresponding author on reasonable request.

References

  1. Siegel RL, Miller KD, Fuchs HE, Jemal A. Cancer statistics, 2021. CA: Cancer J Clin. 2021;71:7–33.

    PubMed  Google Scholar 

  2. Langyel E. Ovarian cancer development and metastasis. Am J Pathol. 2010;177:1053–64.

    Article  Google Scholar 

  3. Balkwill FR, Capasso M, Hagemann T. The tumor microenvironment at a glance. J Cell Sci. 2012;125:5591–6.

    Article  CAS  PubMed  Google Scholar 

  4. Spill F, Reynolds DS, Kamm RD, Zaman MH. Impact of the physical microenvironment on tumor progression and metastasis. Curr Opin Biotech. 2016;40:41–8.

    Article  CAS  PubMed  Google Scholar 

  5. Grivennikov SI, Greten FR, Karin M. Immunity, inflammation, and cancer. Cell. 2010;140:883–99.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Han CC, Liu TY, Yin R. Biomarkers for cancer-associated fibroblasts. Biomark Res. 2020;8(1):64.

    Article  PubMed  PubMed Central  Google Scholar 

  7. Orimo A, Gupta PB, Sgroi DC, Arenzana-Seisdedos F, Delaunay T, Naeem R, et al. Stromal fibroblasts present in invasive human breast carcinomas promote tumor growth and angiogenesis through elevated SDF-1/CXCL12 secretion. Cell. 2005;121:335–48.

    Article  CAS  PubMed  Google Scholar 

  8. Fiori ME, Di Franco S, Villanova L, Bianca P, Stassi G, De Maria R. Cancer-associated fibroblasts as abettors of tumor progression at the crossroads of EMT and therapy resistance. Mol Cancer. 2019;18(1):1–6.

    Article  Google Scholar 

  9. Bremnes RM, Donnem T, Al-Saad S, Al-Shibli K, Andersen S, Sirera R, et al. The role of tumor stroma in cancer progression and prognosis: emphasis on carcinoma-associated fibroblasts and non-small cell lung cancer. J Thorac Oncol: Off Publ Int Assoc Study Lung Cancer. 2011;6:209–17.

    Article  Google Scholar 

  10. Hiscox S, Barrett-Lee P, Nicholson RI. Therapeutic targeting of tumor-stroma interactions. Expert Opin Ther Targets. 2011;15:609–21.

    Article  CAS  PubMed  Google Scholar 

  11. Augsten M, Hagglof C, Pena C, Ostman A. A digest on the role of the tumor microenvironment in gastrointestinal cancers. Cancer Microenvironment: Off J Int Cancer Microenvironment Soc. 2010;3:167–76.

    Article  CAS  Google Scholar 

  12. 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.

    Article  PubMed  Google Scholar 

  13. Kalluri R. The biology and function of fibroblasts in cancer. Nat Rev Cancer. 2016;16:582–98.

    Article  CAS  PubMed  Google Scholar 

  14. Neesse A, Bauer CA, Ohlund D, Lauth M, Buchholz M, Michl P, et al. Stromal biology and therapy in pancreatic cancer: ready for clinical translation? Gut. 2019;68:159–71.

    Article  CAS  PubMed  Google Scholar 

  15. Ohlund D, Elyada E, Tuveson D. Fibroblast heterogeneity in the cancer wound. J Exp Med. 2014;211:1503–23.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Gieniec KA, Butler LM, Worthley DL, Woods SL. Cancer-associated fibroblasts-heroes or villains? Brit J Cancer. 2019;121:293–302.

    Article  PubMed  PubMed Central  Google Scholar 

  17. Ishii G, Ochiai A, Neri S. Phenotypic and functional heterogeneity of cancer-associated fibroblast within the tumor microenvironment. Adv Drug Deliver Rev. 2016;99:186–96.

    Article  CAS  Google Scholar 

  18. Mezawa Y, Orimo A. The roles of tumor- and metastasis-promoting carcinoma-associated fibroblasts in human carcinomas. Cell Tissue Res. 2016;365:675–89.

    Article  CAS  PubMed  Google Scholar 

  19. Bertran E, Crosas-Molist E, Sancho P, Caja L, Lopez-Luque J, Navarro E, et al. Overactivation of the TGF-beta pathway confers a mesenchymal-like phenotype and CXCR4-dependent migratory properties to liver tumor cells. Hepatology. 2013;58:2032–44.

    Article  CAS  PubMed  Google Scholar 

  20. Roy I, Zimmerman NP, Mackinnon AC, Tsai S, Evans DB, Dwinell MB. CXCL12 chemokine expression suppresses human pancreatic cancer growth and metastasis. PLoS ONE. 2014;9: e90400.

    Article  PubMed  PubMed Central  Google Scholar 

  21. Choi YH, Burdick MD, Strieter BA, Mehrad B, Strieter RM. CXCR4, but not CXCR7, discriminates metastatic behavior in non-small cell lung cancer cells. Mol Cancer Res. 2014;12:38–47.

    Article  CAS  PubMed  Google Scholar 

  22. Conley-LaComb MK, Saliganan A, Kandagatla P, Chen YQ, Cher ML, Chinni SR. PTEN loss mediated Akt activation promotes prostate tumor growth and metastasis via CXCL12/CXCR4 signaling. Mol Cancer. 2013;12:85.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Singh S, Srivastava SK, Bhardwaj A, Owen LB, Singh AP. CXCL12-CXCR4 signalling axis confers gemcitabine resistance to pancreatic cancer cells: a novel target for therapy. Br J Cancer. 2010;103:1671–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Bhowmick NA, Neilson EG, Moses HL. Stromal fibroblasts in cancer initiation and progression. Nature. 2004;432:332–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Hwang RF, Moore T, Arumugam T, Ramachandran V, Amos KD, Rivera A, et al. Cancer-associated stromal fibroblasts promote pancreatic tumor progression. Cancer Res. 2008;68:918–26.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Grugan KD, Miller CG, Yao Y, Michaylira CZ, Ohashi S, Klein-Szanto AJ, et al. Fibroblast-secreted hepatocyte growth factor plays a functional role in esophageal squamous cell carcinoma invasion. Proc Natl Acad Sci USA. 2010;107:11026–31.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Allen M, Jones JL. Jekyll and Hyde: the role of the microenvironment on the progression of cancer. J Pathol. 2011;223:162–76.

    Article  CAS  PubMed  Google Scholar 

  28. Teng F, Tian W, Wang Y, Zhang Y, Guo F, Zhao J, et al. Cancer-associated fibroblasts promote the progression of endometrial cancer via the SDF-1/CXCR4 axis. J Hematol Oncol. 2016;9:8.

    Article  PubMed  PubMed Central  Google Scholar 

  29. Schauer IG, Sood AK, Mok S, Liu J. Cancer-associated fibroblasts and their putative role in potentiating the initiation and development of epithelial ovarian cancer. Neoplasia. 2011;13:393–405.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Gaggioli C, Hooper S, Hidalgo-Carcedo C, Grosse R, Marshall JF, Harrington K, et al. Fibroblast-led collective invasion of carcinoma cells with differing roles for RhoGTPases in leading and following cells. Nat Cell Biol. 2007;9:1392-U92.

    Article  CAS  PubMed  Google Scholar 

  31. Wels J, Kaplan RN, Rafii S, Lyden D. Migratory neighbors and distant invaders: tumor-associated niche cells. Gene Dev. 2008;22:559–74.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Zhang Y, Tang H, Cai J, Zhang T, Guo J, Feng D, et al. Ovarian cancer-associated fibroblasts contribute to epithelial ovarian carcinoma metastasis by promoting angiogenesis, lymphangiogenesis and tumor cell invasion. Cancer Lett. 2011;303:47–55.

    Article  CAS  PubMed  Google Scholar 

  33. Kim J, Takeuchi H, Lam ST, Turner RR, Wang HJ, Kuo C, et al. Chemokine receptor CXCR4 expression in colorectal cancer patients increases the risk for recurrence and for poor survival. J Clin Oncol. 2005;23:2744–53.

    Article  CAS  PubMed  Google Scholar 

  34. Pollard JW. Tumour-educated macrophages promote tumour progression and metastasis. Nat Rev Cancer. 2004;4:71–8.

    Article  CAS  PubMed  Google Scholar 

  35. Kajiyama H, Shibata K, Terauchi M, Ino K, Nawa A, Kikkawa F. Involvement of SDF-1alpha/CXCR4 axis in the enhanced peritoneal metastasis of epithelial ovarian carcinoma. Int J Cancer. 2008;122(1):91–9.

    Article  CAS  PubMed  Google Scholar 

  36. Pils D, Pinter A, Reibenwein J, Alfanz A, Horak P, Schmid BC, et al. In ovarian cancer the prognostic influence of HER2/neu is not dependent on the CXCR4/SDF-1 signalling pathway. Br J Cancer. 2007;96(3):485–91.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Funding

This work was supported by a grant from the National Natural Science Foundation of China (NSFC NO. 81072120), Chongqing Science and Technology Commission Project (cstc2017jcyjAX0194), Hospital-level Incubation Project of The Fifth People's Hospital of Shanghai, Fudan University (2019WYFY05).

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Author notes

  1. Jie-min Dai and Ke Sun have contributed equally to this work.

Authors and Affiliations

  1. Department of Obstetrics and Gynecology, Shanghai Fifth People’s Hospital, Fudan University, Shanghai, 200240, China

    Jie-min Dai, Ke Sun, Chang Li, Jun-hua Guan, Li-na Yang & Li-wen Zhang

  2. Department of Obstetrics and Gynecology, First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, China

    Min Cheng

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  1. Jie-min Dai
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Contributions

All authors contributed to the study conception and design. Material preparation, data collection and analysis were performed by JD and KS. The first draft of the manuscript was written by JD and revised by LY. All authors read and approved the final manuscript.

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Correspondence to Li-na Yang or Li-wen Zhang.

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The authors have no relevant financial or non-financial interests to disclose.

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This study was performed in line with the principles of the Declaration of Helsinki. Approval was granted by the Ethics Committee of Chongqing Medical University.

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Dai, Jm., Sun, K., Li, C. et al. Cancer-associated fibroblasts contribute to cancer metastasis and apoptosis resistance in human ovarian cancer via paracrine SDF-1α. Clin Transl Oncol 25, 1606–1616 (2023). https://doi.org/10.1007/s12094-022-03054-9

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