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Oxaliplatin inhibits colorectal cancer progression by inhibiting CXCL11 secreted by cancer-associated fibroblasts and the CXCR3/PI3K/AKT pathway

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Abstract

Purpose

Colorectal cancer (CRC) is a malignant tumor. Oxaliplatin (OXA) can inhibit cancer-associated fibroblasts (CAFs)-induced cancer progression. This study sought to explore the mechanism of OXA in CAFs-induced CRC development.

Methods

CRC cell lines (Caco-2, SW620), normal fibroblasts (NFs), and CAFs were treated with OXA. NFs and CAFs were cultured. CAFs were treated with/without OXA (0.4 mM), and the supernatant was extracted as the conditioned medium (CM) to culture CRC cells. Cell malignant episodes, E-cadherin and Vimentin levels, CXCL1, CXCL2, CXCL3, CXCL8, and CXCL11 mRNA levels, CXCL11 protein level, and extracellular release were assessed. CAFs were transfected with interfering RNA sh-CXCL11 to silence CXCL11 or transfected with CXCL11 overexpression plasmids and treated with OXA to explore the role of CXCL11 in OXA-mediated CRC cells through CAFs. CXCL11 receptor CXCR3 levels in CRC cells and the PI3K/AKT pathway changes were examined. The xenogeneic tumor was transplanted in nude mice. CXCL11 and CXCR3 levels in tumor tissues, tumor volume, shape, size, weight, and Ki67 positive expressions were assessed.

Results

CRC cell growths and epithelial–mesenchymal transformation were stimulated after culture with CAFs–CM, while OXA averted these trends. CXCL11 mRNA level was elevated most significantly, and its protein and extracellular secretion levels were raised, while OXA diminished the levels. CXCL11 silencing weakened the effects of CAFs–CM on promoting CRC proliferation and malignant episodes and CXCL11 overexpression averted OXA property on inhibiting CAFs-promoted CRC cell growth. CXCR3 and PI3K and AKT1 phosphorylation levels were raised in the CAFs–CM group but diminished by OXA. CXCL11 overexpression in CAFs averted OXA property on inhibiting CAFs-activated CXCR3/PI3K/AKT in CRC cells. OXA also inhibited the progression of xenograft tumors by limiting CAFs-secreted CXCL11.

Conclusions

OXA repressed CRC progression by inhibiting CAFs-secreted CXCL11 and the CXCR3/PI3K/AKT pathway.

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All the data generated or analyzed during this study are included in this published article.

References

  1. Brenner H, Kloor M, Pox CP. Colorectal cancer. Lancet. 2014;383:1490–502.

    Article  Google Scholar 

  2. Jin K, Ren C, Liu Y, Lan H, Wang Z. An update on colorectal cancer microenvironment, epigenetic and immunotherapy. Int Immunopharmacol. 2020;89: 107041.

    Article  CAS  Google Scholar 

  3. Guo T, Liu D, Peng S, Wang M, Li Y. A positive feedback loop of lncRNA MIR31HG-miR-361-3p -YY1 accelerates colorectal cancer progression through modulating proliferation, angiogenesis, and glycolysis. Front Oncol. 2021;11: 684984.

    Article  Google Scholar 

  4. Zhang T, Yuan K, Wang Y, Xu M, Cai S, Chen C, et al. Identification of candidate biomarkers and prognostic analysis in colorectal cancer liver metastases. Front Oncol. 2021;11: 652354.

    Article  Google Scholar 

  5. Buhrmann C, Brockmueller A, Harsha C, Kunnumakkara AB, Kubatka P, Aggarwal BB, et al. Evidence that tumor microenvironment initiates epithelial-to-mesenchymal transition and calebin a can suppress it in colorectal cancer cells. Front Pharmacol. 2021;12: 699842.

    Article  CAS  Google Scholar 

  6. Catalano V, Turdo A, Di Franco S, Dieli F, Todaro M, Stassi G. Tumor and its microenvironment: a synergistic interplay. Semin Cancer Biol. 2013;23:522–32.

    Article  CAS  Google Scholar 

  7. Zhang J, Li S, Zhang X, Li C, Zhang J, Zhou W. LncRNA HLA-F-AS1 promotes colorectal cancer metastasis by inducing PFN1 in colorectal cancer-derived extracellular vesicles and mediating macrophage polarization. Cancer Gene Ther. 2021;28(12):1269–84.

    Article  CAS  Google Scholar 

  8. Liu T, Zhou L, Li D, Andl T, Zhang Y. Cancer-associated fibroblasts build and secure the tumor microenvironment. Front Cell Dev Biol. 2019;7:60.

    Article  Google Scholar 

  9. Tang L, Mei Y, Shen Y, He S, Xiao Q, Yin Y, et al. Nanoparticle-mediated targeted drug delivery to remodel tumor microenvironment for cancer therapy. Int J Nanomedicine. 2021;16:5811–29.

    Article  Google Scholar 

  10. He C, Wang L, Li L, Zhu G. Extracellular vesicle-orchestrated crosstalk between cancer-associated fibroblasts and tumors. Transl Oncol. 2021;14: 101231.

    Article  CAS  Google Scholar 

  11. Mao X, Xu J, Wang W, Liang C, Hua J, Liu J, et al. Crosstalk between cancer-associated fibroblasts and immune cells in the tumor microenvironment: new findings and future perspectives. Mol Cancer. 2021;20:131.

    Article  CAS  Google Scholar 

  12. Dvorak KM, Pettee KM, Rubinic-Minotti K, Su R, Nestor-Kalinoski A, Eisenmann KM. Carcinoma associated fibroblasts (CAFs) promote breast cancer motility by suppressing mammalian Diaphanous-related formin-2 (mDia2). PLoS One. 2018;13: e0195278.

    Article  Google Scholar 

  13. Lau TS, Chung TK, Cheung TH, Chan LK, Cheung LW, Yim SF, et al. Cancer cell-derived lymphotoxin mediates reciprocal tumour-stromal interactions in human ovarian cancer by inducing CXCL11 in fibroblasts. J Pathol. 2014;232:43–56.

    Article  CAS  Google Scholar 

  14. Liu G, Sun J, Yang ZF, Zhou C, Zhou PY, Guan RY, et al. Cancer-associated fibroblast-derived CXCL11 modulates hepatocellular carcinoma cell migration and tumor metastasis through the circUBAP2/miR-4756/IFIT1/3 axis. Cell Death Dis. 2021;12:260.

    Article  CAS  Google Scholar 

  15. Cao Y, Jiao N, Sun T, Ma Y, Zhang X, Chen H, et al. CXCL11 correlates with antitumor immunity and an improved prognosis in colon cancer. Front Cell Dev Biol. 2021;9: 646252.

    Article  Google Scholar 

  16. Gao Q, Zhang Y. CXCL11 signaling in the tumor microenvironment. Adv Exp Med Biol. 2021;1302:41–50.

    Article  Google Scholar 

  17. Murakami T, Kawada K, Iwamoto M, Akagami M, Hida K, Nakanishi Y, et al. The role of CXCR3 and CXCR4 in colorectal cancer metastasis. Int J Cancer. 2013;132:276–87.

    Article  CAS  Google Scholar 

  18. Wu Z, Han X, Yan J, Pan Y, Gong J, Di J, et al. The prognostic significance of chemokine receptor CXCR3 expression in colorectal carcinoma. Biomed Pharmacother. 2012;66:373–7.

    Article  CAS  Google Scholar 

  19. Guo G, Gao F. CXCR3: latest evidence for the involvement of chemokine signaling in bone cancer pain. Exp Neurol. 2015;265:176–9.

    Article  CAS  Google Scholar 

  20. Zhou H, Wu J, Wang T, Zhang X, Liu D. CXCL10/CXCR3 axis promotes the invasion of gastric cancer via PI3K/AKT pathway-dependent MMPs production. Biomed Pharmacother. 2016;82:479–88.

    Article  CAS  Google Scholar 

  21. Lan H, Liu Y, Liu J, Wang X, Guan Z, Du J, et al. Tumor-associated macrophages promote oxaliplatin resistance via METTL3-mediated m(6)A of TRAF5 and necroptosis in colorectal cancer. Mol Pharm. 2021;18:1026–37.

    Article  CAS  Google Scholar 

  22. Raymond E, Faivre S, Woynarowski JM, Chaney SG. Oxaliplatin: mechanism of action and antineoplastic activity. Semin Oncol. 1998;25:4–12.

    CAS  Google Scholar 

  23. Culy CR, Clemett D, Wiseman LR. Oxaliplatin. A review of its pharmacological properties and clinical efficacy in metastatic colorectal cancer and its potential in other malignancies. Drugs. 2000;60:895–924.

    Article  CAS  Google Scholar 

  24. Tesniere A, Schlemmer F, Boige V, Kepp O, Martins I, Ghiringhelli F, et al. Immunogenic death of colon cancer cells treated with oxaliplatin. Oncogene. 2010;29:482–91.

    Article  CAS  Google Scholar 

  25. Roberts NB, Alqazzaz A, Hwang JR, Qi X, Keegan AD, Kim AJ, et al. Oxaliplatin disrupts pathological features of glioma cells and associated macrophages independent of apoptosis induction. J Neurooncol. 2018;140:497–507.

    Article  CAS  Google Scholar 

  26. Cross-Knorr S, Lu S, Perez K, Guevara S, Brilliant K, Pisano C, et al. RKIP phosphorylation and STAT3 activation is inhibited by oxaliplatin and camptothecin and are associated with poor prognosis in stage II colon cancer patients. BMC Cancer. 2013;13:463.

    Article  Google Scholar 

  27. Bruno PM, Liu Y, Park GY, Murai J, Koch CE, Eisen TJ, et al. A subset of platinum-containing chemotherapeutic agents kills cells by inducing ribosome biogenesis stress. Nat Med. 2017;23:461–71.

    Article  CAS  Google Scholar 

  28. Li M, Li M, Yin T, Shi H, Wen Y, Zhang B, et al. Targeting of cancerassociated fibroblasts enhances the efficacy of cancer chemotherapy by regulating the tumor microenvironment. Mol Med Rep. 2016;13:2476–84.

    Article  CAS  Google Scholar 

  29. Yang X, Wei Y, Sheng F, Xu Y, Liu J, Gao L, et al. Comprehensive analysis of the prognosis and immune infiltration for CXC chemokines in colorectal cancer. Aging (Albany NY). 2021;13:17548–67.

    Article  CAS  Google Scholar 

  30. Roncucci L, Mariani F. Prevention of colorectal cancer: How many tools do we have in our basket? Eur J Intern Med. 2015;26:752–6.

    Article  Google Scholar 

  31. Mauri G, Gori V, Bonazzina E, Amatu A, Tosi F, Bencardino K, et al. Oxaliplatin retreatment in metastatic colorectal cancer: systematic review and future research opportunities. Cancer Treat Rev. 2020;91: 102112.

    Article  CAS  Google Scholar 

  32. Mosa MH, Michels BE, Menche C, Nicolas AM, Darvishi T, Greten FR, et al. A Wnt-induced phenotypic switch in cancer-associated fibroblasts inhibits EMT in colorectal cancer. Cancer Res. 2020;80:5569–82.

    Article  CAS  Google Scholar 

  33. Wei C, Yang C, Wang S, Shi D, Zhang C, Lin X, et al. Crosstalk between cancer cells and tumor associated macrophages is required for mesenchymal circulating tumor cell-mediated colorectal cancer metastasis. Mol Cancer. 2019;18:64.

    Article  Google Scholar 

  34. Asif PJ, Longobardi C, Hahne M, Medema JP. The role of cancer-associated fibroblasts in cancer invasion and metastasis. Cancers (Basel). 2021;13:4720.

    Article  CAS  Google Scholar 

  35. 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.

    Article  CAS  Google Scholar 

  36. Zheng H, Liu H, Ge Y, Wang X. Integrated single-cell and bulk RNA sequencing analysis identifies a cancer associated fibroblast-related signature for predicting prognosis and therapeutic responses in colorectal cancer. Cancer Cell Int. 2021;21:552.

    Article  CAS  Google Scholar 

  37. Xiao Z, Liu Y, Li Q, Liu Q, Liu Y, Luo Y, et al. EVs delivery of miR-1915-3p improves the chemotherapeutic efficacy of oxaliplatin in colorectal cancer. Cancer Chemother Pharmacol. 2021;88:1021–31.

    Article  CAS  Google Scholar 

  38. Meng J, Su R, Liao Y, Li Y, Li L. Identification of 10 Hub genes related to the progression of colorectal cancer by co-expression analysis. PeerJ. 2020;8: e9633.

    Article  Google Scholar 

  39. Gao YJ, Liu L, Li S, Yuan GF, Li L, Zhu HY, et al. Down-regulation of CXCL11 inhibits colorectal cancer cell growth and epithelial-mesenchymal transition. Onco Targets Ther. 2018;11:7333–43.

    Article  CAS  Google Scholar 

  40. Narayanankutty A. PI3K/ Akt/ mTOR pathway as a therapeutic target for colorectal cancer: a review of preclinical and clinical evidence. Curr Drug Targets. 2019;20:1217–26.

    Article  CAS  Google Scholar 

  41. Gu J, Li Z, Zhou J, Sun Z, Bai C. Response prediction to oxaliplatin plus 5-fluorouracil chemotherapy in patients with colorectal cancer using a four-protein immunohistochemical model. Oncol Lett. 2019;18:2091–101.

    CAS  Google Scholar 

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Authors and Affiliations

  1. Department of Proctology, Aikang Hospital, Huangshi, 435000, Hubei Province, China

    Caifu Lu

  2. Department of Acupuncture, Huangshi Traditional Chinese Medicine Hospital, 6 Square Road, Huangshi, 435000, Hubei Province, China

    Cong Zhang

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  1. Caifu Lu
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  2. Cong Zhang
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Contributions

CFL is the guarantor of the integrity of the entire study, responsible for the study concept, study design, definition of intellectual content, literature research, clinical and experimental studies; CZ is responsible for data acquisition, data analysis, statistical analysis, manuscript preparation, editing and review. All authors read and approved the final manuscript.

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Correspondence to Cong Zhang.

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The authors declare that they have no competing interests.

Ethical statement

The experiments were authorized by the academic ethics committee of Huangshi Traditional Chinese Medicine Hospital. All procedures were strictly implemented by the code of ethics. Significant efforts were made to minimize the mice and their pains.

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Lu, C., Zhang, C. Oxaliplatin inhibits colorectal cancer progression by inhibiting CXCL11 secreted by cancer-associated fibroblasts and the CXCR3/PI3K/AKT pathway. Clin Transl Oncol 25, 160–172 (2023). https://doi.org/10.1007/s12094-022-02922-8

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  • DOI: https://doi.org/10.1007/s12094-022-02922-8

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