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Mesenchymal stromal cells confer breast cancer doxorubicin resistance by producing hyaluronan – Oncogene

  • Siegel RL, Miller KD, Fuchs HE, Jemal A. Cancer statistics, 2022. CA Cancer J Clin. 2022;72:7–33.

    Article  PubMed  Google Scholar 

  • Harbeck N, Gnant M. Breast cancer. Lancet. 2017;389:1134–50.

    Article  PubMed  Google Scholar 

  • Ostman A. The tumor microenvironment controls drug sensitivity. Nat Med. 2012;18:1332–4.

    Article  PubMed  Google Scholar 

  • Meads MB, Gatenby RA, Dalton WS. Environment-mediated drug resistance: a major contributor to minimal residual disease. Nat Rev Cancer. 2009;9:665–74.

    Article  CAS  PubMed  Google Scholar 

  • Muerkoster S, Wegehenkel K, Arlt A, Witt M, Sipos B, Kruse ML, et al. Tumor stroma interactions induce chemoresistance in pancreatic ductal carcinoma cells involving increased secretion and paracrine effects of nitric oxide and in terleukin-1 beta. Cancer Res. 2004;64:1331–7.

    Article  PubMed  Google Scholar 

  • Wang W, Kryczek I, Dostál L, Lin H, Tan L, Zhao L, et al. Effector T cells abrogate stroma-mediated chemoresistance in ovarian. Cancer Cell. 2016;165:1092–105.

    CAS  Google Scholar 

  • Su S, Chen J, Yao H, Liu J, Yu S, Lao L, et al. CD10(+)GPR77(+) cancer-associated fibroblasts promote cancer formation and chemoresistance by sustaining cancer stemness. Cell. 2018;172:841–56.e816.

    Article  CAS  PubMed  Google Scholar 

  • Biffi G, Tuveson DA. Diversity and biology of cancer-associated fibroblasts. Physiol Rev. 2021;101:147–76.

    Article  CAS  PubMed  Google Scholar 

  • Chen X, Song E. Turning foes to friends: targeting cancer-associated fibroblasts. Nat Rev Drug Discov. 2019;18:99–115.

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  • Shi Y, Du L, Lin L, Wang Y. Tumour-associated mesenchymal stem/stromal cells: emerging therapeutic targets. Nat Rev Drug Discov. 2016;16:35–52.

    Article  PubMed  Google Scholar 

  • Roodhart Jeanine ML, Daenen Laura GM, Stigter Edwin CA, Prins H-J, Gerrits J, Houthuijzen Julia M, et al. Mesenchymal stem cells induce resistance to chemotherapy through the release of platinum-induced fatty acids. Cancer Cell. 2011;20:370–83.

    Article  CAS  PubMed  Google Scholar 

  • Zheng Z, Li YN, Jia S, Zhu M, Cao L, Tao M, et al. Lung mesenchymal stromal cells influenced by Th2 cytokines mobilize neutrophils and facilitate metastasis by producing complement C3. Nat Commun. 2021;12:6202.

    Article  PubMed  PubMed Central  Google Scholar 

  • Quante M, Tu SP, Tomita H, Gonda T, Wang SS, Takashi S, et al. Bone marrow-derived myofibroblasts contribute to the mesenchymal stem cell niche and promote tumor growth. Cancer Cell. 2011;19:257–72.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Coffman LG, Pearson AT, Frisbie LG, Freeman Z, Christie E, Bowtell DD, et al. Ovarian carcinoma-associated mesenchymal stem cells arise from tissue-specific normal stroma. Stem Cells. 2019;37:257–69.

    Article  CAS  PubMed  Google Scholar 

  • Weber CE, Kothari AN, Wai PY, Li NY, Driver J, Zapf MA, et al. Osteopontin mediates an MZF1-TGF-beta1-dependent transformation of mesenchymal stem cells into cancer-associated fibroblasts in breast cancer. Oncogene. 2015;34:4821–33.

    Article  CAS  PubMed  Google Scholar 

  • Ren G, Zhao X, Wang Y, Zhang X, Chen X, Xu C, et al. CCR2-dependent recruitment of macrophages by tumor-educated mesenchymal stromal cells promotes tumor development and is mimicked by TNFalpha. Cell Stem Cell. 2012;11:812–24.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Fiaschi T, Marini A, Giannoni E, Taddei ML, Gandellini P, De Donatis A, et al. Reciprocal metabolic reprogramming through lactate shuttle coordinately influences tumor-stroma interplay. Cancer Res. 2012;72:5130–40.

    Article  CAS  PubMed  Google Scholar 

  • Ippolito L, Morandi A, Taddei ML, Parri M, Comito G, Iscaro A, et al. Cancer-associated fibroblasts promote prostate cancer malignancy via metabolic rewiring and mitochondrial transfer. Oncogene. 2019;38:5339–55.

    Article  CAS  PubMed  Google Scholar 

  • Minotti G, Menna P, Salvatorelli E, Cairo G, Gianni L. Anthracyclines: molecular advances and pharmacologic developments in antitumor activity and cardiotoxicity. Pharmacol Rev. 2004;56:185–229.

    Article  CAS  PubMed  Google Scholar 

  • Revet I, Feeney L, Bruguera S, Wilson W, Dong TK, Oh DH, et al. Functional relevance of the histone gamma H2Ax in the response to DNA damaging agents. Proc Natl Acad Sci USA. 2011;108:8663–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Bellamy WT, Dalton WS, Kailey JM, Gleason MC, Mccloskey TM, Dorr RT, et al. Verapamil reversal of doxorubicin resistance in multidrug-resistant human myeloma cells and association with drug accumulation and DNA damage. Cancer Res. 1988;48:6365–70.

    CAS  PubMed  Google Scholar 

  • Kauffman MK, Kauffman ME, Zhu H, Jia Z, Li YR. Fluorescence-based assays for measuring doxorubicin in biological systems. React Oxyg Species. 2016;2:432–9.

    Google Scholar 

  • Triller N, Korosec P, Kern I, Kosnik M, Debeljak A. Multidrug resistance, in small cell lung cancer: expression of P-glycoprotein, multidrug resistance protein 1 and lung resistance protein in chemo-naive patients and in relapsed disease. Lung Cancer. 2006;54:235–40.

    Article  PubMed  Google Scholar 

  • Nooter K, delaRiviere GB, Look MP, vanWingerden KE, HenzenLogmans SC, Scheper RJ, et al. The prognostic significance of expression of the multidrug resistance associated protein (MRP) in primary breast cancer. Br J Cancer. 1997;76:486–93.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Doyle LA, Yang WD, Abruzzo LV, Krogmann T, Gao YM, Rishi AK, et al. A multidrug resistance transporter from human MCF-7 breast cancer cells. Proc Natl Acad Sci USA. 1998;95:15665–70.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Qu C, Rilla K, Tammi R, Tammi M, Kroger H, Lammi MJ. Extensive CD44-dependent hyaluronan coats on human bone marrow-derived mesenchymal stem cells produced by hyaluronan synthases HAS1, HAS2 and HAS3. Int J Biochem Cell Biol. 2014;48:45–54.

    Article  CAS  PubMed  Google Scholar 

  • Arasu UT, Karna R, Harkonen K, Oikari S, Koistinen A, Kroger H, et al. Human mesenchymal stem cells secrete hyaluronan-coated extracellular vesicles. Matrix Biol. 2017;64:54–68.

    Article  CAS  PubMed  Google Scholar 

  • Jha AK, Xu XA, Duncan RL, Jia XQ. Controlling the adhesion and differentiation of mesenchymal stem cells using hyaluronic acid-based, doubly crosslinked networks. Biomaterials. 2011;32:2466–78.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Chen J, Meng JL, Jin C, Mo F, Ding Y, Gao XM, et al. 4-Methylumbelliferone treatment and hyaluronan inhibition as a therapeutic strategy for chronic prostatitis. Prostate. 2021;81:1078–90.

    Article  CAS  PubMed  Google Scholar 

  • Karnoub AE, Dash AB, Vo AP, Sullivan A, Brooks MW, Bell GW, et al. Mesenchymal stem cells within tumour stroma promote breast cancer metastasis. Nature. 2007;449:557–63.

    Article  CAS  PubMed  Google Scholar 

  • Raz Y, Cohen N, Shani O, Bell RE, Novitskiy SV, Abramovitz L, et al. Bone marrow-derived fibroblasts are a functionally distinct stromal cell population in breast cancer. J Exp Med. 2018;215:3075–93.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Lankelma J, Dekker H, Luque FR, Luykx S, Hoekman K, van der Valk P, et al. Doxorubicin gradients in human breast cancer. Clin Cancer Res. 1999;5:1703–7.

    CAS  PubMed  Google Scholar 

  • Tacar O, Sriamornsak P, Dass CR. Doxorubicin: an update on anticancer molecular action, toxicity and novel drug delivery systems. J Pharm Pharm. 2013;65:157–70.

    Article  CAS  Google Scholar 

  • Klemm F, Joyce JA. Microenvironmental regulation of therapeutic response in cancer. Trends Cell Biol. 2015;25:198–213.

    Article  PubMed  Google Scholar 

  • Velaei K, Samadi N, Barazvan B, Rad JS. Tumor microenvironment-mediated chemoresistance in breast cancer. Breast. 2016;30:92–100.

    Article  PubMed  Google Scholar 

  • Farmer P, Bonnefoi H, Anderle P, Cameron D, Wirapati P, Becette V, et al. A stroma-related gene signature predicts resistance to neoadjuvant chemotherapy in breast cancer. Nat Med. 2009;15:68–74.

    Article  CAS  PubMed  Google Scholar 

  • Tsujino T, Seshimo I, Yamamoto H, Ngan CY, Ezumi K, Takemasa I, et al. Stromal myofibroblasts predict disease recurrence for colorectal cancer. Clin Cancer Res. 2007;13:2082–90.

    Article  CAS  PubMed  Google Scholar 

  • Cox TR. The matrix in cancer. Nat Rev Cancer. 2021;21:217–38.

    Article  CAS  PubMed  Google Scholar 

  • Bonnans C, Chou J, Werb Z. Remodelling the extracellular matrix in development and disease. Nat Rev Mol Cell Biol. 2014;15:786–801.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Bohaumilitzky L, Huber AK, Stork EM, Wengert S, Woelfl F, Boehm H. A trickster in disguise: Hyaluronan’s ambivalent roles in the matrix. Front Oncol. 2017;7:242.

    Article  PubMed  PubMed Central  Google Scholar 

  • Tavianatou AG, Caon I, Franchi M, Piperigkou Z, Galesso D, Karamanos NK. Hyaluronan: molecular size-dependent signaling and biological functions in inflammation and cancer. FEBS J. 2019;286:2883–908.

    Article  CAS  PubMed  Google Scholar 

  • Price ZK, Lokman NA, Ricciardelli C. Differing roles of hyaluronan molecular weight on cancer cell behavior and chemotherapy resistance. Cancers. 2018;10:482–502.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Tian X, Azpurua J, Hine C, Vaidya A, Myakishev-Rempel M, Ablaeva J, et al. High-molecular-mass hyaluronan mediates the cancer resistance of the naked mole rat. Nature. 2013;499:346–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Dominguez-Gutierrez PR, Kwenda EP, Donelan W, O’Malley P, Crispen PL, Kusmartsev S. Hyal2 expression in tumor-associated myeloid cells mediates cancer-related inflammation in bladder cancer. Cancer Res. 2021;81:648–57.

    Article  CAS  PubMed  Google Scholar 

  • Schmaus A, Klusmeier S, Rothley M, Dimmler A, Sipos B, Faller G, et al. Accumulation of small hyaluronan oligosaccharides in tumour interstitial fluid correlates with lymphatic invasion and lymph node metastasis. Br J Cancer. 2014;111:559–67.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Liu D, Pearlman E, Diaconu E, Guo K, Mori H, Haqqi T, et al. Expression of hyaluronidase by tumor cells induces angiogenesis in vivo. Proc Natl Acad Sci USA. 1996;93:7832–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Carvalho AM, Reis RL, Pashkuleva I. Hyaluronan receptors as mediators and modulators of the tumor microenvironment. Adv Healthcare Mater. 2023;12:e2202118.

    Article  Google Scholar 

  • Tammi MI, Oikari S, Pasonen-Seppanen S, Rilla K, Auvinen P, Tammi RH. Activated hyaluronan metabolism in the tumor matrix—causes and consequences. Matrix Biol. 2019;78-79:147–64.

    Article  CAS  PubMed  Google Scholar 

  • Toole BP, Slomiany MG. Hyaluronan, CD44 and emmprin: partners in cancer cell chemoresistance. Drug Resist Updat. 2008;11:110–21.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ohashi R, Takahashi F, Cui R, Yoshioka M, Gu T, Sasaki S, et al. Interaction between CD44 and hyaluronate induces chemoresistance in non-small cell lung cancer cell. Cancer Lett. 2007;252:225–34.

    Article  CAS  PubMed  Google Scholar 

  • Gilg AG, Tye SL, Tolliver LB, Wheeler WG, Visconti RP, Duncan JD, et al. Targeting hyaluronan interactions in malignant gliomas and their drug-resistant multipotent progenitors. Clin Cancer Res. 2008;14:1804–13.

    Article  CAS  PubMed  Google Scholar 

  • Compagnone M, Gatti V, Presutti D, Ruberti G, Fierro C, Markert EK, et al. DeltaNp63-mediated regulation of hyaluronic acid metabolism and signaling supports HNSCC tumorigenesis. Proc Natl Acad Sci USA. 2017;114:13254–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Provenzano PP, Hingorani SR. Hyaluronan, fluid pressure, and stromal resistance in pancreas cancer. Br J Cancer. 2013;108:1–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Jacobetz MA, Chan DS, Neesse A, Bapiro TE, Cook N, Frese KK, et al. Hyaluronan impairs vascular function and drug delivery in a mouse model of pancreatic cancer. Gut. 2013;62:112–20.

    Article  CAS  PubMed  Google Scholar 

  • Provenzano PP, Cuevas C, Chang AE, Goel VK, Von Hoff DD, Hingorani SR. Enzymatic targeting of the stroma ablates physical barriers to treatment of pancreatic ductal adenocarcinoma. Cancer Cell. 2012;21:418–29.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Hingorani SR, Harris WP, Beck JT, Berdov BA, Wagner SA, Pshevlotsky EM, et al. Phase Ib study of pegylated recombinant human hyaluronidase and gemcitabine in patients with advanced pancreatic cancer. Clin Cancer Res. 2016;22:2848–54.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Tammi RH, Passi AG, Rilla K, Karousou E, Vigetti D, Makkonen K, et al. Transcriptional and post-translational regulation of hyaluronan synthesis. FEBS J. 2011;278:1419–28.

    Article  CAS  PubMed  Google Scholar 

  • Jokela TA, Karna R, Makkonen KM, Laitinen JT, Tammi RH, Tammi MI. Extracellular UDP-glucose activates P2Y14 receptor and induces signal transducer and activator of transcription 3 (STAT3) Tyr705 phosphorylation and binding to hyaluronan synthase 2 (HAS2) promoter, stimulating hyaluronan synthesis of keratinocytes. J Biol Chem. 2014;289:18569–81.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Jokela T, Karna R, Rauhala L, Bart G, Pasonen-Seppanen S, Oikari S, et al. Human keratinocytes respond to extracellular UTP by induction of hyaluronan synthase 2 expression and increased hyaluronan synthesis. J Biol Chem. 2017;292:4861–72.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Rauhala L, Jokela T, Karna R, Bart G, Takabe P, Oikari S, et al. Extracellular ATP activates hyaluronan synthase 2 (HAS2) in epidermal keratinocytes via P2Y2, Ca(2+) signaling, and MAPK pathways. Biochem J. 2018;475:1755–72.

    Article  CAS  PubMed  Google Scholar 

  • Wang G, Cao K, Liu K, Xue Y, Roberts AI, Li F, et al. Kynurenic acid, an IDO metabolite, controls TSG-6-mediated immunosuppression of human mesenchymal stem cells. Cell Death Differ. 2017;25:1209–23.

    Article  PubMed  PubMed Central  Google Scholar