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01-12-2021 | Breast Cancer | Research article

Inhibition of stromal biglycan promotes normalization of the tumor microenvironment and enhances chemotherapeutic efficacy

Authors: Li Cong, Nako Maishi, Dorcas A. Annan, Marian F. Young, Hirofumi Morimoto, Masahiro Morimoto, Jin-Min Nam, Yasuhiro Hida, Kyoko Hida

Published in: Breast Cancer Research | Issue 1/2021

Abstract

Background

Biglycan is a proteoglycan found in the extracellular matrix. We have previously shown that biglycan is secreted from tumor endothelial cells and induces tumor angiogenesis and metastasis. However, the function of stroma biglycan in breast cancer is still unclear.

Methods

Biglycan gene analysis and its prognostic values in human breast cancers were based on TCGA data. E0771 breast cancer cells were injected into WT and Bgn KO mice, respectively.

Results

Breast cancer patients with high biglycan expression had worse distant metastasis-free survival. Furthermore, biglycan expression was higher in the tumor stromal compartment compared to the epithelial compartment. Knockout of biglycan in the stroma (Bgn KO) in E0771 tumor-bearing mice inhibited metastasis to the lung. Bgn KO also impaired tumor angiogenesis and normalized tumor vasculature by repressing tumor necrosis factor-ɑ/angiopoietin 2 signaling. Moreover, fibrosis was suppressed and CD8+ T cell infiltration was increased in tumor-bearing Bgn KO mice. Furthermore, chemotherapy drug delivery and efficacy were improved in vivo in Bgn KO mice.

Conclusion

Our results suggest that targeting stromal biglycan may yield a potent and superior anticancer effect in breast cancer.

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Nagy JA, Chang SH, Dvorak AM, Dvorak HF. Why are tumour blood vessels abnormal and why is it important to know? Br J Cancer. 2009;100(6):865–9. https://doi.org/10.1038/sj.bjc.6604929.CrossRefPubMedPubMedCentral

Jain RK, Tong RT, Munn LL. Effect of vascular normalization by antiangiogenic therapy on interstitial hypertension, peritumor edema, and lymphatic metastasis: insights from a mathematical model. Cancer Res. 2007;67(6):2729–35. https://doi.org/10.1158/0008-5472.CAN-06-4102.CrossRefPubMedPubMedCentral

Stylianopoulos T, Munn LL, Jain RK. Reengineering the tumor vasculature: improving drug delivery and efficacy. Trends Cancer. 2018;4(4):258–9. https://doi.org/10.1016/j.trecan.2018.02.010.CrossRefPubMedPubMedCentral

Miller K, Wang M, Gralow J, Dickler M, Cobleigh M, Perez EA, Shenkier T, Cella D, Davidson NE. Paclitaxel plus bevacizumab versus paclitaxel alone for metastatic breast cancer. N Engl J Med. 2007;357(26):2666–76. https://doi.org/10.1056/NEJMoa072113.CrossRefPubMed

Xu L, Duda DG, di Tomaso E, Ancukiewicz M, Chung DC, Lauwers GY, Samuel R, Shellito P, Czito BG, Lin PC, Poleski M, Bentley R, Clark JW, Willett CG, Jain RK. Direct evidence that bevacizumab, an anti-VEGF antibody, up-regulates SDF1alpha, CXCR4, CXCL6, and neuropilin 1 in tumors from patients with rectal cancer. Cancer Res. 2009;69(20):7905–10. https://doi.org/10.1158/0008-5472.CAN-09-2099.CrossRefPubMedPubMedCentral

Ueda S, Saeki T, Osaki A, Yamane T, Kuji I. Bevacizumab induces acute hypoxia and cancer progression in patients with refractory breast cancer: multimodal functional imaging and multiplex cytokine analysis. Clin Cancer Res. 2017;23(19):5769–78. https://doi.org/10.1158/1078-0432.CCR-17-0874.CrossRefPubMed

Tolaney SM, Boucher Y, Duda DG, Martin JD, Seano G, Ancukiewicz M, Barry WT, Goel S, Lahdenrata J, Isakoff SJ, Yeh ED, Jain SR, Golshan M, Brock J, Snuderl M, Winer EP, Krop IE, Jain RK. Role of vascular density and normalization in response to neoadjuvant bevacizumab and chemotherapy in breast cancer patients. Proc Natl Acad Sci U S A. 2015;112(46):14325–30. https://doi.org/10.1073/pnas.1518808112.CrossRefPubMedPubMedCentral

Luck HJ, Lubbe K, Reinisch M, Maass N, Feisel-Schwickardi G, Tome O, Janni W, Aydogdu M, Neunhoffer T, Ober A, et al. Phase III study on efficacy of taxanes plus bevacizumab with or without capecitabine as first-line chemotherapy in metastatic breast cancer. Breast Cancer Res Treat. 2015;149(1):141–9. https://doi.org/10.1007/s10549-014-3217-y.CrossRefPubMed

Welt A, Marschner N, Lerchenmueller C, Decker T, Steffens CC, Koehler A, Depenbusch R, Busies S, Hegewisch-Becker S. Capecitabine and bevacizumab with or without vinorelbine in first-line treatment of HER2/neu-negative metastatic or locally advanced breast cancer: final efficacy and safety data of the randomised, open-label superiority phase 3 CARIN trial. Breast Cancer Res Treat. 2016;156(1):97–107. https://doi.org/10.1007/s10549-016-3727-x.CrossRefPubMedPubMedCentral

10.

Hida K, Hida Y, Shindoh M. Understanding tumor endothelial cell abnormalities to develop ideal anti-angiogenic therapies. Cancer Sci. 2008;99(3):459–66. https://doi.org/10.1111/j.1349-7006.2007.00704.x.CrossRefPubMed

11.

Matsuda K, Ohga N, Hida Y, Muraki C, Tsuchiya K, Kurosu T, Akino T, Shih SC, Totsuka Y, Klagsbrun M, Shindoh M, Hida K. Isolated tumor endothelial cells maintain specific character during long-term culture. Biochem Biophys Res Commun. 2010;394(4):947–54. https://doi.org/10.1016/j.bbrc.2010.03.089.CrossRefPubMed

12.

Ohga N, Hida K, Hida Y, Muraki C, Tsuchiya K, Matsuda K, Ohiro Y, Totsuka Y, Shindoh M. Inhibitory effects of epigallocatechin-3 gallate, a polyphenol in green tea, on tumor-associated endothelial cells and endothelial progenitor cells. Cancer Sci. 2009;100(10):1963–70. https://doi.org/10.1111/j.1349-7006.2009.01255.x.CrossRefPubMed

13.

Amin DN, Hida K, Bielenberg DR, Klagsbrun M. Tumor endothelial cells express epidermal growth factor receptor (EGFR) but not ErbB3 and are responsive to EGF and to EGFR kinase inhibitors. Cancer Res. 2006;66(4):2173–80. https://doi.org/10.1158/0008-5472.CAN-05-3387.CrossRefPubMed

14.

Hida K, Hida Y, Amin DN, Flint AF, Panigrahy D, Morton CC, Klagsbrun M. Tumor-associated endothelial cells with cytogenetic abnormalities. Cancer Res. 2004;64(22):8249–55. https://doi.org/10.1158/0008-5472.CAN-04-1567.CrossRefPubMed

15.

Yamamoto K, Ohga N, Hida Y, Maishi N, Kawamoto T, Kitayama K, Akiyama K, Osawa T, Kondoh M, Matsuda K, Onodera Y, Fujie M, Kaga K, Hirano S, Shinohara N, Shindoh M, Hida K. Biglycan is a specific marker and an autocrine angiogenic factor of tumour endothelial cells. Br J Cancer. 2012;106(6):1214–23. https://doi.org/10.1038/bjc.2012.59.CrossRefPubMedPubMedCentral

16.

Iozzo RV. The biology of the small leucine-rich proteoglycans. Functional network of interactive proteins. J Biol Chem. 1999;274(27):18843–6. https://doi.org/10.1074/jbc.274.27.18843.CrossRefPubMed

17.

Poluzzi C, Nastase MV, Zeng-Brouwers J, Roedig H, Hsieh LT, Michaelis JB, Buhl EM, Rezende F, Manavski Y, Bleich A, et al. Biglycan evokes autophagy in macrophages via a novel CD44/toll-like receptor 4 signaling axis in ischemia/reperfusion injury. Kidney Int. 2019;95(3):540–62. https://doi.org/10.1016/j.kint.2018.10.037.CrossRefPubMed

18.

Tufvesson E, Westergren-Thorsson G. Biglycan and decorin induce morphological and cytoskeletal changes involving signalling by the small GTPases RhoA and Rac1 resulting in lung fibroblast migration. J Cell Sci. 2003;116(Pt 23):4857–64. https://doi.org/10.1242/jcs.00808.CrossRefPubMed

19.

Ameye L, Aria D, Jepsen K, Oldberg A, Xu T, Young MF. Abnormal collagen fibrils in tendons of biglycan/fibromodulin-deficient mice lead to gait impairment, ectopic ossification, and osteoarthritis. FASEB J. 2002;16(7):673–80. https://doi.org/10.1096/fj.01-0848com.CrossRefPubMed

20.

Moreth K, Brodbeck R, Babelova A, Gretz N, Spieker T, Zeng-Brouwers J, Pfeilschifter J, Young MF, Schaefer RM, Schaefer L. The proteoglycan biglycan regulates expression of the B cell chemoattractant CXCL13 and aggravates murine lupus nephritis. J Clin Invest. 2010;120(12):4251–72. https://doi.org/10.1172/JCI42213.CrossRefPubMedPubMedCentral

21.

Maishi N, Ohba Y, Akiyama K, Ohga N, Hamada J, Nagao-Kitamoto H, Alam MT, Yamamoto K, Kawamoto T, Inoue N, Taketomi A, Shindoh M, Hida Y, Hida K. Tumour endothelial cells in high metastatic tumours promote metastasis via epigenetic dysregulation of biglycan. Sci Rep. 2016;6(1):28039. https://doi.org/10.1038/srep28039.CrossRefPubMedPubMedCentral

22.

Aprile G, Avellini C, Reni M, Mazzer M, Foltran L, Rossi D, Cereda S, Iaiza E, Fasola G, Piga A. Biglycan expression and clinical outcome in patients with pancreatic adenocarcinoma. Tumour Biol. 2013;34(1):131–7. https://doi.org/10.1007/s13277-012-0520-2.CrossRefPubMed

23.

Liu Y, Li W, Li X, Tai Y, Lu Q, Yang N, Jiang J. Expression and significance of biglycan in endometrial cancer. Arch Gynecol Obstet. 2014;289(3):649–55. https://doi.org/10.1007/s00404-013-3017-3.CrossRefPubMed

24.

Schulz GB, Grimm T, Sers C, Riemer P, Elmasry M, Kirchner T, Stief CG, Karl A, Horst D. Prognostic value and association with epithelial-mesenchymal transition and molecular subtypes of the proteoglycan biglycan in advanced bladder cancer. Urol Oncol. 2019;37(8):530 e539–18.CrossRef

25.

Xu T, Bianco P, Fisher LW, Longenecker G, Smith E, Goldstein S, Bonadio J, Boskey A, Heegaard AM, Sommer B, Satomura K, Dominguez P, Zhao C, Kulkarni AB, Robey PG, Young MF. Targeted disruption of the biglycan gene leads to an osteoporosis-like phenotype in mice. Nat Genet. 1998;20(1):78–82. https://doi.org/10.1038/1746.CrossRefPubMed

26.

Kurosu T, Ohga N, Hida Y, Maishi N, Akiyama K, Kakuguchi W, Kuroshima T, Kondo M, Akino T, Totsuka Y, Shindoh M, Higashino F, Hida K. HuR keeps an angiogenic switch on by stabilising mRNA of VEGF and COX-2 in tumour endothelium. Br J Cancer. 2011;104(5):819–29. https://doi.org/10.1038/bjc.2011.20.CrossRefPubMedPubMedCentral

27.

Corsi A, Xu T, Chen XD, Boyde A, Liang J, Mankani M, Sommer B, Iozzo RV, Eichstetter I, Robey PG, Bianco P, Young MF. Phenotypic effects of biglycan deficiency are linked to collagen fibril abnormalities, are synergized by decorin deficiency, and mimic Ehlers-Danlos-like changes in bone and other connective tissues. J Bone Miner Res. 2002;17(7):1180–9. https://doi.org/10.1359/jbmr.2002.17.7.1180.CrossRefPubMed

28.

Hayashi M, Sakata M, Takeda T, Yamamoto T, Okamoto Y, Sawada K, Kimura A, Minekawa R, Tahara M, Tasaka K, Murata Y. Induction of glucose transporter 1 expression through hypoxia-inducible factor 1alpha under hypoxic conditions in trophoblast-derived cells. J Endocrinol. 2004;183(1):145–54. https://doi.org/10.1677/joe.1.05599.CrossRefPubMed

29.

Carmeliet P, Jain RK. Principles and mechanisms of vessel normalization for cancer and other angiogenic diseases. Nat Rev Drug Discov. 2011;10(6):417–27. https://doi.org/10.1038/nrd3455.CrossRefPubMed

30.

Schaefer L, Babelova A, Kiss E, Hausser HJ, Baliova M, Krzyzankova M, Marsche G, Young MF, Mihalik D, Gotte M, et al. The matrix component biglycan is proinflammatory and signals through toll-like receptors 4 and 2 in macrophages. J Clin Invest. 2005;115(8):2223–33. https://doi.org/10.1172/JCI23755.CrossRefPubMedPubMedCentral

31.

Schonherr E, Witsch-Prehm P, Harrach B, Robenek H, Rauterberg J, Kresse H. Interaction of biglycan with type I collagen. J Biol Chem. 1995;270(6):2776–83. https://doi.org/10.1074/jbc.270.6.2776.CrossRefPubMed

32.

Anders HJ, Schaefer L. Beyond tissue injury-damage-associated molecular patterns, toll-like receptors, and inflammasomes also drive regeneration and fibrosis. J Am Soc Nephrol. 2014;25(7):1387–400. https://doi.org/10.1681/ASN.2014010117.CrossRefPubMedPubMedCentral

33.

Sahai E, Astsaturov I, Cukierman E, DeNardo DG, Egeblad M, Evans RM, Fearon D, Greten FR, Hingorani SR, Hunter T, et al. A framework for advancing our understanding of cancer-associated fibroblasts. Nat Rev Cancer. 2020;20(3):174–86. https://doi.org/10.1038/s41568-019-0238-1.CrossRefPubMedPubMedCentral

34.

Shrimali RK, Yu Z, Theoret MR, Chinnasamy D, Restifo NP, Rosenberg SA. Antiangiogenic agents can increase lymphocyte infiltration into tumor and enhance the effectiveness of adoptive immunotherapy of cancer. Cancer Res. 2010;70(15):6171–80. https://doi.org/10.1158/0008-5472.CAN-10-0153.CrossRefPubMedPubMedCentral

35.

Chen IX, Chauhan VP, Posada J, Ng MR, Wu MW, Adstamongkonkul P, Huang P, Lindeman N, Langer R, Jain RK. Blocking CXCR4 alleviates desmoplasia, increases T-lymphocyte infiltration, and improves immunotherapy in metastatic breast cancer. Proc Natl Acad Sci U S A. 2019;116(10):4558–66. https://doi.org/10.1073/pnas.1815515116.CrossRefPubMedPubMedCentral

36.

Chauhan VP, Martin JD, Liu H, Lacorre DA, Jain SR, Kozin SV, Stylianopoulos T, Mousa AS, Han X, Adstamongkonkul P, Popović Z, Huang P, Bawendi MG, Boucher Y, Jain RK. Angiotensin inhibition enhances drug delivery and potentiates chemotherapy by decompressing tumour blood vessels. Nat Commun. 2013;4(1):2516. https://doi.org/10.1038/ncomms3516.CrossRefPubMedPubMedCentral

37.

Hu L, Duan YT, Li JF, Su LP, Yan M, Zhu ZG, Liu BY, Yang QM. Biglycan enhances gastric cancer invasion by activating FAK signaling pathway. Oncotarget. 2014;5(7):1885–96. https://doi.org/10.18632/oncotarget.1871.CrossRefPubMedPubMedCentral

38.

Xing X, Gu X, Ma T, Ye H. Biglycan up-regulated vascular endothelial growth factor (VEGF) expression and promoted angiogenesis in colon cancer. Tumour Biol. 2015;36(3):1773–80. https://doi.org/10.1007/s13277-014-2779-y.CrossRefPubMed

39.

Hu L, Zang MD, Wang HX, Li JF, Su LP, Yan M, Li C, Yang QM, Liu BY, Zhu ZG. Biglycan stimulates VEGF expression in endothelial cells by activating the TLR signaling pathway. Mol Oncol. 2016;10(9):1473–84. https://doi.org/10.1016/j.molonc.2016.08.002.CrossRefPubMedPubMedCentral

40.

Jain RK. Normalizing tumor microenvironment to treat cancer: bench to bedside to biomarkers. J Clin Oncol. 2013;31(17):2205–18. https://doi.org/10.1200/JCO.2012.46.3653.CrossRefPubMedPubMedCentral

41.

Vosseler S, Mirancea N, Bohlen P, Mueller MM, Fusenig NE. Angiogenesis inhibition by vascular endothelial growth factor receptor-2 blockade reduces stromal matrix metalloproteinase expression, normalizes stromal tissue, and reverts epithelial tumor phenotype in surface heterotransplants. Cancer Res. 2005;65(4):1294–305. https://doi.org/10.1158/0008-5472.CAN-03-3986.CrossRefPubMed

42.

Hirofumi Morimoto YH, Nako Maishi, Hiroshi Nishihara, Yutaka Hatanaka, Cong LI, Yoshihiro Matsuno, Toru Nakamur, Satoshi Hirano, Kyoko Hida. Biglycan, tumor endothelial cell secreting proteoglycan, as possible biomarker for lung cancer (in press). Thoracic Cancer 2021.

43.

Andrlova H, Mastroianni J, Madl J, Kern JS, Melchinger W, Dierbach H, Wernet F, Follo M, Technau-Hafsi K, Has C, et al. Biglycan expression in the melanoma microenvironment promotes invasiveness via increased tissue stiffness inducing integrin-beta1 expression. Oncotarget. 2017;8(26):42901–16. https://doi.org/10.18632/oncotarget.17160.CrossRefPubMedPubMedCentral

44.

Armulik A, Abramsson A, Betsholtz C. Endothelial/pericyte interactions. Circ Res. 2005;97(6):512–23. https://doi.org/10.1161/01.RES.0000182903.16652.d7.CrossRefPubMed

45.

Greenberg JI, Shields DJ, Barillas SG, Acevedo LM, Murphy E, Huang J, Scheppke L, Stockmann C, Johnson RS, Angle N, Cheresh DA. A role for VEGF as a negative regulator of pericyte function and vessel maturation. Nature. 2008;456(7223):809–13. https://doi.org/10.1038/nature07424.CrossRefPubMedPubMedCentral

46.

Augustin HG, Koh GY, Thurston G, Alitalo K. Control of vascular morphogenesis and homeostasis through the angiopoietin-Tie system. Nat Rev Mol Cell Biol. 2009;10(3):165–77. https://doi.org/10.1038/nrm2639.CrossRefPubMed

47.

Keskin D, Kim J, Cooke VG, Wu CC, Sugimoto H, Gu C, De Palma M, Kalluri R, LeBleu VS. Targeting vascular pericytes in hypoxic tumors increases lung metastasis via angiopoietin-2. Cell Rep. 2015;10(7):1066–81. https://doi.org/10.1016/j.celrep.2015.01.035.CrossRefPubMedPubMedCentral

48.

Chui A, Gunatillake T, Brennecke SP, Ignjatovic V, Monagle PT, Whitelock JM, van Zanten DE, Eijsink J, Wang Y, Deane J, Borg AJ, Stevenson J, Erwich JJ, Said JM, Murthi P. Expression of Biglycan in first trimester chorionic villous sampling placental samples and altered function in telomerase-immortalized microvascular endothelial cells. Arterioscler Thromb Vasc Biol. 2017;37(6):1168–79. https://doi.org/10.1161/ATVBAHA.117.309422.CrossRefPubMed

49.

Montfort A, Colacios C, Levade T, Andrieu-Abadie N, Meyer N, Segui B. The TNF paradox in Cancer progression and immunotherapy. Front Immunol. 2019;10:1818. https://doi.org/10.3389/fimmu.2019.01818.CrossRefPubMedPubMedCentral

50.

Leibovich SJ, Polverini PJ, Shepard HM, Wiseman DM, Shively V, Nuseir N. Macrophage-induced angiogenesis is mediated by tumour necrosis factor-alpha. Nature. 1987;329(6140):630–2. https://doi.org/10.1038/329630a0.CrossRefPubMed

51.

Baluk P, Yao LC, Feng J, Romano T, Jung SS, Schreiter JL, Yan L, Shealy DJ, McDonald DM. TNF-alpha drives remodeling of blood vessels and lymphatics in sustained airway inflammation in mice. J Clin Invest. 2009;119(10):2954–64. https://doi.org/10.1172/JCI37626.CrossRefPubMedPubMedCentral

52.

Izquierdo E, Canete JD, Celis R, Santiago B, Usategui A, Sanmarti R, Del Rey MJ, Pablos JL. Immature blood vessels in rheumatoid synovium are selectively depleted in response to anti-TNF therapy. PLoS One. 2009;4(12):e8131. https://doi.org/10.1371/journal.pone.0008131.CrossRefPubMedPubMedCentral

53.

Kim I, Kim JH, Ryu YS, Liu M, Koh GY. Tumor necrosis factor-alpha upregulates angiopoietin-2 in human umbilical vein endothelial cells. Biochem Biophys Res Commun. 2000;269(2):361–5. https://doi.org/10.1006/bbrc.2000.2296.CrossRefPubMed

54.

Hao NB, Lu MH, Fan YH, Cao YL, Zhang ZR, Yang SM. Macrophages in tumor microenvironments and the progression of tumors. Clin Dev Immunol. 2012;2012:948098.CrossRef

55.

Rolny C, Mazzone M, Tugues S, Laoui D, Johansson I, Coulon C, Squadrito ML, Segura I, Li X, Knevels E, Costa S, Vinckier S, Dresselaer T, Åkerud P, de Mol M, Salomäki H, Phillipson M, Wyns S, Larsson E, Buysschaert I, Botling J, Himmelreich U, van Ginderachter JA, de Palma M, Dewerchin M, Claesson-Welsh L, Carmeliet P. HRG inhibits tumor growth and metastasis by inducing macrophage polarization and vessel normalization through downregulation of PlGF. Cancer Cell. 2011;19(1):31–44. https://doi.org/10.1016/j.ccr.2010.11.009.CrossRefPubMed

56.

Moreth K, Frey H, Hubo M, Zeng-Brouwers J, Nastase MV, Hsieh LT, Haceni R, Pfeilschifter J, Iozzo RV, Schaefer L. Biglycan-triggered TLR-2- and TLR-4-signaling exacerbates the pathophysiology of ischemic acute kidney injury. Matrix Biol. 2014;35:143–51. https://doi.org/10.1016/j.matbio.2014.01.010.CrossRefPubMedPubMedCentral

57.

Bani-Hani AH, Leslie JA, Asanuma H, Dinarello CA, Campbell MT, Meldrum DR, Zhang H, Hile K, Meldrum KK. IL-18 neutralization ameliorates obstruction-induced epithelial-mesenchymal transition and renal fibrosis. Kidney Int. 2009;76(5):500–11. https://doi.org/10.1038/ki.2009.216.CrossRefPubMed

58.

Babelova A, Moreth K, Tsalastra-Greul W, Zeng-Brouwers J, Eickelberg O, Young MF, Bruckner P, Pfeilschifter J, Schaefer RM, Grone HJ, et al. Biglycan, a danger signal that activates the NLRP3 inflammasome via toll-like and P2X receptors. J Biol Chem. 2009;284(36):24035–48. https://doi.org/10.1074/jbc.M109.014266.CrossRefPubMedPubMedCentral

59.

Jones LK, O'Sullivan KM, Semple T, Kuligowski MP, Fukami K, Ma FY, Nikolic-Paterson DJ, Holdsworth SR, Kitching AR. IL-1RI deficiency ameliorates early experimental renal interstitial fibrosis. Nephrol Dial Transplant. 2009;24(10):3024–32. https://doi.org/10.1093/ndt/gfp214.CrossRefPubMed

60.

Martin JD, Seano G, Jain RK. Normalizing function of tumor vessels: Progress, opportunities, and challenges. Annu Rev Physiol. 2019;81(1):505–34. https://doi.org/10.1146/annurev-physiol-020518-114700.CrossRefPubMedPubMedCentral

61.

Jain RK. Antiangiogenesis strategies revisited: from starving tumors to alleviating hypoxia. Cancer Cell. 2014;26(5):605–22. https://doi.org/10.1016/j.ccell.2014.10.006.CrossRefPubMedPubMedCentral

62.

Cleator S, Heller W, Coombes RC. Triple-negative breast cancer: therapeutic options. Lancet Oncol. 2007;8(3):235–44. https://doi.org/10.1016/S1470-2045(07)70074-8.CrossRefPubMed

63.

Schmid P, Chui SY, Emens LA. Atezolizumab and nab-paclitaxel in advanced triple-negative breast cancer. Reply N Engl J Med. 2019;380(10):987–8. https://doi.org/10.1056/NEJMc1900150.CrossRefPubMed

64.

Wang W, Chapman NM, Zhang B, Li M, Fan M, Laribee RN, Zaidi MR, Pfeffer LM, Chi H, Wu ZH. Upregulation of PD-L1 via HMGB1-activated IRF3 and NF-kappaB contributes to UV radiation-induced immune suppression. Cancer Res. 2019;79(11):2909–22. https://doi.org/10.1158/0008-5472.CAN-18-3134.CrossRefPubMedPubMedCentral

Title: Inhibition of stromal biglycan promotes normalization of the tumor microenvironment and enhances chemotherapeutic efficacy
Authors: Li Cong
Nako Maishi
Dorcas A. Annan
Marian F. Young
Hirofumi Morimoto
Masahiro Morimoto
Jin-Min Nam
Yasuhiro Hida
Kyoko Hida
Publication date: 01-12-2021
Publisher: BioMed Central
Keywords: Breast Cancer
Breast Cancer
Published in: Breast Cancer Research / Issue 1/2021
Electronic ISSN: 1465-542X
DOI: https://doi.org/10.1186/s13058-021-01423-w

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