Advertisement

Stiffness heterogeneity-induced double-edged sword behaviors of carcinoma-associated fibroblasts in antitumor therapy

  • Jiantao Feng (冯建涛)
  • Shivani Sharma
  • Elizabeth Rao
  • Xiang Li (李想)
  • Qiang Zhang (张强)
  • Fulong Liao (廖福龙)
  • Jie He (赫捷)Email author
  • Dong Han (韩东)
  • Jianyu Rao (饶建宇)
Articles
  • 8 Downloads

Abstract

Carcinoma-associated fibroblasts (CAFs) function as a double-edged sword in tumor progression. However, factors affecting the transition between tumor promotion and inhibition remain to be investigated. Here, we found that the transition was determined by stiffness heterogeneity of the tumor stroma in which tumor cells and CAFs were grown. When tumor cells were grown on a rigid plastic substrate, supernatants from CAFs inhibited the cytotoxic effects of 5- fluorouracil. In contrast, when tumor cells were grown on a soft substrate (5.3 kPa), supernatants from CAFs grown on a soft substrate increased the cytotoxicity of 5-fluorouracil. The diverse effects of CAFs were mediated by mechanotransduction factors, including stroma stiffness-induced cytokine expression in CAFs and signal transduction associated with stress fiber formation of CAFs. Moreover, we found that the cytokine expression in CAFs was regulated by nuclear Yesassociated protein, which changed according to cell stiffness, as characterized by atomic force microscopy. Overall, these findings suggested that modulating the mechanotransduction of the stroma together with CAFs might be important for increasing the efficacy of chemotherapy.

Keywords

stiffness carcinoma-associated fibroblast tumor microenvironment chemotherapy atomic force microscopy 

肿瘤刚度异质性诱导的肿瘤相关成纤维细胞双刃剑行为研究

摘要

肿瘤相关成纤维细胞(CAFs)在肿瘤的发展过程中发挥着双刃剑的作用, 但导致CAFs促进或者抑制肿瘤生存的关键因素还有待深入 研究. 本文中, 我们发现肿瘤细胞与CAFs所生长的基底的刚度异质性决定了上述两个相反的作用: 在化疗药物5-氟尿嘧啶作用下, 当肿瘤 细胞培养在硬基底(塑料基底)上时, CAFs的条件培养液促进了肿瘤细胞的生存; 当肿瘤细胞与CAFs分别培养在软基底(5.3 kPa)上时, CAFs的条件培养液抑制了肿瘤细胞的生存. 基于原子力显微镜技术、激光共聚焦技术以及细胞因子芯片技术, 我们发现CAFs中力学信 号传导下游的应力纤维分布以及YAP蛋白核迁移与CAFs的双刃剑行为密切相关. 因此调控肿瘤基质的力学传导有助于增强抗肿瘤药物 的疗效.

Notes

Acknowledgements

This work was financially supported by the Postdoctoral Science Foundation Program of Chinese Academy of Medical Sciences & Peking Union Medical College, the National Natural Science Foundation of China (NSFC) (31470905), and National Institutes of Health/National Cancer Institute (NIH/NCI) Grant R21, CA208196.

Supplementary material

40843_2018_9383_MOESM1_ESM.pdf (1.6 mb)
Stiffness heterogeneity-induced double-edged sword behaviors of carcinoma-associated fibroblasts in antitumor therapy

References

  1. 1.
    Mitchell MJ, Jain RK, Langer R. Engineering and physical sciences in oncology: Challenges and opportunities. Nat Rev Cancer, 2017, 17: 659–675CrossRefGoogle Scholar
  2. 2.
    Liu L, Zhang SX, Liao W, et al. Mechanoresponsive stem cells to target cancer metastases through biophysical cues. Sci Transl Med, 2017, 9: eaan2966CrossRefGoogle Scholar
  3. 3.
    Plodinec M, Loparic M, Monnier CA, et al. The nanomechanical signature of breast cancer. Nat Nanotech, 2012, 7: 757–765CrossRefGoogle Scholar
  4. 4.
    Acerbi I, Cassereau L, Dean I, et al. Human breast cancer invasion and aggression correlates with ECM stiffening and immune cell infiltration. Integr Biol, 2015, 7: 1120–1134CrossRefGoogle Scholar
  5. 5.
    Hu N, Cao Y, Ao Z, et al. Flow behavior of liquid metal in the connected fascial space: Intervaginal space injection in the rat wrist and mice with tumor. Nano Res, 2017, 11: 2265–2276CrossRefGoogle Scholar
  6. 6.
    Kalluri R. The biology and function of fibroblasts in cancer. Nat Rev Cancer, 2016, 16: 582–598CrossRefGoogle Scholar
  7. 7.
    Kharaishvili G, Simkova D, Bouchalova K, et al. The role of cancerassociated fibroblasts, solid stress and other microenvironmental factors in tumor progression and therapy resistance. Cancer Cell Int, 2014, 14: 41CrossRefGoogle Scholar
  8. 8.
    Kalli M, Papageorgis P, Gkretsi V, et al. Solid stress facilitates fibroblasts activation to promote pancreatic cancer cell migration. Ann Biomed Eng, 2018, 46: 657–669CrossRefGoogle Scholar
  9. 9.
    Levental KR, Yu H, Kass L, et al. Matrix crosslinking forces tumor progression by enhancing integrin signaling. Cell, 2009, 139: 891–906CrossRefGoogle Scholar
  10. 10.
    Yaqoob U, Cao S, Shergill U, et al. Neuropilin-1 stimulates tumor growth by increasing fibronectin fibril assembly in the tumor microenvironment. Cancer Res, 2012, 72: 4047–4059CrossRefGoogle Scholar
  11. 11.
    Schrader J, Gordon-Walker TT, Aucott RL, et al. Matrix stiffness modulates proliferation, chemotherapeutic response, and dormancy in hepatocellular carcinoma cells. Hepatology, 2011, 53: 1192–1205CrossRefGoogle Scholar
  12. 12.
    Ulrich TA, de Juan Pardo EM, Kumar S. The mechanical rigidity of the extracellular matrix regulates the structure, motility, and proliferation of glioma cells. Cancer Res, 2009, 69: 4167–4174CrossRefGoogle Scholar
  13. 13.
    Nune KC, Li S, Misra RDK. Advancements in three-dimensional titanium alloy mesh scaffolds fabricated by electron beam melting for biomedical devices: Mechanical and biological aspects. Sci China Mater, 2018, 61: 455–474CrossRefGoogle Scholar
  14. 14.
    Feng J, Tang Y, Xu Y, et al. Substrate stiffness influences the outcome of antitumor drug screening in vitro. Clin Hemorheol Microcirc, 2013, 55: 121–131Google Scholar
  15. 15.
    Liu C, Li X, Hua W, et al. Porous matrix stiffness modulates response to targeted therapy in breast carcinoma. Small, 2016, 12: 4675–4681CrossRefGoogle Scholar
  16. 16.
    Sun Y. Tumor microenvironment and cancer therapy resistance. Cancer Lett, 2016, 380: 205–215CrossRefGoogle Scholar
  17. 17.
    Krishnan V, Schaar B, Tallapragada S, et al. Tumor associated macrophages in gynecologic cancers. Gynecol Oncol, 2018, 149: 205–213CrossRefGoogle Scholar
  18. 18.
    Chen J, Lin L, Yan N, et al. Macrophages loaded CpG and GNRPEI for combination of tumor photothermal therapy and immunotherapy. Sci China Mater, 2018, 61: 1484–1494CrossRefGoogle Scholar
  19. 19.
    Yamamura Y, Asai N, Enomoto A, et al. Akt-Girdin signaling in cancer-associated fibroblasts contributes to tumor progression. Cancer Res, 2015, 75: 813–823CrossRefGoogle Scholar
  20. 20.
    Öhlund D, Elyada E, Tuveson D. Fibroblast heterogeneity in the cancer wound. J Exp Med, 2014, 211: 1503–1523CrossRefGoogle Scholar
  21. 21.
    Özdemir BC, Pentcheva-Hoang T, Carstens JL, et al. Depletion of carcinoma-associated fibroblasts and fibrosis induces immunosuppression and accelerates pancreas cancer with reduced survival. Cancer Cell, 2014, 25: 719–734CrossRefGoogle Scholar
  22. 22.
    Geng L, Feng J, Sun Q, et al. Nanomechanical clues from morphologically normal cervical squamous cells could improve cervical cancer screening. Nanoscale, 2015, 7: 15589–15593CrossRefGoogle Scholar
  23. 23.
    Butt HJ, Cappella B, Kappl M. Force measurements with the atomic force microscope: Technique, interpretation and applications. Surf Sci Rep, 2005, 59: 1–152CrossRefGoogle Scholar
  24. 24.
    Paszek MJ, Zahir N, Johnson KR, et al. Tensional homeostasis and the malignant phenotype. Cancer Cell, 2005, 8: 241–254CrossRefGoogle Scholar
  25. 25.
    Farmer P, Bonnefoi H, Anderle P, et al. A stroma-related gene signature predicts resistance to neoadjuvant chemotherapy in breast cancer. Nat Med, 2009, 15: 68–74CrossRefGoogle Scholar
  26. 26.
    Dupont S, Morsut L, Aragona M, et al. Role of YAP/TAZ in mechanotransduction. Nature, 2011, 474: 179–183CrossRefGoogle Scholar
  27. 27.
    Sharif GM, Schmidt MO, Yi C, et al. Cell growth density modulates cancer cell vascular invasion via hippo pathway activity and CXCR2 signaling. Oncogene, 2015, 34: 5879–5889CrossRefGoogle Scholar
  28. 28.
    Wang G, Lu X, Dey P, et al. Targeting YAP-dependent MDSC infiltration impairs tumor progression. Cancer Discov, 2016, 6: 80–95CrossRefGoogle Scholar
  29. 29.
    Calvo F, Ege N, Grande-Garcia A, et al. Mechanotransduction and YAP-dependent matrix remodelling is required for the generation and maintenance of cancer-associated fibroblasts. Nat Cell Biol, 2013, 15: 637–646CrossRefGoogle Scholar
  30. 30.
    Cole SW, Nagaraja AS, Lutgendorf SK, et al. Sympathetic nervous system regulation of the tumour microenvironment. Nat Rev Cancer, 2015, 15: 563–572CrossRefGoogle Scholar
  31. 31.
    Quail DF, Joyce JA. Microenvironmental regulation of tumor progression and metastasis. Nat Med, 2013, 19: 1423–1437CrossRefGoogle Scholar
  32. 32.
    De Palma M, Biziato D, Petrova TV. Microenvironmental regulation of tumour angiogenesis. Nat Rev Cancer, 2017, 17: 457–474CrossRefGoogle Scholar
  33. 33.
    Straussman R, Morikawa T, Shee K, et al. Tumour micro-environment elicits innate resistance to RAF inhibitors through HGF secretion. Nature, 2012, 487: 500–504CrossRefGoogle Scholar
  34. 34.
    Wilson TR, Fridlyand J, Yan Y, et al. Widespread potential for growth-factor-driven resistance to anticancer kinase inhibitors. Nature, 2012, 487: 505–509CrossRefGoogle Scholar
  35. 35.
    Holohan C, Van Schaeybroeck S, Longley DB, et al. Cancer drug resistance: An evolving paradigm. Nat Rev Cancer, 2013, 13: 714–726CrossRefGoogle Scholar
  36. 36.
    Wu Y, Wang D, Li Y. Understanding of the major reactions in solution synthesis of functional nanomaterials. Sci China Mater, 2016, 59: 938–996CrossRefGoogle Scholar
  37. 37.
    Xu X, Lu Y, Yang Y, et al. Tuning the growth of metal-organic framework nanocrystals by using polyoxometalates as coordination modulators. Sci China Mater, 2015, 58: 370–377CrossRefGoogle Scholar
  38. 38.
    Paraiso KHT, Smalley KSM. Fibroblast-mediated drug resistance in cancer. Biochem Pharmacol, 2013, 85: 1033–1041CrossRefGoogle Scholar
  39. 39.
    Brunen D, Willems SM, Kellner U, et al. TGF-ß: An emerging player in drug resistance. Cell Cycle, 2013, 12: 2960–2968CrossRefGoogle Scholar
  40. 40.
    Leight JL, Wozniak MA, Chen S, et al. Matrix rigidity regulates a switch between TGF-ß1–induced apoptosis and epithelial–mesenchymal transition. Mol Bio Cell, 2012, 23: 781–791CrossRefGoogle Scholar
  41. 41.
    Liu Y, He K, Hu Y, et al. YAP modulates TGF-ß1-induced simultaneous apoptosis and EMT through upregulation of the EGF receptor. Sci Rep, 2017, 7: 45523CrossRefGoogle Scholar
  42. 42.
    Kawamura M, Toiyama Y, Tanaka K, et al. CXCL5, a promoter of cell proliferation, migration and invasion, is a novel serum prognostic marker in patients with colorectal cancer. Eur J Cancer, 2012, 48: 2244–2251CrossRefGoogle Scholar
  43. 43.
    Wang B, Hendricks DT, Wamunyokoli F, et al. A growth-related oncogene/CXC chemokine receptor 2 autocrine loop contributes to cellular proliferation in esophageal cancer. Cancer Res, 2006, 66: 3071–3077CrossRefGoogle Scholar
  44. 44.
    Low BC, Pan CQ, Shivashankar GV, et al. YAP/TAZ as mechanosensors and mechanotransducers in regulating organ size and tumor growth. FEBS Lett, 2014, 588: 2663–2670CrossRefGoogle Scholar
  45. 45.
    Liu F, Lagares D, Choi KM, et al. Mechanosignaling through YAP and TAZ drives fibroblast activation and fibrosis. Am J Physiol-Lung Cellular Mol Physiol, 2015, 308: L344–L357CrossRefGoogle Scholar
  46. 46.
    Oria R, Wiegand T, Escribano J, et al. Force loading explains spatial sensing of ligands by cells. Nature, 2017, 196: 219–224Google Scholar
  47. 47.
    Zhao B, Ye X, Yu J, et al. Tead mediates YAP-dependent gene induction and growth control. Genes Dev, 2008, 22: 1962–1971CrossRefGoogle Scholar
  48. 48.
    Hasebe T. Tumor–stromal interactions in breast tumor progression–significance of histological heterogeneity of tumor–stromal fibroblasts. Expert Opin Therap Targets, 2013, 17: 449–460CrossRefGoogle Scholar
  49. 49.
    Sharma S, Santiskulvong C, Bentolila LA, et al. Correlative nanomechanical profiling with super-resolution F-actin imaging reveals novel insights into mechanisms of cisplatin resistance in ovarian cancer cells. Nanomed-Nanotechnol Biol Med, 2012, 8: 757–766CrossRefGoogle Scholar
  50. 50.
    Cross SE, Jin YS, Rao J, et al. Nanomechanical analysis of cells from cancer patients. Nat Nanotech, 2007, 2: 780–783CrossRefGoogle Scholar
  51. 51.
    Adams JL, Smothers J, Srinivasan R, et al. Big opportunities for small molecules in immuno-oncology. Nat Rev Drug Discov, 2015, 14: 603–622CrossRefGoogle Scholar
  52. 52.
    Schmid D, Park CG, Hartl CA, et al. T cell-targeting nanoparticles focus delivery of immunotherapy to improve antitumor immunity. Nat Commun, 2017, 8: 1747CrossRefGoogle Scholar
  53. 53.
    Tu Y. The discovery of artemisinin (qinghaosu) and gifts from Chinese medicine. Nat Med, 2011, 17: 1217–1220CrossRefGoogle Scholar
  54. 54.
    Liao F, Li M, Han D, et al. Biomechanopharmacology: A new borderline discipline. Trends Pharmacol Sci, 2006, 27: 287–289CrossRefGoogle Scholar

Copyright information

© Science China Press and Springer-Verlag GmbH Germany, part of Springer Nature 2019

Authors and Affiliations

  • Jiantao Feng (冯建涛)
    • 1
  • Shivani Sharma
    • 2
    • 3
    • 4
  • Elizabeth Rao
    • 2
  • Xiang Li (李想)
    • 5
  • Qiang Zhang (张强)
    • 5
  • Fulong Liao (廖福龙)
    • 5
    • 6
  • Jie He (赫捷)
    • 1
    Email author
  • Dong Han (韩东)
    • 5
  • Jianyu Rao (饶建宇)
    • 2
    • 3
    • 4
  1. 1.Cancer Hospital, Chinese Academy of Medical SciencesBeijingChina
  2. 2.Department of Pathology and Laboratory MedicineUniversity of CaliforniaLos AngelesUSA
  3. 3.California NanoSystems InstituteUniversity of CaliforniaLos AngelesUSA
  4. 4.Jonhson Comprehensive Cancer InstituteUniversity of CaliforniaLos AngelesUSA
  5. 5.National Center for Nanoscience and TechnologyBeijingChina
  6. 6.Institute of Chinese Materia Medica China Academy of Chinese Medical SciencesBeijingChina

Personalised recommendations