We use cookies to improve your experience. By continuing to browse this site, you accept our cookie policy.×
Skip main navigation
Aging Health
Bioelectronics in Medicine
Biomarkers in Medicine
Breast Cancer Management
CNS Oncology
Colorectal Cancer
Concussion
Epigenomics
Future Cardiology
Future Medicine AI
Future Microbiology
Future Neurology
Future Oncology
Future Rare Diseases
Future Virology
Hepatic Oncology
HIV Therapy
Immunotherapy
International Journal of Endocrine Oncology
International Journal of Hematologic Oncology
Journal of 3D Printing in Medicine
Lung Cancer Management
Melanoma Management
Nanomedicine
Neurodegenerative Disease Management
Pain Management
Pediatric Health
Personalized Medicine
Pharmacogenomics
Regenerative Medicine

Modulation of cancer-associated fibroblasts by nanodelivery system to enhance efficacy of tumor therapy

    Wei Ai

    College of Life Science & Technology, Changchun University of Science & Technology, Changchun, Jilin, 130022, China

    ,
    Tianhui Liu

    College of Life Science & Technology, Changchun University of Science & Technology, Changchun, Jilin, 130022, China

    ,
    Changshun Lv

    College of Life Science & Technology, Changchun University of Science & Technology, Changchun, Jilin, 130022, China

    ,
    Xiangru Feng

    *Author for correspondence:

    E-mail Address: xrfeng@cust.edu.cn

    College of Life Science & Technology, Changchun University of Science & Technology, Changchun, Jilin, 130022, China

    &
    Qingshuang Wang

    College of Life Science & Technology, Changchun University of Science & Technology, Changchun, Jilin, 130022, China

    Published Online:https://doi.org/10.2217/nnm-2023-0088

    Cancer-associated fibroblasts (CAFs) are the most common cells in the tumor stroma and are essential for tumor development and metastasis. While decreasing the release and infiltration of nanomedicine through nonspecific internalization, CAFs specifically increase solid tumor pressure and interstitial fluid pressure by secreting tumor growth- and migration-promoting cytokines, which increases vascular and organ pressure caused by solid tumor pressure. Nanoparticles have good permeability and can penetrate tumor tissue to reach the lesion area, inhibiting tumor growth. Thus, CAFs are used as modifiable targets. Here, the authors review the biological functions, origins and biomarkers of CAFs and summarize strategies for modulating CAFs in nanodelivery systems. This study provides a prospective guide to modulating CAFs to enhance oncology treatment.

    Plain language summary

    Cancer-associated fibroblasts (CAFs) participate in the growth and metastasis of cancer and also suppress the penetration of antitumor drugs into the deep tumor tissue. Therefore, many researchers have sought to improve the therapeutic efficacy of nanomedicine through the regulation of CAFs. Some nanoparticles that can precisely target CAFs can slow their growth while also assisting the immune system in fighting cancer cells and releasing pressure within the tumor. These nanoparticles may pass through tumors and inhibit the growth of cancer cells. Therefore, the modulation of CAFs with nanomedicines to enhance tumor therapy is essential.

    Papers of special note have been highlighted as: • of interest; •• of considerable interest

    References

    • 1. Guo J, Zeng H, Chen Y. Emerging nano drug delivery systems targeting cancer-associated fibroblasts for improved antitumor effect and tumor drug penetration. Mol. Pharm. 17(4), 1028–1048 (2020). •• Describes the biological mechanisms by which cancer-associated fibroblasts (CAFs) interfere with nanotherapies and the strategies associated with nanodelivery systems targeting CAFs. Guiding implications are provided for the current research.
    • 2. Belli C, Trapani D, Viale G et al. Targeting the microenvironment in solid tumors. Cancer Treat. Rev. 65, 22–32 (2018). • Describes the characteristics of the tumor microenvironment and the interconnection between CAFs and tumors. It describes theoretical aspects that assist the current research.
    • 3. Du Y, Cao M, Liu Y et al. Tumor microenvironment remodeling modulates macrophage phenotype in breast cancer lymphangiogenesis. FASEB J. 36(4), e22248 (2022).
    • 4. Lawrie TA, Rabbie R, Thoma C. Pegylated liposomal doxorubicin for first-line treatment of epithelial ovarian cancer. Cochrane Database Syst. Rev. 10, London, UK (2013).
    • 5. Fernandes C, Suares D, Yergeri MC. Tumor microenvironment targeted nanotherapy. Front. Pharmacol. 9, doi:10.3389/fphar.2018.01230 (2018).
    • 6. Yang M, Li J, Gu P et al. The application of nanoparticles in cancer immunotherapy: targeting tumor microenvironment. Bioact. Mater. 6(7), 1973–1987 (2021).
    • 7. Batra H, Pawar S, Bahl D. Curcumin in combination with anti-cancer drugs: a nanomedicine review. Pharmacol. Res. 139, 91–105 (2019).
    • 8. Colombo M, Rizzuto MA, Pacini C et al. Half-chain cetuximab nanoconjugates allow multitarget therapy of triple negative breast cancer. Bioconjug. Chem. 29(11), 3817–3832 (2018).
    • 9. Saw PE, Chen J, Song E. Targeting CAFs to overcome anticancer therapeutic resistance. Trends Cancer 8(7), 527–555 (2022).
    • 10. Cirri P, Chiarugi P. Cancer associated fibroblasts: the dark side of the coin. Am. J. Cancer Res. 1(4), 482 (2011).
    • 11. Hinz B, Phan SH, Thannickal VJ et al. Recent developments in myofibroblast biology: paradigms for connective tissue remodeling. Am. J. Pathol. 180(4), 1340–1355 (2012).
    • 12. Kalluri R. The biology and function of fibroblasts in cancer. Nat. Rev. Cancer 16(9), 582–598 (2016).
    • 13. Augsten M. Cancer-associated fibroblasts as another polarized cell type of the tumor microenvironment. Front. Oncol. 4, 62 (2014).
    • 14. Shiga K, Hara M, Nagasaki T et al. Cancer-associated fibroblasts: their characteristics and their roles in tumor growth. Cancers 7(4), 2443–2458 (2015).
    • 15. Gascard P, Tlsty TD. Carcinoma-associated fibroblasts: orchestrating the composition of malignancy. Genes Dev. 30(9), 1002–1019 (2016).
    • 16. Erez N, Truitt M, Olson P et al. Cancer-associated fibroblasts are activated in incipient neoplasia to orchestrate tumor-promoting inflammation in an NF-κB-dependent manner. Cancer Cell 17(2), 135–147 (2010).
    • 17. Kraman M, Bambrough PJ, Arnold JN et al. Suppression of antitumor immunity by stromal cells expressing fibroblast activation protein–α. Science 330(6005), 827–830 (2010).
    • 18. Sahai E, Astsaturov I, Cukierman E et al. A framework for advancing our understanding of cancer-associated fibroblasts. Nat. Rev. Cancer 20(3), 174–186 (2020).
    • 19. Hay ED. An overview of epithelio-mesenchymal transformation. Cells Tissues Organs 154(1), 8–20 (1995).
    • 20. Forino M, Torregrossa R, Ceol M et al. TGFβ1 induces epithelial–mesenchymal transition, but not myofibroblast transdifferentiation of human kidney tubular epithelial cells in primary culture. Int. J. Exp. Pathol. 87(3), 197–208 (2006).
    • 21. Direkze NC, Hodivala-Dilke K, Jeffery R et al. Bone marrow contribution to tumor-associated myofibroblasts and fibroblasts. Cancer Res. 64(23), 8492–8495 (2004).
    • 22. Mishra PJ, Mishra PJ, Humeniuk R et al. Carcinoma-associated fibroblast–like differentiation of human mesenchymal stem cells. Cancer Res. 68(11), 4331–4339 (2008).
    • 23. Yeon JH, Jeong HE, Seo H et al. Cancer-derived exosomes trigger endothelial to mesenchymal transition followed by the induction of cancer-associated fibroblasts. Acta Biomater. 76, 146–153 (2018).
    • 24. Zeisberg EM, Potenta S, Xie L et al. Discovery of endothelial to mesenchymal transition as a source for carcinoma-associated fibroblasts. Cancer Res. 67(21), 10123–10128 (2007).
    • 25. He Q, Guo S, Qian Z et al. Development of individualized anti-metastasis strategies by engineering nanomedicines. Chem. Soc. Rev. 44(17), 6258–6286 (2015).
    • 26. Chang C-H, Qiu J, O'Sullivan D et al. Metabolic competition in the tumor microenvironment is a driver of cancer progression. Cell 162(6), 1229–1241 (2015).
    • 27. Altmann A, Haberkorn U, Siveke J. The latest developments in imaging of fibroblast activation protein. J. Nucl. Med. 62(2), 160–167 (2021).
    • 28. Fearon DT. The carcinoma-associated fibroblast expressing fibroblast activation protein and escape from immune surveillance. Cancer Immunol. Res. 2(3), 187–193 (2014).
    • 29. Yang X, Lin Y, Shi Y et al. FAP promotes immunosuppression by cancer-associated fibroblasts in the tumor microenvironment via STAT3–CCL2 signaling. Cancer Res. 76(14), 4124–4135 (2016).
    • 30. Cheng JD, Dunbrack RL Jr, Valianou M et al. Promotion of tumor growth by murine fibroblast activation protein, a serine protease, in an animal model. Cancer Res. 62(16), 4767–4772 (2002).
    • 31. Cherng S, Young J, Ma H. Alpha-smooth muscle actin (α-SMA). J. Am. Sci. 4(4), 7–9 (2008).
    • 32. 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 25(6), 719–734 (2014).
    • 33. Yin L, Tang Y, Yuan Y. An overview of the advances in research on the molecular function and specific role of circular RNA in cardiovascular diseases. BioMed Res. Int. 2022, 1–10 (2022).
    • 34. Becker LM, O'Connell JT, Vo AP et al. Epigenetic reprogramming of cancer-associated fibroblasts deregulates glucose metabolism and facilitates progression of breast cancer. Cell Rep. 31(9), doi:10.1016/j.celrep.2020.107701 (2020).
    • 35. Wang Z, Li W, Guo Q et al. Insulin-like growth factor-1 signaling in lung development and inflammatory lung diseases. BioMed Res. Int. 2018, doi:10.1155/2018/6057589 (2018).
    • 36. Lelièvre P, Sancey L, Coll J-L et al. Iron dysregulation in human cancer: altered metabolism, biomarkers for diagnosis, prognosis, monitoring and rationale for therapy. Cancers 12(12), 3524 (2020).
    • 37. Long X, Xiong W, Zeng X et al. Cancer-associated fibroblasts promote cisplatin resistance in bladder cancer cells by increasing IGF-1/ERβ/Bcl-2 signalling. Cell Death Dis. 10(5), 1–16 (2019).
    • 38. Yi Y, Zeng S, Wang Z et al. Cancer-associated fibroblasts promote epithelial-mesenchymal transition and EGFR-TKI resistance of non-small-cell lung cancers via HGF/IGF-1/ANXA2 signaling. Biochim. Biophys. Acta Mol. Basis Dis. 1864(3), 793–803 (2018).
    • 39. Fassnacht M, Berruti A, Baudin E et al. Linsitinib (OSI-906) versus placebo for patients with locally advanced or metastatic adrenocortical carcinoma: a double-blind, randomised, phase 3 study. Lancet Oncol. 16(4), 426–435 (2015).
    • 40. Kazlauskas A. PDGFs and their receptors. Gene 614, 1–7 (2017).
    • 41. Mai W, Chen M, Huang M et al. Targeting platelet-derived growth factor receptor β inhibits the proliferation and motility of human pterygial fibroblasts. Expert Opin. Ther. Targets 23(9), 805–817 (2019).
    • 42. Primac I, Maquoi E, Blacher S et al. Stromal integrin α11 regulates PDGFRβ signaling and promotes breast cancer progression. J. Clin. Invest. 129(11), 4609–4628 (2019).
    • 43. Suzuki J, Aokage K, Neri S et al. Relationship between podoplanin-expressing cancer-associated fibroblasts and the immune microenvironment of early lung squamous cell carcinoma. Lung Cancer 153, 1–10 (2021).
    • 44. Takiguchi K, Shoda K, Nakayama T et al. Soluble podoplanin as a biomarker in diffuse-type gastric cancer. Oncol. Rep. 47(3), 1–7 (2022).
    • 45. Suzuki H, Kaneko MK, Kato Y. Roles of podoplanin in malignant progression of tumor. Cells 11(3), 575 (2022).
    • 46. Jenkins BH, Buckingham JF, Hanley CJ et al. Targeting cancer-associated fibroblasts: challenges, opportunities and future directions. Pharmacol. Ther. 240, doi:10.1016/j.pharmthera.2022.108231 (2022).
    • 47. Gilardi L, Airò Farulla LS, Demirci E et al. Imaging cancer-associated fibroblasts (CAFs) with FAPi PET. Biomedicines 10(3), 523 (2022).
    • 48. Ji T, Zhao Y, Ding Y et al. Transformable peptide nanocarriers for expeditious drug release and effective cancer therapy via cancer-associated fibroblast activation. Angew. Chem. Int. Ed. 55(3), 1050–1055 (2016).
    • 49. Lang J, Zhao X, Qi Y et al. Reshaping prostate tumor microenvironment to suppress metastasis via cancer-associated fibroblast inactivation with peptide-assembly-based nanosystem. ACS Nano 13(11), 12357–12371 (2019).
    • 50. Yu Q, Qiu Y, Li J et al. Targeting cancer-associated fibroblasts by dual-responsive lipid-albumin nanoparticles to enhance drug perfusion for pancreatic tumor therapy. J. Control. Rel. 321, 564–575 (2020).
    • 51. Zheng S, Wang J, Ding N et al. Prodrug polymeric micelles integrating cancer-associated fibroblasts deactivation and synergistic chemotherapy for gastric cancer. Nanobiotechnology 19(1), 1–18 (2021).
    • 52. Kong FH, Ye QF, Miao XY et al. Current status of sorafenib nanoparticle delivery systems in the treatment of hepatocellular carcinoma. Theranostics 11(11), 5464 (2021).
    • 53. Piersma B, Hayward M-K, Weaver VM. Fibrosis and cancer: a strained relationship. Biochim. Biophys. Acta Rev. Cancer 1873(2), doi:10.1016/j.bbcan.2020.188356 (2020).
    • 54. Evanko SP, Potter-Perigo S, Bollyky PL et al. Hyaluronan and versican in the control of human T-lymphocyte adhesion and migration. Matrix Biol. 31(2), 90–100 (2012).
    • 55. Knops AM, South A, Rodeck U et al. Cancer-associated fibroblast density, prognostic characteristics, and recurrence in head and neck squamous cell carcinoma: a meta-analysis. Front. Oncol. 10, doi:10.3389/fonc.2020.565306 (2020).
    • 56. Jacobetz MA, Chan DS, Neesse A et al. Hyaluronan impairs vascular function and drug delivery in a mouse model of pancreatic cancer. Gut 62(1), 112–120 (2013).
    • 57. Lokeshwar VB, Mirza S, Jordan A. Targeting hyaluronic acid family for cancer chemoprevention and therapy. Adv. Cancer Res. 123, 35–65 (2014).
    • 58. Sato N, Cheng X-B, Kohi S et al. Targeting hyaluronan for the treatment of pancreatic ductal adenocarcinoma. Acta Pharm. Sin. B 6(2), 101–105 (2016).
    • 59. Yu X, Su Q, Chang X et al. Multimodal obstruction of tumorigenic energy supply via bionic nanocarriers for effective tumor therapy. Biomaterials 278, doi:10.1016/j.biomaterials.2021.121181 (2021).
    • 60. Zuo T, Zhang J, Yang J et al. On-demand responsive nanoplatform mediated targeting of CAFs and down-regulating mtROS-PYK2 signaling for antitumor metastasis. Biomater. Sci. 9(5), 1872–1885 (2021).
    • 61. Zhang Y, Zhou J, Chen X et al. Modulating tumor-stromal crosstalk via a redox-responsive nanomedicine for combination tumor therapy. J. Control. Rel. 356, 525–541 (2023).
    • 62. Zhu Y, Wen L, Shao S et al. Inhibition of tumor-promoting stroma to enforce subsequently targeting AT1R on tumor cells by pathological inspired micelles. Biomaterials 161, 33–46 (2018).
    • 63. Farhood B, Najafi M, Mortezaee K. Cancer-associated fibroblasts: secretions, interactions, and therapy. J. Cell. Biochem. 120(3), 2791–2800 (2019).
    • 64. Fu R, Zhang Y, Li H et al. LW106, a novel inhibitor of IDO1, suppresses tumor progression by limiting stroma-immune crosstalk and cancer stem cell enrichment in the tumor microenvironment. Br. J. Pharmacol. 175, 3034–3049 (2018).
    • 65. Panagi M, Voutouri C, Mpekris F et al. TGF-β inhibition combined with cytotoxic nanomedicine normalizes triple negative breast cancer microenvironment towards anti-tumor immunity. Theranostics 10(4), 1910 (2020).
    • 66. Mardhian DF, Storm G, Bansal R et al. Nano-targeted relaxin impairs fibrosis and tumor growth in pancreatic cancer and improves the efficacy of gemcitabine in vivo. J. Control. Rel. 290, 1–10 (2018).
    • 67. Xia J, Zhang S, Zhang R et al. Targeting therapy and tumor microenvironment remodeling of triple-negative breast cancer by ginsenoside Rg3 based liposomes. J. Nanobiotechnol. 20(1), 1–22 (2022).
    • 68. Teixeira AF, Ten Dijke P, Zhu H-J. On-target anti-TGF-β therapies are not succeeding in clinical cancer treatments: what are remaining challenges? Front. Cell Dev. Biol. 8, 605 (2020).
    • 69. Higashino N, Koma Y-I, Hosono M et al. Fibroblast activation protein-positive fibroblasts promote tumor progression through secretion of CCL2 and interleukin-6 in esophageal squamous cell carcinoma. Lab. Invest. 99(6), 777–792 (2019).
    • 70. Wan Z, Huang H, West RE III et al. Overcoming pancreatic cancer immune resistance by codelivery of CCR2 antagonist using a STING-activating gemcitabine-based nanocarrier. Mater. Today 62, 33–50 (2022).
    • 71. Ullah A, Chen G, Yibang Z et al. A new approach based on CXCR4-targeted combination liposomes for the treatment of liver fibrosis. Biomater. Sci. 10(10), 2650–2664 (2022). • Describes a new approach based on CXCR4-targeted combinatorial liposomes for the treatment of liver fibrosis, providing a summary of advanced nanosystems to modulate CAFs and treat tumors.
    • 72. Cai H, Dai X, Wang X et al. A nanostrategy for efficient imaging-guided antitumor therapy through a stimuli-responsive branched polymeric prodrug. Adv. Sci. 7(6), doi:10.1002/advs.201903243 (2020).
    • 73. Ji Y, Liu X, Huang M et al. Development of self-assembled multi-arm polyrotaxanes nanocarriers for systemic plasmid delivery in vivo. Biomaterials 192, 416–428 (2019).
    • 74. Chen E, Han S, Song B et al. Mechanism investigation of hyaluronidase-combined multistage nanoparticles for solid tumor penetration and antitumor effect. Int. J. Nanomed. 15, 6311–6324 (2020).
    • 75. Afshari AR, Sanati M, Mollazadeh H et al. Nanoparticle-based drug delivery systems in cancer: a focus on inflammatory pathways. Semin. Cancer Biol. 86(2), 860–872 (2022).
    • 76. Chen Y, McAndrews KM, Kalluri R. Clinical and therapeutic relevance of cancer-associated fibroblasts. Nat. Rev. Clin. Oncol. 18(12), 792–804 (2021).
    • 77. Bai J, Liu T, Tu B et al. Autophagy loss impedes cancer-associated fibroblast activation via downregulating proline biosynthesis. Autophagy 19(2), 632–643 (2022).
    • 78. Zhen Z, Tang W, Wang M et al. Protein nanocage mediated fibroblast-activation protein targeted photoimmunotherapy to enhance cytotoxic T cell infiltration and tumor control. Nano Lett. 17(2), 862–869 (2017).
    • 79. Klymenko Y, Nephew KP. Epigenetic crosstalk between the tumor microenvironment and ovarian cancer cells: a therapeutic road less traveled. Cancers 10(9), 295 (2018).
    • 80. Tan P, Chen X, Zhang H et al. Artificial intelligence aids in development of nanomedicines for cancer management. Semin. Cancer Biol. 89, 61–75 (2023). •• Describes advances in artificially intelligent nanomedicines for cancer management in diagnosis, monitoring and treatment and in the development of precision medicine, providing assistance for future applications in nanosystem modulation of CAFs to improve oncology treatment outcomes.