Skip to main content
Top

Open Access 11-04-2024 | Targeted Therapy | REVIEW

Cancer-associated fibroblasts: a versatile mediator in tumor progression, metastasis, and targeted therapy

Authors: Tianchen Guo, Junfen Xu

Published in: Cancer and Metastasis Reviews

Login to get access

Abstract

Tumor microenvironment (TME) has been demonstrated to play a significant role in tumor initiation, progression, and metastasis. Cancer-associated fibroblasts (CAFs) are the major component of TME and exhibit heterogeneous properties in their communication with tumor cells. This heterogeneity of CAFs can be attributed to various origins, including quiescent fibroblasts, mesenchymal stem cells (MSCs), adipocytes, pericytes, endothelial cells, and mesothelial cells. Moreover, single-cell RNA sequencing has identified diverse phenotypes of CAFs, with myofibroblastic CAFs (myCAFs) and inflammatory CAFs (iCAFs) being the most acknowledged, alongside newly discovered subtypes like antigen-presenting CAFs (apCAFs). Due to these heterogeneities, CAFs exert multiple functions in tumorigenesis, cancer stemness, angiogenesis, immunosuppression, metabolism, and metastasis. As a result, targeted therapies aimed at the TME, particularly focusing on CAFs, are rapidly developing, fueling the promising future of advanced tumor-targeted therapy.
Literature
2.
go back to reference Rahmanian, M., Seyfoori, A., Ghasemi, M., Shamsi, M., Kolahchi, A. R., Modarres, H. P. ,…, Majidzadeh-A, K. (2021). In-vitro tumor microenvironment models containing physical and biological barriers for modelling multidrug resistance mechanisms and multidrug delivery strategies. Journal of Controlled Release: Official Journal of the Controlled Release Society, 334, 164–177. https://doi.org/10.1016/j.jconrel.2021.04.024 Rahmanian, M., Seyfoori, A., Ghasemi, M., Shamsi, M., Kolahchi, A. R., Modarres, H. P. ,…, Majidzadeh-A, K. (2021). In-vitro tumor microenvironment models containing physical and biological barriers for modelling multidrug resistance mechanisms and multidrug delivery strategies. Journal of Controlled Release: Official Journal of the Controlled Release Society, 334, 164–177. https://​doi.​org/​10.​1016/​j.​jconrel.​2021.​04.​024
3.
go back to reference Marozzi, M., Parnigoni, A., Negri, A., Viola, M., Vigetti, D., Passi, A. ,…, Rizzi, F. (2021). Inflammation, extracellular matrix remodeling, and proteostasis in tumor microenvironment. International Journal of Molecular Sciences, 22(15), 8102. https://doi.org/10.3390/ijms22158102 Marozzi, M., Parnigoni, A., Negri, A., Viola, M., Vigetti, D., Passi, A. ,…, Rizzi, F. (2021). Inflammation, extracellular matrix remodeling, and proteostasis in tumor microenvironment. International Journal of Molecular Sciences, 22(15), 8102. https://​doi.​org/​10.​3390/​ijms22158102
4.
5.
go back to reference Bartoschek, M., Oskolkov, N., Bocci, M., Lövrot, J., Larsson, C., Sommarin, M. ,…, Pietras, K. (2018). Spatially and functionally distinct subclasses of breast cancer-associated fibroblasts revealed by single cell RNA sequencing. Nature Communications, 9(1), 5150. https://doi.org/10.1038/s41467-018-07582-3 Bartoschek, M., Oskolkov, N., Bocci, M., Lövrot, J., Larsson, C., Sommarin, M. ,…, Pietras, K. (2018). Spatially and functionally distinct subclasses of breast cancer-associated fibroblasts revealed by single cell RNA sequencing. Nature Communications, 9(1), 5150. https://​doi.​org/​10.​1038/​s41467-018-07582-3
7.
go back to reference Montori, M., Scorzoni, C., Argenziano, M. E., Balducci, D., De Blasio, F., Martini, F. ,…, Maroni, L. (2022). Cancer-associated fibroblasts in cholangiocarcinoma: Current knowledge and possible implications for therapy. Journal of Clinical Medicine, 11(21), 6498. https://doi.org/10.3390/jcm11216498 Montori, M., Scorzoni, C., Argenziano, M. E., Balducci, D., De Blasio, F., Martini, F. ,…, Maroni, L. (2022). Cancer-associated fibroblasts in cholangiocarcinoma: Current knowledge and possible implications for therapy. Journal of Clinical Medicine, 11(21), 6498. https://​doi.​org/​10.​3390/​jcm11216498
12.
15.
go back to reference Li, Z., Low, V., Luga, V., Sun, J., Earlie, E., Parang, B. ,…, Blenis, J. (2022). Tumor-produced and aging-associated oncometabolite methylmalonic acid promotes cancer-associated fibroblast activation to drive metastatic progression. Nature Communications, 13(1), 6239. https://doi.org/10.1038/s41467-022-33862-0 Li, Z., Low, V., Luga, V., Sun, J., Earlie, E., Parang, B. ,…, Blenis, J. (2022). Tumor-produced and aging-associated oncometabolite methylmalonic acid promotes cancer-associated fibroblast activation to drive metastatic progression. Nature Communications, 13(1), 6239. https://​doi.​org/​10.​1038/​s41467-022-33862-0
16.
21.
go back to reference Ang, H. L., Mohan, C. D., Shanmugam, M. K., Leong, H. C., Makvandi, P., Rangappa, K. S. ,…, Sethi, G. (2023). Mechanism of epithelial-mesenchymal transition in cancer and its regulation by natural compounds. Medicinal Research Reviews, 43(4), 1141–1200. https://doi.org/10.1002/med.21948 Ang, H. L., Mohan, C. D., Shanmugam, M. K., Leong, H. C., Makvandi, P., Rangappa, K. S. ,…, Sethi, G. (2023). Mechanism of epithelial-mesenchymal transition in cancer and its regulation by natural compounds. Medicinal Research Reviews, 43(4), 1141–1200. https://​doi.​org/​10.​1002/​med.​21948
23.
go back to reference Adjuto-Saccone, M., Soubeyran, P., Garcia, J., Audebert, S., Camoin, L., Rubis, M. ,…, Tournaire, R. (2021). TNF-α induces endothelial-mesenchymal transition promoting stromal development of pancreatic adenocarcinoma. Cell Death & Disease, 12(7), 649. https://doi.org/10.1038/s41419-021-03920-4 Adjuto-Saccone, M., Soubeyran, P., Garcia, J., Audebert, S., Camoin, L., Rubis, M. ,…, Tournaire, R. (2021). TNF-α induces endothelial-mesenchymal transition promoting stromal development of pancreatic adenocarcinoma. Cell Death & Disease, 12(7), 649. https://​doi.​org/​10.​1038/​s41419-021-03920-4
25.
27.
go back to reference Bochet, L., Lehuédé, C., Dauvillier, S., Wang, Y. Y., Dirat, B., Laurent, V. ,…, Muller, C. (2013). Adipocyte-derived fibroblasts promote tumor progression and contribute to the desmoplastic reaction in breast cancer. Cancer Research, 73(18), 5657–5668. https://doi.org/10.1158/0008-5472.CAN-13-0530 Bochet, L., Lehuédé, C., Dauvillier, S., Wang, Y. Y., Dirat, B., Laurent, V. ,…, Muller, C. (2013). Adipocyte-derived fibroblasts promote tumor progression and contribute to the desmoplastic reaction in breast cancer. Cancer Research, 73(18), 5657–5668. https://​doi.​org/​10.​1158/​0008-5472.​CAN-13-0530
28.
go back to reference Iyoshi, S., Yoshihara, M., Nakamura, K., Sugiyama, M., Koya, Y., Kitami, K. ,…, Kajiyama, H. (2021). Pro-tumoral behavior of omental adipocyte-derived fibroblasts in tumor microenvironment at the metastatic site of ovarian cancer. International Journal of Cancer, 149(11), 1961–1972. https://doi.org/10.1002/ijc.33770 Iyoshi, S., Yoshihara, M., Nakamura, K., Sugiyama, M., Koya, Y., Kitami, K. ,…, Kajiyama, H. (2021). Pro-tumoral behavior of omental adipocyte-derived fibroblasts in tumor microenvironment at the metastatic site of ovarian cancer. International Journal of Cancer, 149(11), 1961–1972. https://​doi.​org/​10.​1002/​ijc.​33770
29.
30.
go back to reference Yao, F., Luo, Y., Liu, Y.-C., Chen, Y.-H., Li, Y.-T., Hu, X.-Y. ,…, Jing, J.-H. (2022). Imatinib inhibits pericyte-fibroblast transition and inflammation and promotes axon regeneration by blocking the PDGF-BB/PDGFRβ pathway in spinal cord injury. Inflammation and Regeneration, 42(1), 44. https://doi.org/10.1186/s41232-022-00223-9 Yao, F., Luo, Y., Liu, Y.-C., Chen, Y.-H., Li, Y.-T., Hu, X.-Y. ,…, Jing, J.-H. (2022). Imatinib inhibits pericyte-fibroblast transition and inflammation and promotes axon regeneration by blocking the PDGF-BB/PDGFRβ pathway in spinal cord injury. Inflammation and Regeneration, 42(1), 44. https://​doi.​org/​10.​1186/​s41232-022-00223-9
31.
go back to reference Hosaka, K., Yang, Y., Seki, T., Fischer, C., Dubey, O., Fredlund, E. ,…, Cao, Y. (2016). Pericyte-fibroblast transition promotes tumor growth and metastasis. Proceedings of the National Academy of Sciences of the United States of America, 113(38), E5618–5627. https://doi.org/10.1073/pnas.1608384113 Hosaka, K., Yang, Y., Seki, T., Fischer, C., Dubey, O., Fredlund, E. ,…, Cao, Y. (2016). Pericyte-fibroblast transition promotes tumor growth and metastasis. Proceedings of the National Academy of Sciences of the United States of America, 113(38), E5618–5627. https://​doi.​org/​10.​1073/​pnas.​1608384113
32.
go back to reference Tang, P. C.-T., Chung, J. Y.-F., Xue, V. W.-W., Xiao, J., Meng, X.-M., Huang, X.-R. ,…, Lan, H.-Y. (2022). Smad3 promotes cancer-associated fibroblasts generation via macrophage-myofibroblast transition. Advanced Science (Weinheim, Baden-Wurttemberg, Germany), 9(1), e2101235. https://doi.org/10.1002/advs.202101235 Tang, P. C.-T., Chung, J. Y.-F., Xue, V. W.-W., Xiao, J., Meng, X.-M., Huang, X.-R. ,…, Lan, H.-Y. (2022). Smad3 promotes cancer-associated fibroblasts generation via macrophage-myofibroblast transition. Advanced Science (Weinheim, Baden-Wurttemberg, Germany), 9(1), e2101235. https://​doi.​org/​10.​1002/​advs.​202101235
33.
go back to reference Huang, H., Wang, Z., Zhang, Y., Pradhan, R. N., Ganguly, D., Chandra, R. ,…, Brekken, R. A. (2022). Mesothelial cell-derived antigen-presenting cancer-associated fibroblasts induce expansion of regulatory T cells in pancreatic cancer. Cancer Cell, 40(6), 656–673.e7. https://doi.org/10.1016/j.ccell.2022.04.011 Huang, H., Wang, Z., Zhang, Y., Pradhan, R. N., Ganguly, D., Chandra, R. ,…, Brekken, R. A. (2022). Mesothelial cell-derived antigen-presenting cancer-associated fibroblasts induce expansion of regulatory T cells in pancreatic cancer. Cancer Cell, 40(6), 656–673.e7. https://​doi.​org/​10.​1016/​j.​ccell.​2022.​04.​011
36.
37.
39.
go back to reference Öhlund, D., Handly-Santana, A., Biffi, G., Elyada, E., Almeida, A. S., Ponz-Sarvise, M. ,…, Tuveson, D. A. (2017). Distinct populations of inflammatory fibroblasts and myofibroblasts in pancreatic cancer. The Journal of Experimental Medicine, 214(3), 579–596. https://doi.org/10.1084/jem.20162024 Öhlund, D., Handly-Santana, A., Biffi, G., Elyada, E., Almeida, A. S., Ponz-Sarvise, M. ,…, Tuveson, D. A. (2017). Distinct populations of inflammatory fibroblasts and myofibroblasts in pancreatic cancer. The Journal of Experimental Medicine, 214(3), 579–596. https://​doi.​org/​10.​1084/​jem.​20162024
40.
go back to reference Chen, Z., Zhou, L., Liu, L., Hou, Y., Xiong, M., Yang, Y. ,…, Chen, K. (2020). Single-cell RNA sequencing highlights the role of inflammatory cancer-associated fibroblasts in bladder urothelial carcinoma. Nature Communications, 11(1), 5077. https://doi.org/10.1038/s41467-020-18916-5 Chen, Z., Zhou, L., Liu, L., Hou, Y., Xiong, M., Yang, Y. ,…, Chen, K. (2020). Single-cell RNA sequencing highlights the role of inflammatory cancer-associated fibroblasts in bladder urothelial carcinoma. Nature Communications, 11(1), 5077. https://​doi.​org/​10.​1038/​s41467-020-18916-5
42.
43.
go back to reference Zheng, S., Hu, C., Lin, H., Li, G., Xia, R., Zhang, X., … Chen, R. (2022). circCUL2 induces an inflammatory CAF phenotype in pancreatic ductal adenocarcinoma via the activation of the MyD88-dependent NF-κB signaling pathway. Journal of experimental & clinical cancer research: CR, 41(1), 71. https://doi.org/10.1186/s13046-021-02237-6 Zheng, S., Hu, C., Lin, H., Li, G., Xia, R., Zhang, X., … Chen, R. (2022). circCUL2 induces an inflammatory CAF phenotype in pancreatic ductal adenocarcinoma via the activation of the MyD88-dependent NF-κB signaling pathway. Journal of experimental & clinical cancer research: CR, 41(1), 71. https://​doi.​org/​10.​1186/​s13046-021-02237-6
44.
46.
47.
go back to reference Elyada, E., Bolisetty, M., Laise, P., Flynn, W. F., Courtois, E. T., Burkhart, R. A. ,…, Tuveson, D. A. (2019). Cross-species single-cell analysis of pancreatic ductal adenocarcinoma reveals antigen-presenting cancer-associated fibroblasts. Cancer Discovery, 9(8), 1102–1123. https://doi.org/10.1158/2159-8290.CD-19-0094 Elyada, E., Bolisetty, M., Laise, P., Flynn, W. F., Courtois, E. T., Burkhart, R. A. ,…, Tuveson, D. A. (2019). Cross-species single-cell analysis of pancreatic ductal adenocarcinoma reveals antigen-presenting cancer-associated fibroblasts. Cancer Discovery, 9(8), 1102–1123. https://​doi.​org/​10.​1158/​2159-8290.​CD-19-0094
50.
go back to reference Hu, B., Wu, C., Mao, H., Gu, H., Dong, H., Yan, J. ,…, Long, J. (2022). Subpopulations of cancer-associated fibroblasts link the prognosis and metabolic features of pancreatic ductal adenocarcinoma. Annals of Translational Medicine, 10(5), 262. https://doi.org/10.21037/atm-22-407 Hu, B., Wu, C., Mao, H., Gu, H., Dong, H., Yan, J. ,…, Long, J. (2022). Subpopulations of cancer-associated fibroblasts link the prognosis and metabolic features of pancreatic ductal adenocarcinoma. Annals of Translational Medicine, 10(5), 262. https://​doi.​org/​10.​21037/​atm-22-407
53.
go back to reference Venning, F. A., Zornhagen, K. W., Wullkopf, L., Sjölund, J., Rodriguez-Cupello, C., Kjellman, P. ,…, Madsen, C. D. (2021). Deciphering the temporal heterogeneity of cancer-associated fibroblast subpopulations in breast cancer. Journal of experimental & clinical cancer research: CR, 40(1), 175. https://doi.org/10.1186/s13046-021-01944-4 Venning, F. A., Zornhagen, K. W., Wullkopf, L., Sjölund, J., Rodriguez-Cupello, C., Kjellman, P. ,…, Madsen, C. D. (2021). Deciphering the temporal heterogeneity of cancer-associated fibroblast subpopulations in breast cancer. Journal of experimental & clinical cancer research: CR, 40(1), 175. https://​doi.​org/​10.​1186/​s13046-021-01944-4
55.
58.
go back to reference Lin, T.-Y., Chan, H.-H., Chen, S.-H., Sarvagalla, S., Chen, P.-S., Coumar, M. S. ,…, Cheung, C. H. A. (2020). BIRC5/Survivin is a novel ATG12-ATG5 conjugate interactor and an autophagy-induced DNA damage suppressor in human cancer and mouse embryonic fibroblast cells. Autophagy, 16(7), 1296–1313. https://doi.org/10.1080/15548627.2019.1671643 Lin, T.-Y., Chan, H.-H., Chen, S.-H., Sarvagalla, S., Chen, P.-S., Coumar, M. S. ,…, Cheung, C. H. A. (2020). BIRC5/Survivin is a novel ATG12-ATG5 conjugate interactor and an autophagy-induced DNA damage suppressor in human cancer and mouse embryonic fibroblast cells. Autophagy, 16(7), 1296–1313. https://​doi.​org/​10.​1080/​15548627.​2019.​1671643
66.
go back to reference Szot, C., Saha, S., Zhang, X. M., Zhu, Z., Hilton, M. B., Morris, K. ,…, St Croix, B. (2018). Tumor stroma-targeted antibody-drug conjugate triggers localized anticancer drug release. The Journal of Clinical Investigation, 128(7), 2927–2943. https://doi.org/10.1172/JCI120481 Szot, C., Saha, S., Zhang, X. M., Zhu, Z., Hilton, M. B., Morris, K. ,…, St Croix, B. (2018). Tumor stroma-targeted antibody-drug conjugate triggers localized anticancer drug release. The Journal of Clinical Investigation, 128(7), 2927–2943. https://​doi.​org/​10.​1172/​JCI120481
67.
go back to reference Zeltz, C., Alam, J., Liu, H., Erusappan, P. M., Hoschuetzky, H., Molven, A. ,…, Gullberg, D. (2019). α11β1 integrin is induced in a subset of cancer-associated fibroblasts in desmoplastic tumor stroma and mediates in vitro cell migration. Cancers, 11(6), 765. https://doi.org/10.3390/cancers11060765 Zeltz, C., Alam, J., Liu, H., Erusappan, P. M., Hoschuetzky, H., Molven, A. ,…, Gullberg, D. (2019). α11β1 integrin is induced in a subset of cancer-associated fibroblasts in desmoplastic tumor stroma and mediates in vitro cell migration. Cancers, 11(6), 765. https://​doi.​org/​10.​3390/​cancers11060765
68.
go back to reference Hwang, W. L., Jagadeesh, K. A., Guo, J. A., Hoffman, H. I., Yadollahpour, P., Reeves, J. W. ,…, Regev, A. (2022). Single-nucleus and spatial transcriptome profiling of pancreatic cancer identifies multicellular dynamics associated with neoadjuvant treatment. Nature Genetics, 54(8), 1178–1191. https://doi.org/10.1038/s41588-022-01134-8 Hwang, W. L., Jagadeesh, K. A., Guo, J. A., Hoffman, H. I., Yadollahpour, P., Reeves, J. W. ,…, Regev, A. (2022). Single-nucleus and spatial transcriptome profiling of pancreatic cancer identifies multicellular dynamics associated with neoadjuvant treatment. Nature Genetics, 54(8), 1178–1191. https://​doi.​org/​10.​1038/​s41588-022-01134-8
69.
go back to reference Aghamaliyev, U., Gaitantzi, H., Thomas, M., Simon-Keller, K., Gaiser, T., Marx, A. ,…, Breitkopf-Heinlein, K. (2019). Downregulation of SPARC is associated with epithelial-mesenchymal transition and low differentiation state of biliary tract cancer cells. European Surgical Research. Europaische Chirurgische Forschung. Recherches Chirurgicales Europeennes, 60(1–2), 1–12. https://doi.org/10.1159/000494734 Aghamaliyev, U., Gaitantzi, H., Thomas, M., Simon-Keller, K., Gaiser, T., Marx, A. ,…, Breitkopf-Heinlein, K. (2019). Downregulation of SPARC is associated with epithelial-mesenchymal transition and low differentiation state of biliary tract cancer cells. European Surgical Research. Europaische Chirurgische Forschung. Recherches Chirurgicales Europeennes, 60(1–2), 1–12. https://​doi.​org/​10.​1159/​000494734
70.
go back to reference Silini, A., Ghilardi, C., Figini, S., Sangalli, F., Fruscio, R., Dahse, R. ,…, Bani, M. (2012). Regulator of G-protein signaling 5 (RGS5) protein: A novel marker of cancer vasculature elicited and sustained by the tumor’s proangiogenic microenvironment. Cellular and molecular life sciences: CMLS, 69(7), 1167–1178. https://doi.org/10.1007/s00018-011-0862-8 Silini, A., Ghilardi, C., Figini, S., Sangalli, F., Fruscio, R., Dahse, R. ,…, Bani, M. (2012). Regulator of G-protein signaling 5 (RGS5) protein: A novel marker of cancer vasculature elicited and sustained by the tumor’s proangiogenic microenvironment. Cellular and molecular life sciences: CMLS, 69(7), 1167–1178. https://​doi.​org/​10.​1007/​s00018-011-0862-8
72.
go back to reference Houthuijzen, J. M., de Bruijn, R., van der Burg, E., Drenth, A. P., Wientjens, E., Filipovic, T. ,…, Jonkers, J. (2023). CD26-negative and CD26-positive tissue-resident fibroblasts contribute to functionally distinct CAF subpopulations in breast cancer. Nature Communications, 14(1), 183. https://doi.org/10.1038/s41467-023-35793-w Houthuijzen, J. M., de Bruijn, R., van der Burg, E., Drenth, A. P., Wientjens, E., Filipovic, T. ,…, Jonkers, J. (2023). CD26-negative and CD26-positive tissue-resident fibroblasts contribute to functionally distinct CAF subpopulations in breast cancer. Nature Communications, 14(1), 183. https://​doi.​org/​10.​1038/​s41467-023-35793-w
74.
go back to reference Neuzillet, C., Nicolle, R., Raffenne, J., Tijeras-Raballand, A., Brunel, A., Astorgues-Xerri, L. ,…, Bousquet, C. (2022). Periostin- and podoplanin-positive cancer-associated fibroblast subtypes cooperate to shape the inflamed tumor microenvironment in aggressive pancreatic adenocarcinoma. The Journal of Pathology, 258(4), 408–425. https://doi.org/10.1002/path.6011 Neuzillet, C., Nicolle, R., Raffenne, J., Tijeras-Raballand, A., Brunel, A., Astorgues-Xerri, L. ,…, Bousquet, C. (2022). Periostin- and podoplanin-positive cancer-associated fibroblast subtypes cooperate to shape the inflamed tumor microenvironment in aggressive pancreatic adenocarcinoma. The Journal of Pathology, 258(4), 408–425. https://​doi.​org/​10.​1002/​path.​6011
75.
76.
go back to reference Peran, I., Dakshanamurthy, S., McCoy, M. D., Mavropoulos, A., Allo, B., Sebastian, A. ,…, Byers, S. W. (2021). Cadherin 11 promotes immunosuppression and extracellular matrix deposition to support growth of pancreatic tumors and resistance to gemcitabine in mice. Gastroenterology, 160(4), 1359–1372.e13. https://doi.org/10.1053/j.gastro.2020.11.044 Peran, I., Dakshanamurthy, S., McCoy, M. D., Mavropoulos, A., Allo, B., Sebastian, A. ,…, Byers, S. W. (2021). Cadherin 11 promotes immunosuppression and extracellular matrix deposition to support growth of pancreatic tumors and resistance to gemcitabine in mice. Gastroenterology, 160(4), 1359–1372.e13. https://​doi.​org/​10.​1053/​j.​gastro.​2020.​11.​044
80.
81.
go back to reference Tang, X., Hou, Y., Yang, G., Wang, X., Tang, S., Du, Y.-E. ,…, Liu, M. (2016). Stromal miR-200s contribute to breast cancer cell invasion through CAF activation and ECM remodeling. Cell Death and Differentiation, 23(1), 132–145. https://doi.org/10.1038/cdd.2015.78 Tang, X., Hou, Y., Yang, G., Wang, X., Tang, S., Du, Y.-E. ,…, Liu, M. (2016). Stromal miR-200s contribute to breast cancer cell invasion through CAF activation and ECM remodeling. Cell Death and Differentiation, 23(1), 132–145. https://​doi.​org/​10.​1038/​cdd.​2015.​78
82.
go back to reference Jain, S., Rick, J. W., Joshi, R. S., Beniwal, A., Spatz, J., Gill, S. ,…, Aghi, M. K. (2023). Single-cell RNA sequencing and spatial transcriptomics reveal cancer-associated fibroblasts in glioblastoma with protumoral effects. The Journal of Clinical Investigation, 133(5), e147087. https://doi.org/10.1172/JCI147087 Jain, S., Rick, J. W., Joshi, R. S., Beniwal, A., Spatz, J., Gill, S. ,…, Aghi, M. K. (2023). Single-cell RNA sequencing and spatial transcriptomics reveal cancer-associated fibroblasts in glioblastoma with protumoral effects. The Journal of Clinical Investigation, 133(5), e147087. https://​doi.​org/​10.​1172/​JCI147087
83.
88.
go back to reference Zou, Z., Lin, Z., Wu, C., Tan, J., Zhang, J., Peng, Y. ,…, Zhang, Y. (2023). Micro-engineered organoid-on-a-chip based on mesenchymal stromal cells to predict immunotherapy responses of HCC patients. Advanced Science (Weinheim, Baden-Wurttemberg, Germany), 10(27), e2302640. https://doi.org/10.1002/advs.202302640 Zou, Z., Lin, Z., Wu, C., Tan, J., Zhang, J., Peng, Y. ,…, Zhang, Y. (2023). Micro-engineered organoid-on-a-chip based on mesenchymal stromal cells to predict immunotherapy responses of HCC patients. Advanced Science (Weinheim, Baden-Wurttemberg, Germany), 10(27), e2302640. https://​doi.​org/​10.​1002/​advs.​202302640
93.
go back to reference Pandey, S., Lee, M., Lim, J., Park, S., Choung, Y.-H., Kim, J. E. ,…, Chung, J. H. (2023). SMO-CRISPR-mediated apoptosis in CD133-targeted cancer stem cells and tumor growth inhibition. Journal of Controlled Release: Official Journal of the Controlled Release Society, 357, 94–108. https://doi.org/10.1016/j.jconrel.2023.03.023 Pandey, S., Lee, M., Lim, J., Park, S., Choung, Y.-H., Kim, J. E. ,…, Chung, J. H. (2023). SMO-CRISPR-mediated apoptosis in CD133-targeted cancer stem cells and tumor growth inhibition. Journal of Controlled Release: Official Journal of the Controlled Release Society, 357, 94–108. https://​doi.​org/​10.​1016/​j.​jconrel.​2023.​03.​023
94.
go back to reference Zhao, R., He, B., Bie, Q., Cao, J., Lu, H., Zhang, Z. ,…, Zhang, B. (2022). AQP5 complements LGR5 to determine the fates of gastric cancer stem cells through regulating ULK1 ubiquitination. Journal of Experimental & Clinical Cancer Research: CR, 41(1), 322. https://doi.org/10.1186/s13046-022-02532-w Zhao, R., He, B., Bie, Q., Cao, J., Lu, H., Zhang, Z. ,…, Zhang, B. (2022). AQP5 complements LGR5 to determine the fates of gastric cancer stem cells through regulating ULK1 ubiquitination. Journal of Experimental & Clinical Cancer Research: CR, 41(1), 322. https://​doi.​org/​10.​1186/​s13046-022-02532-w
98.
go back to reference Hu, J. L., Wang, W., Lan, X. L., Zeng, Z. C., Liang, Y. S., Yan, Y. R. ,…, Liang, L. (2019). CAFs secreted exosomes promote metastasis and chemotherapy resistance by enhancing cell stemness and epithelial-mesenchymal transition in colorectal cancer. Molecular Cancer, 18(1), 91. https://doi.org/10.1186/s12943-019-1019-x Hu, J. L., Wang, W., Lan, X. L., Zeng, Z. C., Liang, Y. S., Yan, Y. R. ,…, Liang, L. (2019). CAFs secreted exosomes promote metastasis and chemotherapy resistance by enhancing cell stemness and epithelial-mesenchymal transition in colorectal cancer. Molecular Cancer, 18(1), 91. https://​doi.​org/​10.​1186/​s12943-019-1019-x
99.
go back to reference Lin, Y., Cai, Q., Chen, Y., Shi, T., Liu, W., Mao, L. ,…, He, R. (2022). CAFs shape myeloid-derived suppressor cells to promote stemness of intrahepatic cholangiocarcinoma through 5-lipoxygenase. Hepatology (Baltimore, Md.), 75(1), 28–42. https://doi.org/10.1002/hep.32099 Lin, Y., Cai, Q., Chen, Y., Shi, T., Liu, W., Mao, L. ,…, He, R. (2022). CAFs shape myeloid-derived suppressor cells to promote stemness of intrahepatic cholangiocarcinoma through 5-lipoxygenase. Hepatology (Baltimore, Md.), 75(1), 28–42. https://​doi.​org/​10.​1002/​hep.​32099
105.
go back to reference Orimo, A., Gupta, P. B., Sgroi, D. C., Arenzana-Seisdedos, F., Delaunay, T., Naeem, R. ,…, Weinberg, R. A. (2005). Stromal fibroblasts present in invasive human breast carcinomas promote tumor growth and angiogenesis through elevated SDF-1/CXCL12 secretion. Cell, 121(3), 335–348. https://doi.org/10.1016/j.cell.2005.02.034 Orimo, A., Gupta, P. B., Sgroi, D. C., Arenzana-Seisdedos, F., Delaunay, T., Naeem, R. ,…, Weinberg, R. A. (2005). Stromal fibroblasts present in invasive human breast carcinomas promote tumor growth and angiogenesis through elevated SDF-1/CXCL12 secretion. Cell, 121(3), 335–348. https://​doi.​org/​10.​1016/​j.​cell.​2005.​02.​034
109.
114.
go back to reference Li, M., Zhang, X., Wang, M., Wang, Y., Qian, J., Xing, X. ,…, Ren, Z. (2022). Activation of Piezo1 contributes to matrix stiffness-induced angiogenesis in hepatocellular carcinoma. Cancer Communications (London, England), 42(11), 1162–1184. https://doi.org/10.1002/cac2.12364 Li, M., Zhang, X., Wang, M., Wang, Y., Qian, J., Xing, X. ,…, Ren, Z. (2022). Activation of Piezo1 contributes to matrix stiffness-induced angiogenesis in hepatocellular carcinoma. Cancer Communications (London, England), 42(11), 1162–1184. https://​doi.​org/​10.​1002/​cac2.​12364
117.
go back to reference Kugeratski, F. G., Atkinson, S. J., Neilson, L. J., Lilla, S., Knight, J. R. P., Serneels, J. ,…, Zanivan, S. (2019). Hypoxic cancer-associated fibroblasts increase NCBP2-AS2/HIAR to promote endothelial sprouting through enhanced VEGF signaling. Science Signaling, 12(567), eaan8247. https://doi.org/10.1126/scisignal.aan8247 Kugeratski, F. G., Atkinson, S. J., Neilson, L. J., Lilla, S., Knight, J. R. P., Serneels, J. ,…, Zanivan, S. (2019). Hypoxic cancer-associated fibroblasts increase NCBP2-AS2/HIAR to promote endothelial sprouting through enhanced VEGF signaling. Science Signaling, 12(567), eaan8247. https://​doi.​org/​10.​1126/​scisignal.​aan8247
118.
121.
122.
go back to reference Desbois, M., Udyavar, A. R., Ryner, L., Kozlowski, C., Guan, Y., Dürrbaum, M. ,…, Wang, Y. (2020). Integrated digital pathology and transcriptome analysis identifies molecular mediators of T-cell exclusion in ovarian cancer. Nature Communications, 11(1), 5583. https://doi.org/10.1038/s41467-020-19408-2 Desbois, M., Udyavar, A. R., Ryner, L., Kozlowski, C., Guan, Y., Dürrbaum, M. ,…, Wang, Y. (2020). Integrated digital pathology and transcriptome analysis identifies molecular mediators of T-cell exclusion in ovarian cancer. Nature Communications, 11(1), 5583. https://​doi.​org/​10.​1038/​s41467-020-19408-2
125.
126.
go back to reference Ene–Obong, A., Clear, A. J., Watt, J., Wang, J., Fatah, R., Riches, J. C. ,…, Kocher, H. M. (2013). Activated pancreatic stellate cells sequester cd8+ t cells to reduce their infiltration of the juxtatumoral compartment of pancreatic ductal adenocarcinoma. Gastroenterology, 145(5), 1121–1132. https://doi.org/10.1053/j.gastro.2013.07.025 Ene–Obong, A., Clear, A. J., Watt, J., Wang, J., Fatah, R., Riches, J. C. ,…, Kocher, H. M. (2013). Activated pancreatic stellate cells sequester cd8+ t cells to reduce their infiltration of the juxtatumoral compartment of pancreatic ductal adenocarcinoma. Gastroenterology, 145(5), 1121–1132. https://​doi.​org/​10.​1053/​j.​gastro.​2013.​07.​025
127.
go back to reference Li, X., Sun, Z., Peng, G., Xiao, Y., Guo, J., Wu, B. ,…, Wang, X. (2022). Single-cell RNA sequencing reveals a pro-invasive cancer-associated fibroblast subgroup associated with poor clinical outcomes in patients with gastric cancer. Theranostics, 12(2), 620–638. https://doi.org/10.7150/thno.60540 Li, X., Sun, Z., Peng, G., Xiao, Y., Guo, J., Wu, B. ,…, Wang, X. (2022). Single-cell RNA sequencing reveals a pro-invasive cancer-associated fibroblast subgroup associated with poor clinical outcomes in patients with gastric cancer. Theranostics, 12(2), 620–638. https://​doi.​org/​10.​7150/​thno.​60540
128.
go back to reference Cheng, Y., Li, H., Deng, Y., Tai, Y., Zeng, K., Zhang, Y. ,…, Yang, Y. (2018). Cancer-associated fibroblasts induce PDL1+ neutrophils through the IL6-STAT3 pathway that foster immune suppression in hepatocellular carcinoma. Cell Death & Disease, 9(4), 422. https://doi.org/10.1038/s41419-018-0458-4 Cheng, Y., Li, H., Deng, Y., Tai, Y., Zeng, K., Zhang, Y. ,…, Yang, Y. (2018). Cancer-associated fibroblasts induce PDL1+ neutrophils through the IL6-STAT3 pathway that foster immune suppression in hepatocellular carcinoma. Cell Death & Disease, 9(4), 422. https://​doi.​org/​10.​1038/​s41419-018-0458-4
129.
go back to reference Kato, T., Noma, K., Ohara, T., Kashima, H., Katsura, Y., Sato, H. ,…, Fujiwara, T. (2018). Cancer-associated fibroblasts affect intratumoral CD8+ and FoxP3+ T cells via IL6 in the tumor microenvironment. Clinical Cancer Research: An Official Journal of the American Association for Cancer Research, 24(19), 4820–4833. https://doi.org/10.1158/1078-0432.CCR-18-0205 Kato, T., Noma, K., Ohara, T., Kashima, H., Katsura, Y., Sato, H. ,…, Fujiwara, T. (2018). Cancer-associated fibroblasts affect intratumoral CD8+ and FoxP3+ T cells via IL6 in the tumor microenvironment. Clinical Cancer Research: An Official Journal of the American Association for Cancer Research, 24(19), 4820–4833. https://​doi.​org/​10.​1158/​1078-0432.​CCR-18-0205
133.
go back to reference Jaworska, M., Szczudło, J., Pietrzyk, A., Shah, J., Trojan, S. E., Ostrowska, B., & Kocemba-Pilarczyk, K. A. (2023). The Warburg effect: A score for many instruments in the concert of cancer and cancer niche cells. Pharmacological reports: PR. https://doi.org/10.1007/s43440-023-00504-1 Jaworska, M., Szczudło, J., Pietrzyk, A., Shah, J., Trojan, S. E., Ostrowska, B., & Kocemba-Pilarczyk, K. A. (2023). The Warburg effect: A score for many instruments in the concert of cancer and cancer niche cells. Pharmacological reports: PR. https://​doi.​org/​10.​1007/​s43440-023-00504-1
134.
go back to reference Mao, X., Wong, S. Y. S., Tse, E. Y. T., Ko, F. C. F., Tey, S. K., Yeung, Y. S. ,…, Yam, J. W. P. (2016). Mechanisms through which hypoxia-induced caveolin-1 drives tumorigenesis and metastasis in hepatocellular carcinoma. Cancer Research, 76(24), 7242–7253. https://doi.org/10.1158/0008-5472.CAN-16-1031 Mao, X., Wong, S. Y. S., Tse, E. Y. T., Ko, F. C. F., Tey, S. K., Yeung, Y. S. ,…, Yam, J. W. P. (2016). Mechanisms through which hypoxia-induced caveolin-1 drives tumorigenesis and metastasis in hepatocellular carcinoma. Cancer Research, 76(24), 7242–7253. https://​doi.​org/​10.​1158/​0008-5472.​CAN-16-1031
135.
139.
go back to reference Zhang, T., Li, X., He, Y., Wang, Y., Shen, J., Wang, S. ,…, Shen, L. (2022). Cancer-associated fibroblasts-derived HAPLN1 promotes tumour invasion through extracellular matrix remodeling in gastric cancer. Gastric Cancer: Official Journal of the International Gastric Cancer Association and the Japanese Gastric Cancer Association, 25(2), 346–359. https://doi.org/10.1007/s10120-021-01259-5 Zhang, T., Li, X., He, Y., Wang, Y., Shen, J., Wang, S. ,…, Shen, L. (2022). Cancer-associated fibroblasts-derived HAPLN1 promotes tumour invasion through extracellular matrix remodeling in gastric cancer. Gastric Cancer: Official Journal of the International Gastric Cancer Association and the Japanese Gastric Cancer Association, 25(2), 346–359. https://​doi.​org/​10.​1007/​s10120-021-01259-5
140.
go back to reference Sakamoto, H., Koma, Y.-I., Higashino, N., Kodama, T., Tanigawa, K., Shimizu, M. ,…, Yokozaki, H. (2021). PAI-1 derived from cancer-associated fibroblasts in esophageal squamous cell carcinoma promotes the invasion of cancer cells and the migration of macrophages. Laboratory Investigation; a Journal of Technical Methods and Pathology, 101(3), 353–368. https://doi.org/10.1038/s41374-020-00512-2 Sakamoto, H., Koma, Y.-I., Higashino, N., Kodama, T., Tanigawa, K., Shimizu, M. ,…, Yokozaki, H. (2021). PAI-1 derived from cancer-associated fibroblasts in esophageal squamous cell carcinoma promotes the invasion of cancer cells and the migration of macrophages. Laboratory Investigation; a Journal of Technical Methods and Pathology, 101(3), 353–368. https://​doi.​org/​10.​1038/​s41374-020-00512-2
141.
go back to reference Sun, L.-P., Xu, K., Cui, J., Yuan, D.-Y., Zou, B., Li, J. ,…, Zhang, B. (2019). Cancer‑associated fibroblast‑derived exosomal miR‑382‑5p promotes the migration and invasion of oral squamous cell carcinoma. Oncology Reports, 42(4), 1319–1328. https://doi.org/10.3892/or.2019.7255 Sun, L.-P., Xu, K., Cui, J., Yuan, D.-Y., Zou, B., Li, J. ,…, Zhang, B. (2019). Cancer‑associated fibroblast‑derived exosomal miR‑382‑5p promotes the migration and invasion of oral squamous cell carcinoma. Oncology Reports, 42(4), 1319–1328. https://​doi.​org/​10.​3892/​or.​2019.​7255
142.
go back to reference Yan, Z., Sheng, Z., Zheng, Y., Feng, R., Xiao, Q., Shi, L. ,…, Zhang, B. (2021). Cancer-associated fibroblast-derived exosomal miR-18b promotes breast cancer invasion and metastasis by regulating TCEAL7. Cell Death & Disease, 12(12), 1120. https://doi.org/10.1038/s41419-021-04409-w Yan, Z., Sheng, Z., Zheng, Y., Feng, R., Xiao, Q., Shi, L. ,…, Zhang, B. (2021). Cancer-associated fibroblast-derived exosomal miR-18b promotes breast cancer invasion and metastasis by regulating TCEAL7. Cell Death & Disease, 12(12), 1120. https://​doi.​org/​10.​1038/​s41419-021-04409-w
143.
144.
go back to reference Wei, S. C., Fattet, L., Tsai, J. H., Guo, Y., Pai, V. H., Majeski, H. E. ,…, Yang, J. (2015). Matrix stiffness drives epithelial-mesenchymal transition and tumour metastasis through a TWIST1-G3BP2 mechanotransduction pathway. Nature Cell Biology, 17(5), 678–688. https://doi.org/10.1038/ncb3157 Wei, S. C., Fattet, L., Tsai, J. H., Guo, Y., Pai, V. H., Majeski, H. E. ,…, Yang, J. (2015). Matrix stiffness drives epithelial-mesenchymal transition and tumour metastasis through a TWIST1-G3BP2 mechanotransduction pathway. Nature Cell Biology, 17(5), 678–688. https://​doi.​org/​10.​1038/​ncb3157
145.
go back to reference Labernadie, A., Kato, T., Brugués, A., Serra-Picamal, X., Derzsi, S., Arwert, E. ,…, Trepat, X. (2017). A mechanically active heterotypic E-cadherin/N-cadherin adhesion enables fibroblasts to drive cancer cell invasion. Nature Cell Biology, 19(3), 224–237. https://doi.org/10.1038/ncb3478 Labernadie, A., Kato, T., Brugués, A., Serra-Picamal, X., Derzsi, S., Arwert, E. ,…, Trepat, X. (2017). A mechanically active heterotypic E-cadherin/N-cadherin adhesion enables fibroblasts to drive cancer cell invasion. Nature Cell Biology, 19(3), 224–237. https://​doi.​org/​10.​1038/​ncb3478
146.
go back to reference Erdogan, B., Ao, M., White, L. M., Means, A. L., Brewer, B. M., Yang, L. ,…, Webb, D. J. (2017). Cancer-associated fibroblasts promote directional cancer cell migration by aligning fibronectin. The Journal of Cell Biology, 216(11), 3799–3816. https://doi.org/10.1083/jcb.201704053 Erdogan, B., Ao, M., White, L. M., Means, A. L., Brewer, B. M., Yang, L. ,…, Webb, D. J. (2017). Cancer-associated fibroblasts promote directional cancer cell migration by aligning fibronectin. The Journal of Cell Biology, 216(11), 3799–3816. https://​doi.​org/​10.​1083/​jcb.​201704053
147.
go back to reference Sabeh, F., Ota, I., Holmbeck, K., Birkedal-Hansen, H., Soloway, P., Balbin, M. ,…, Weiss, S. J. (2004). Tumor cell traffic through the extracellular matrix is controlled by the membrane-anchored collagenase MT1-MMP. The Journal of Cell Biology, 167(4), 769–781. https://doi.org/10.1083/jcb.200408028 Sabeh, F., Ota, I., Holmbeck, K., Birkedal-Hansen, H., Soloway, P., Balbin, M. ,…, Weiss, S. J. (2004). Tumor cell traffic through the extracellular matrix is controlled by the membrane-anchored collagenase MT1-MMP. The Journal of Cell Biology, 167(4), 769–781. https://​doi.​org/​10.​1083/​jcb.​200408028
150.
go back to reference Wu, D., Deng, S., Li, L., Liu, T., Zhang, T., Li, J. ,…, Xu, Y. (2021). TGF-β1-mediated exosomal lnc-MMP2–2 increases blood-brain barrier permeability via the miRNA-1207–5p/EPB41L5 axis to promote non-small cell lung cancer brain metastasis. Cell Death & Disease, 12(8), 721. https://doi.org/10.1038/s41419-021-04004-z Wu, D., Deng, S., Li, L., Liu, T., Zhang, T., Li, J. ,…, Xu, Y. (2021). TGF-β1-mediated exosomal lnc-MMP2–2 increases blood-brain barrier permeability via the miRNA-1207–5p/EPB41L5 axis to promote non-small cell lung cancer brain metastasis. Cell Death & Disease, 12(8), 721. https://​doi.​org/​10.​1038/​s41419-021-04004-z
152.
go back to reference Wei, W.-F., Chen, X.-J., Liang, L.-J., Yu, L., Wu, X.-G., Zhou, C.-F. ,…, Wang, W. (2021). Periostin+ cancer-associated fibroblasts promote lymph node metastasis by impairing the lymphatic endothelial barriers in cervical squamous cell carcinoma. Molecular Oncology, 15(1), 210–227. https://doi.org/10.1002/1878-0261.12837 Wei, W.-F., Chen, X.-J., Liang, L.-J., Yu, L., Wu, X.-G., Zhou, C.-F. ,…, Wang, W. (2021). Periostin+ cancer-associated fibroblasts promote lymph node metastasis by impairing the lymphatic endothelial barriers in cervical squamous cell carcinoma. Molecular Oncology, 15(1), 210–227. https://​doi.​org/​10.​1002/​1878-0261.​12837
154.
155.
go back to reference Sharma, U., Medina-Saenz, K., Miller, P. C., Troness, B., Spartz, A., Sandoval-Leon, A. ,…, El-Ashry, D. (2021). Heterotypic clustering of circulating tumor cells and circulating cancer-associated fibroblasts facilitates breast cancer metastasis. Breast Cancer Research and Treatment, 189(1), 63–80. https://doi.org/10.1007/s10549-021-06299-0 Sharma, U., Medina-Saenz, K., Miller, P. C., Troness, B., Spartz, A., Sandoval-Leon, A. ,…, El-Ashry, D. (2021). Heterotypic clustering of circulating tumor cells and circulating cancer-associated fibroblasts facilitates breast cancer metastasis. Breast Cancer Research and Treatment, 189(1), 63–80. https://​doi.​org/​10.​1007/​s10549-021-06299-0
156.
go back to reference Hurtado, P., Martínez-Pena, I., Yepes-Rodríguez, S., Bascoy-Otero, M., Abuín, C., Fernández-Santiago, C. ,…, Piñeiro, R. (2023). Modelling metastasis in zebrafish unveils regulatory interactions of cancer-associated fibroblasts with circulating tumour cells. Frontiers in Cell and Developmental Biology, 11, 1076432. https://doi.org/10.3389/fcell.2023.1076432 Hurtado, P., Martínez-Pena, I., Yepes-Rodríguez, S., Bascoy-Otero, M., Abuín, C., Fernández-Santiago, C. ,…, Piñeiro, R. (2023). Modelling metastasis in zebrafish unveils regulatory interactions of cancer-associated fibroblasts with circulating tumour cells. Frontiers in Cell and Developmental Biology, 11, 1076432. https://​doi.​org/​10.​3389/​fcell.​2023.​1076432
157.
158.
go back to reference Zeng, H., Hou, Y., Zhou, X., Lang, L., Luo, H., Sun, Y. ,…, Liu, M. (2022). Cancer-associated fibroblasts facilitate premetastatic niche formation through lncRNA SNHG5-mediated angiogenesis and vascular permeability in breast cancer. Theranostics, 12(17), 7351–7370. https://doi.org/10.7150/thno.74753 Zeng, H., Hou, Y., Zhou, X., Lang, L., Luo, H., Sun, Y. ,…, Liu, M. (2022). Cancer-associated fibroblasts facilitate premetastatic niche formation through lncRNA SNHG5-mediated angiogenesis and vascular permeability in breast cancer. Theranostics, 12(17), 7351–7370. https://​doi.​org/​10.​7150/​thno.​74753
159.
go back to reference Kong, J., Tian, H., Zhang, F., Zhang, Z., Li, J., Liu, X. ,…, Liu, T. (2019). Extracellular vesicles of carcinoma-associated fibroblasts creates a pre-metastatic niche in the lung through activating fibroblasts. Molecular Cancer, 18(1), 175. https://doi.org/10.1186/s12943-019-1101-4 Kong, J., Tian, H., Zhang, F., Zhang, Z., Li, J., Liu, X. ,…, Liu, T. (2019). Extracellular vesicles of carcinoma-associated fibroblasts creates a pre-metastatic niche in the lung through activating fibroblasts. Molecular Cancer, 18(1), 175. https://​doi.​org/​10.​1186/​s12943-019-1101-4
160.
go back to reference Pein, M., Insua-Rodríguez, J., Hongu, T., Riedel, A., Meier, J., Wiedmann, L. ,…, Oskarsson, T. (2020). Metastasis-initiating cells induce and exploit a fibroblast niche to fuel malignant colonization of the lungs. Nature Communications, 11(1), 1494. https://doi.org/10.1038/s41467-020-15188-x Pein, M., Insua-Rodríguez, J., Hongu, T., Riedel, A., Meier, J., Wiedmann, L. ,…, Oskarsson, T. (2020). Metastasis-initiating cells induce and exploit a fibroblast niche to fuel malignant colonization of the lungs. Nature Communications, 11(1), 1494. https://​doi.​org/​10.​1038/​s41467-020-15188-x
161.
go back to reference Ji, Q., Zhou, L., Sui, H., Yang, L., Wu, X., Song, Q. ,…, Li, Q. (2020). Primary tumors release ITGBL1-rich extracellular vesicles to promote distal metastatic tumor growth through fibroblast-niche formation. Nature Communications, 11(1), 1211. https://doi.org/10.1038/s41467-020-14869-x Ji, Q., Zhou, L., Sui, H., Yang, L., Wu, X., Song, Q. ,…, Li, Q. (2020). Primary tumors release ITGBL1-rich extracellular vesicles to promote distal metastatic tumor growth through fibroblast-niche formation. Nature Communications, 11(1), 1211. https://​doi.​org/​10.​1038/​s41467-020-14869-x
164.
go back to reference Lu, Y., Jin, Z., Hou, J., Wu, X., Yu, Z., Yao, L. ,…, Su, L. (2023). Calponin 1 increases cancer-associated fibroblasts-mediated matrix stiffness to promote chemoresistance in gastric cancer. Matrix Biology: Journal of the International Society for Matrix Biology, 115, 1–15. https://doi.org/10.1016/j.matbio.2022.11.005 Lu, Y., Jin, Z., Hou, J., Wu, X., Yu, Z., Yao, L. ,…, Su, L. (2023). Calponin 1 increases cancer-associated fibroblasts-mediated matrix stiffness to promote chemoresistance in gastric cancer. Matrix Biology: Journal of the International Society for Matrix Biology, 115, 1–15. https://​doi.​org/​10.​1016/​j.​matbio.​2022.​11.​005
166.
go back to reference Uchihara, T., Miyake, K., Yonemura, A., Komohara, Y., Itoyama, R., Koiwa, M. ,…, Ishimoto, T. (2020). Extracellular vesicles from cancer-associated fibroblasts containing annexin A6 induces FAK-YAP activation by stabilizing β1 integrin, enhancing drug resistance. Cancer Research, 80(16), 3222–3235. https://doi.org/10.1158/0008-5472.CAN-19-3803 Uchihara, T., Miyake, K., Yonemura, A., Komohara, Y., Itoyama, R., Koiwa, M. ,…, Ishimoto, T. (2020). Extracellular vesicles from cancer-associated fibroblasts containing annexin A6 induces FAK-YAP activation by stabilizing β1 integrin, enhancing drug resistance. Cancer Research, 80(16), 3222–3235. https://​doi.​org/​10.​1158/​0008-5472.​CAN-19-3803
167.
go back to reference Sansone, P., Savini, C., Kurelac, I., Chang, Q., Amato, L. B., Strillacci, A. ,…, Bromberg, J. (2017). Packaging and transfer of mitochondrial DNA via exosomes regulate escape from dormancy in hormonal therapy-resistant breast cancer. Proceedings of the National Academy of Sciences of the United States of America, 114(43), E9066–E9075. https://doi.org/10.1073/pnas.1704862114 Sansone, P., Savini, C., Kurelac, I., Chang, Q., Amato, L. B., Strillacci, A. ,…, Bromberg, J. (2017). Packaging and transfer of mitochondrial DNA via exosomes regulate escape from dormancy in hormonal therapy-resistant breast cancer. Proceedings of the National Academy of Sciences of the United States of America, 114(43), E9066–E9075. https://​doi.​org/​10.​1073/​pnas.​1704862114
168.
go back to reference Chen, X., Zhao, J., Herjan, T., Hong, L., Liao, Y., Liu, C. ,…, Li, X. (2022). IL-17-induced HIF1α drives resistance to anti-PD-L1 via fibroblast-mediated immune exclusion. The Journal of Experimental Medicine, 219(6), e20210693. https://doi.org/10.1084/jem.20210693 Chen, X., Zhao, J., Herjan, T., Hong, L., Liao, Y., Liu, C. ,…, Li, X. (2022). IL-17-induced HIF1α drives resistance to anti-PD-L1 via fibroblast-mediated immune exclusion. The Journal of Experimental Medicine, 219(6), e20210693. https://​doi.​org/​10.​1084/​jem.​20210693
169.
go back to reference Ostermann, E., Garin-Chesa, P., Heider, K. H., Kalat, M., Lamche, H., Puri, C. ,…, Adolf, G. R. (2008). Effective immunoconjugate therapy in cancer models targeting a serine protease of tumor fibroblasts. Clinical Cancer Research: An Official Journal of the American Association for Cancer Research, 14(14), 4584–4592. https://doi.org/10.1158/1078-0432.CCR-07-5211 Ostermann, E., Garin-Chesa, P., Heider, K. H., Kalat, M., Lamche, H., Puri, C. ,…, Adolf, G. R. (2008). Effective immunoconjugate therapy in cancer models targeting a serine protease of tumor fibroblasts. Clinical Cancer Research: An Official Journal of the American Association for Cancer Research, 14(14), 4584–4592. https://​doi.​org/​10.​1158/​1078-0432.​CCR-07-5211
173.
go back to reference Bhattacharjee, S., Hamberger, F., Ravichandra, A., Miller, M., Nair, A., Affo, S. ,…, Schwabe, R. F. (2021). Tumor restriction by type I collagen opposes tumor-promoting effects of cancer-associated fibroblasts. The Journal of Clinical Investigation, 131(11), e146987, 146987. https://doi.org/10.1172/JCI146987 Bhattacharjee, S., Hamberger, F., Ravichandra, A., Miller, M., Nair, A., Affo, S. ,…, Schwabe, R. F. (2021). Tumor restriction by type I collagen opposes tumor-promoting effects of cancer-associated fibroblasts. The Journal of Clinical Investigation, 131(11), e146987, 146987. https://​doi.​org/​10.​1172/​JCI146987
175.
go back to reference Özdemir, B. C., Pentcheva-Hoang, T., Carstens, J. L., Zheng, X., Wu, C.-C., Simpson, T. R. ,…, Kalluri, R. (2014). Depletion of carcinoma-associated fibroblasts and fibrosis induces immunosuppression and accelerates pancreas cancer with reduced survival. Cancer Cell, 25(6), 719–734. https://doi.org/10.1016/j.ccr.2014.04.005 Özdemir, B. C., Pentcheva-Hoang, T., Carstens, J. L., Zheng, X., Wu, C.-C., Simpson, T. R. ,…, Kalluri, R. (2014). Depletion of carcinoma-associated fibroblasts and fibrosis induces immunosuppression and accelerates pancreas cancer with reduced survival. Cancer Cell, 25(6), 719–734. https://​doi.​org/​10.​1016/​j.​ccr.​2014.​04.​005
179.
go back to reference Ford, K., Hanley, C. J., Mellone, M., Szyndralewiez, C., Heitz, F., Wiesel, P. ,…, Thomas, G. J. (2020). NOX4 inhibition potentiates immunotherapy by overcoming cancer-associated fibroblast-mediated CD8 T-cell Exclusion from tumors. Cancer Research, 80(9), 1846–1860. https://doi.org/10.1158/0008-5472.CAN-19-3158 Ford, K., Hanley, C. J., Mellone, M., Szyndralewiez, C., Heitz, F., Wiesel, P. ,…, Thomas, G. J. (2020). NOX4 inhibition potentiates immunotherapy by overcoming cancer-associated fibroblast-mediated CD8 T-cell Exclusion from tumors. Cancer Research, 80(9), 1846–1860. https://​doi.​org/​10.​1158/​0008-5472.​CAN-19-3158
180.
go back to reference Hanley, C. J., Mellone, M., Ford, K., Thirdborough, S. M., Mellows, T., Frampton, S. J. ,…, Thomas, G. J. (2018). Targeting the myofibroblastic cancer-associated fibroblast phenotype through inhibition of NOX4. Journal of the National Cancer Institute, 110(1), 109–120. https://doi.org/10.1093/jnci/djx121 Hanley, C. J., Mellone, M., Ford, K., Thirdborough, S. M., Mellows, T., Frampton, S. J. ,…, Thomas, G. J. (2018). Targeting the myofibroblastic cancer-associated fibroblast phenotype through inhibition of NOX4. Journal of the National Cancer Institute, 110(1), 109–120. https://​doi.​org/​10.​1093/​jnci/​djx121
181.
go back to reference Dominguez, C. X., Müller, S., Keerthivasan, S., Koeppen, H., Hung, J., Gierke, S. ,…, Turley, S. J. (2020). Single-cell RNA sequencing reveals stromal evolution into lrrc15+ myofibroblasts as a determinant of patient response to cancer immunotherapy. Cancer Discovery, 10(2), 232–253. https://doi.org/10.1158/2159-8290.CD-19-0644 Dominguez, C. X., Müller, S., Keerthivasan, S., Koeppen, H., Hung, J., Gierke, S. ,…, Turley, S. J. (2020). Single-cell RNA sequencing reveals stromal evolution into lrrc15+ myofibroblasts as a determinant of patient response to cancer immunotherapy. Cancer Discovery, 10(2), 232–253. https://​doi.​org/​10.​1158/​2159-8290.​CD-19-0644
182.
go back to reference Demetri, G. D., Luke, J. J., Hollebecque, A., Powderly, J. D., Spira, A. I., Subbiah, V., … Villalobos, V. M. (2021). First-in-human phase I study of abbv-085, an antibody-drug conjugate targeting LRRC15, in sarcomas and other advanced solid tumors. Clinical Cancer Research: An Official Journal of the American Association for Cancer Research, 27(13), 3556–3566. https://doi.org/10.1158/1078-0432.CCR-20-4513 Demetri, G. D., Luke, J. J., Hollebecque, A., Powderly, J. D., Spira, A. I., Subbiah, V., … Villalobos, V. M. (2021). First-in-human phase I study of abbv-085, an antibody-drug conjugate targeting LRRC15, in sarcomas and other advanced solid tumors. Clinical Cancer Research: An Official Journal of the American Association for Cancer Research, 27(13), 3556–3566. https://​doi.​org/​10.​1158/​1078-0432.​CCR-20-4513
183.
go back to reference Herbertz, S., Sawyer, J. S., Stauber, A. J., Gueorguieva, I., Driscoll, K. E., Estrem, S. T. ,…, Lahn, M. M. (2015). Clinical development of galunisertib (LY2157299 monohydrate), a small molecule inhibitor of transforming growth factor-beta signaling pathway. Drug Design, Development and Therapy, 9, 4479–4499. https://doi.org/10.2147/DDDT.S86621 Herbertz, S., Sawyer, J. S., Stauber, A. J., Gueorguieva, I., Driscoll, K. E., Estrem, S. T. ,…, Lahn, M. M. (2015). Clinical development of galunisertib (LY2157299 monohydrate), a small molecule inhibitor of transforming growth factor-beta signaling pathway. Drug Design, Development and Therapy, 9, 4479–4499. https://​doi.​org/​10.​2147/​DDDT.​S86621
184.
go back to reference van den Bulk, J., de Miranda, N. F. C. C., & Ten Dijke, P (2021). Therapeutic targeting of TGF-β in cancer: Hacking a master switch of immune suppression. Clinical Science (London, England: 1979), 135(1), 35–52 https://doi.org/10.1042/CS20201236 van den Bulk, J., de Miranda, N. F. C. C., & Ten Dijke, P (2021). Therapeutic targeting of TGF-β in cancer: Hacking a master switch of immune suppression. Clinical Science (London, England: 1979), 135(1), 35–52 https://​doi.​org/​10.​1042/​CS20201236
185.
go back to reference Yamazaki, T., Gunderson, A. J., Gilchrist, M., Whiteford, M., Kiely, M. X., Hayman, A. ,…, Young, K. H. (2022). Galunisertib plus neoadjuvant chemoradiotherapy in patients with locally advanced rectal cancer: A single-arm, phase 2 trial. The Lancet. Oncology, 23(9), 1189–1200. https://doi.org/10.1016/S1470-2045(22)00446-6 Yamazaki, T., Gunderson, A. J., Gilchrist, M., Whiteford, M., Kiely, M. X., Hayman, A. ,…, Young, K. H. (2022). Galunisertib plus neoadjuvant chemoradiotherapy in patients with locally advanced rectal cancer: A single-arm, phase 2 trial. The Lancet. Oncology, 23(9), 1189–1200. https://​doi.​org/​10.​1016/​S1470-2045(22)00446-6
186.
go back to reference Wei, Y., Kim, T. J., Peng, D. H., Duan, D., Gibbons, D. L., Yamauchi, M. ,…, Chapman, H. A. (2017). Fibroblast-specific inhibition of TGF-β1 signaling attenuates lung and tumor fibrosis. The Journal of Clinical Investigation, 127(10), 3675–3688. https://doi.org/10.1172/JCI94624 Wei, Y., Kim, T. J., Peng, D. H., Duan, D., Gibbons, D. L., Yamauchi, M. ,…, Chapman, H. A. (2017). Fibroblast-specific inhibition of TGF-β1 signaling attenuates lung and tumor fibrosis. The Journal of Clinical Investigation, 127(10), 3675–3688. https://​doi.​org/​10.​1172/​JCI94624
187.
go back to reference Huang, H., Zhang, Y., Gallegos, V., Sorrelle, N., Zaid, M. M., Toombs, J. ,…, Brekken, R. A. (2019). Targeting TGFβR2-mutant tumors exposes vulnerabilities to stromal TGFβ blockade in pancreatic cancer. EMBO molecular medicine, 11(11), e10515. https://doi.org/10.15252/emmm.201910515 Huang, H., Zhang, Y., Gallegos, V., Sorrelle, N., Zaid, M. M., Toombs, J. ,…, Brekken, R. A. (2019). Targeting TGFβR2-mutant tumors exposes vulnerabilities to stromal TGFβ blockade in pancreatic cancer. EMBO molecular medicine, 11(11), e10515. https://​doi.​org/​10.​15252/​emmm.​201910515
188.
go back to reference Diwanji, R., O’Brien, N. A., Choi, J. E., Nguyen, B., Laszewski, T., Grauel, A. L. ,…, Jayaraman, P. (2023). Targeting the IL1β pathway for cancer immunotherapy remodels the tumor microenvironment and enhances antitumor immune responses. Cancer Immunology Research, 11(6), 777–791. https://doi.org/10.1158/2326-6066.CIR-22-0290 Diwanji, R., O’Brien, N. A., Choi, J. E., Nguyen, B., Laszewski, T., Grauel, A. L. ,…, Jayaraman, P. (2023). Targeting the IL1β pathway for cancer immunotherapy remodels the tumor microenvironment and enhances antitumor immune responses. Cancer Immunology Research, 11(6), 777–791. https://​doi.​org/​10.​1158/​2326-6066.​CIR-22-0290
189.
go back to reference Díaz-Maroto, N. G., Garcia-Vicién, G., Polcaro, G., Bañuls, M., Albert, N., Villanueva, A., & Molleví, D. G. (2021). The blockade of tumoral IL1β-mediated signaling in normal colonic fibroblasts sensitizes tumor cells to chemotherapy and prevents inflammatory CAF activation. International Journal of Molecular Sciences, 22(9), 4960. https://doi.org/10.3390/ijms22094960CrossRefPubMedPubMedCentral Díaz-Maroto, N. G., Garcia-Vicién, G., Polcaro, G., Bañuls, M., Albert, N., Villanueva, A., & Molleví, D. G. (2021). The blockade of tumoral IL1β-mediated signaling in normal colonic fibroblasts sensitizes tumor cells to chemotherapy and prevents inflammatory CAF activation. International Journal of Molecular Sciences, 22(9), 4960. https://​doi.​org/​10.​3390/​ijms22094960CrossRefPubMedPubMedCentral
190.
go back to reference Cazet, A. S., Hui, M. N., Elsworth, B. L., Wu, S. Z., Roden, D., Chan, C.-L. ,…, Swarbrick, A. (2018). Targeting stromal remodeling and cancer stem cell plasticity overcomes chemoresistance in triple negative breast cancer. Nature Communications, 9(1), 2897. https://doi.org/10.1038/s41467-018-05220-6 Cazet, A. S., Hui, M. N., Elsworth, B. L., Wu, S. Z., Roden, D., Chan, C.-L. ,…, Swarbrick, A. (2018). Targeting stromal remodeling and cancer stem cell plasticity overcomes chemoresistance in triple negative breast cancer. Nature Communications, 9(1), 2897. https://​doi.​org/​10.​1038/​s41467-018-05220-6
191.
go back to reference Steele, N. G., Biffi, G., Kemp, S. B., Zhang, Y., Drouillard, D., Syu, L. ,…, Pasca di Magliano, M. (2021). Inhibition of hedgehog signaling alters fibroblast composition in pancreatic cancer. Clinical Cancer Research: An Official Journal of the American Association for Cancer Research, 27(7), 2023–2037. https://doi.org/10.1158/1078-0432.CCR-20-3715 Steele, N. G., Biffi, G., Kemp, S. B., Zhang, Y., Drouillard, D., Syu, L. ,…, Pasca di Magliano, M. (2021). Inhibition of hedgehog signaling alters fibroblast composition in pancreatic cancer. Clinical Cancer Research: An Official Journal of the American Association for Cancer Research, 27(7), 2023–2037. https://​doi.​org/​10.​1158/​1078-0432.​CCR-20-3715
193.
go back to reference Beauchamp, E. M., Ringer, L., Bulut, G., Sajwan, K. P., Hall, M. D., Lee, Y.-C. ,…, Uren, A. (2011). Arsenic trioxide inhibits human cancer cell growth and tumor development in mice by blocking Hedgehog/GLI pathway. The Journal of Clinical Investigation, 121(1), 148–160. https://doi.org/10.1172/JCI42874 Beauchamp, E. M., Ringer, L., Bulut, G., Sajwan, K. P., Hall, M. D., Lee, Y.-C. ,…, Uren, A. (2011). Arsenic trioxide inhibits human cancer cell growth and tumor development in mice by blocking Hedgehog/GLI pathway. The Journal of Clinical Investigation, 121(1), 148–160. https://​doi.​org/​10.​1172/​JCI42874
194.
195.
go back to reference Chen, S., Nishi, M., Morine, Y., Shimada, M., Tokunaga, T., Kashihara, H. ,…, Wada, Y. (2022). Epigallocatechin‑3‑gallate hinders metabolic coupling to suppress colorectal cancer malignancy through targeting aerobic glycolysis in cancer‑associated fibroblasts. International Journal of Oncology, 60(2), 19. https://doi.org/10.3892/ijo.2022.5309 Chen, S., Nishi, M., Morine, Y., Shimada, M., Tokunaga, T., Kashihara, H. ,…, Wada, Y. (2022). Epigallocatechin‑3‑gallate hinders metabolic coupling to suppress colorectal cancer malignancy through targeting aerobic glycolysis in cancer‑associated fibroblasts. International Journal of Oncology, 60(2), 19. https://​doi.​org/​10.​3892/​ijo.​2022.​5309
196.
go back to reference Zhang, Q., Cao, W.-S., Wang, X.-Q., Zhang, M., Lu, X.-M., Chen, J.-Q. ,…, Han, H.-Y. (2019). Genistein inhibits nasopharyngeal cancer stem cells through sonic hedgehog signaling. Phytotherapy research: PTR, 33(10), 2783–2791. https://doi.org/10.1002/ptr.6464 Zhang, Q., Cao, W.-S., Wang, X.-Q., Zhang, M., Lu, X.-M., Chen, J.-Q. ,…, Han, H.-Y. (2019). Genistein inhibits nasopharyngeal cancer stem cells through sonic hedgehog signaling. Phytotherapy research: PTR, 33(10), 2783–2791. https://​doi.​org/​10.​1002/​ptr.​6464
201.
go back to reference Zhang, Z., Yu, W., Zheng, M., Liao, X., Wang, J., Yang, D. ,…, Lu, K. P. (2019). Pin1 inhibition potently suppresses gastric cancer growth and blocks PI3K/AKT and Wnt/β-catenin oncogenic pathways. Molecular Carcinogenesis, 58(8), 1450–1464. https://doi.org/10.1002/mc.23027 Zhang, Z., Yu, W., Zheng, M., Liao, X., Wang, J., Yang, D. ,…, Lu, K. P. (2019). Pin1 inhibition potently suppresses gastric cancer growth and blocks PI3K/AKT and Wnt/β-catenin oncogenic pathways. Molecular Carcinogenesis, 58(8), 1450–1464. https://​doi.​org/​10.​1002/​mc.​23027
202.
go back to reference Kitami, K., Yoshihara, M., Tamauchi, S., Sugiyama, M., Koya, Y., Yamakita, Y. ,…, Kajiyama, H. (2022). Peritoneal restoration by repurposing vitamin D inhibits ovarian cancer dissemination via blockade of the TGF-β1/thrombospondin-1 axis. Matrix Biology: Journal of the International Society for Matrix Biology, 109, 70–90. https://doi.org/10.1016/j.matbio.2022.03.003 Kitami, K., Yoshihara, M., Tamauchi, S., Sugiyama, M., Koya, Y., Yamakita, Y. ,…, Kajiyama, H. (2022). Peritoneal restoration by repurposing vitamin D inhibits ovarian cancer dissemination via blockade of the TGF-β1/thrombospondin-1 axis. Matrix Biology: Journal of the International Society for Matrix Biology, 109, 70–90. https://​doi.​org/​10.​1016/​j.​matbio.​2022.​03.​003
204.
go back to reference Li, M., Li, G., Kiyokawa, J., Tirmizi, Z., Richardson, L. G., Ning, J. ,…, Wakimoto, H. (2020). Characterization and oncolytic virus targeting of FAP-expressing tumor-associated pericytes in glioblastoma. Acta Neuropathologica Communications, 8(1), 221. https://doi.org/10.1186/s40478-020-01096-0 Li, M., Li, G., Kiyokawa, J., Tirmizi, Z., Richardson, L. G., Ning, J. ,…, Wakimoto, H. (2020). Characterization and oncolytic virus targeting of FAP-expressing tumor-associated pericytes in glioblastoma. Acta Neuropathologica Communications, 8(1), 221. https://​doi.​org/​10.​1186/​s40478-020-01096-0
207.
go back to reference Mellone, M., Piotrowska, K., Venturi, G., James, L., Bzura, A., Lopez, M. A. ,…, Thomas, G. J. (2022). ATM regulates differentiation of myofibroblastic cancer-associated fibroblasts and can be targeted to overcome immunotherapy Resistance. Cancer Research, 82(24), 4571–4585. https://doi.org/10.1158/0008-5472.CAN-22-0435 Mellone, M., Piotrowska, K., Venturi, G., James, L., Bzura, A., Lopez, M. A. ,…, Thomas, G. J. (2022). ATM regulates differentiation of myofibroblastic cancer-associated fibroblasts and can be targeted to overcome immunotherapy Resistance. Cancer Research, 82(24), 4571–4585. https://​doi.​org/​10.​1158/​0008-5472.​CAN-22-0435
Metadata
Title
Cancer-associated fibroblasts: a versatile mediator in tumor progression, metastasis, and targeted therapy
Authors
Tianchen Guo
Junfen Xu
Publication date
11-04-2024
Publisher
Springer US
Published in
Cancer and Metastasis Reviews
Print ISSN: 0167-7659
Electronic ISSN: 1573-7233
DOI
https://doi.org/10.1007/s10555-024-10186-7
Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras
Prof. Fabrice Barlesi
Developed by: Springer Medicine