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Current Topics in Medicinal Chemistry

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ISSN (Print): 1568-0266
ISSN (Online): 1873-4294

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Review Article

Recent Progress on the Role of Fibronectin in Tumor Stromal Immunity and Immunotherapy

Author(s): Zheng Peng, Xiaolan Lv and Shigao Huang*

Volume 22, Issue 30, 2022

Published on: 27 July, 2022

Page: [2494 - 2505] Pages: 12

DOI: 10.2174/1568026622666220615152647

Price: $65

Abstract

As a major component of the stromal microenvironment of various solid tumors, the extracellular matrix (ECM) has attracted increasing attention in cancer-related studies. ECM in the tumor stroma not only provides an external barrier and framework for tumor cell adhesion and movement, but also acts as an active regulator that modulates the tumor microenvironment, including stromal immunity. Fibronectin (Fn), as a core component of the ECM, plays a key role in the assembly and remodeling of the ECM. Hence, understanding the role of Fn in the modulation of tumor stromal immunity is of great importance for cancer immunotherapy. Hence, in-depth studies on the underlying mechanisms of Fn in tumors are urgently needed to clarify the current understanding and issues and to identify new and specific targets for effective diagnosis and treatment purposes. In this review, we summarize the structure and role of Fn, its potent derivatives in tumor stromal immunity, and their biological effects and mechanisms in tumor development. In addition, we discuss the novel applications of Fn in tumor treatment. Therefore, this review can provide prospective insight into Fn immunotherapeutic applications in tumor treatment.

Keywords: Fibronectin, Extracellular matrix, Tumor, stromal immunity, Immunotherapy, Tumor development, Targeted therapy.

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[1]
Hinshaw, D.C.; Shevde, L.A. The tumor microenvironment innately modulates cancer progression. Cancer Res., 2019, 79(18), 4557-4566.
[http://dx.doi.org/10.1158/0008-5472.CAN-18-3962] [PMID: 31350295]
[2]
Murciano-Goroff, Y.R.; Warner, A.B.; Wolchok, J.D. The future of cancer immunotherapy: Microenvironment-targeting combinations. Cell Res., 2020, 30(6), 507-519.
[http://dx.doi.org/10.1038/s41422-020-0337-2] [PMID: 32467593]
[3]
Huang, J.; Zhang, L.; Wan, D.; Zhou, L.; Zheng, S.; Lin, S.; Qiao, Y. Extracellular matrix and its therapeutic potential for cancer treatment. Signal Transduct. Target. Ther., 2021, 6(1), 153.
[http://dx.doi.org/10.1038/s41392-021-00544-0] [PMID: 33888679]
[4]
Mohan, V.; Das, A.; Sagi, I. Emerging roles of ECM remodeling processes in cancer. Semin. Cancer Biol., 2020, 62, 192-200.
[http://dx.doi.org/10.1016/j.semcancer.2019.09.004] [PMID: 31518697]
[5]
Koliaraki, V.; Prados, A.; Armaka, M.; Kollias, G. The mesenchymal context in inflammation, immunity and cancer. Nat. Immunol., 2020, 21(9), 974-982.
[http://dx.doi.org/10.1038/s41590-020-0741-2] [PMID: 32747813]
[6]
Frevert, C.W.; Felgenhauer, J.; Wygrecka, M.; Nastase, M.V.; Schaefer, L. Danger-associated molecular patterns derived from the extracellular matrix provide temporal control of innate immunity. J. Histochem. Cytochem., 2018, 66(4), 213-227.
[http://dx.doi.org/10.1369/0022155417740880] [PMID: 29290139]
[7]
Kang, I.; Chang, M.Y.; Wight, T.N.; Frevert, C.W. Proteoglycans as immunomodulators of the innate immune response to lung infection. J. Histochem. Cytochem., 2018, 66(4), 241-259.
[http://dx.doi.org/10.1369/0022155417751880] [PMID: 29328866]
[8]
Thankam, F.G.; Roesch, Z.K.; Dilisio, M.F.; Radwan, M.M.; Kovilam, A.; Gross, R.M.; Agrawal, D.K. Association of inflammatory responses and ECM disorganization with HMGB1 upregulation and NLRP3 inflammasome activation in the injured rotator cuff tendon. Sci. Rep., 2018, 8(1), 8918.
[http://dx.doi.org/10.1038/s41598-018-27250-2] [PMID: 29891998]
[9]
Gordon-Weeks, A.; Yuzhalin, A.E. Cancer extracellular matrix proteins regulate tumour immunity. Cancers (Basel), 2020, 12(11), 3331.
[http://dx.doi.org/10.3390/cancers12113331] [PMID: 33187209]
[10]
Tomlin, H.; Piccinini, A.M. A complex interplay between the extracellular matrix and the innate immune response to microbial pathogens. Immunology, 2018, 155(2), 186-201.
[http://dx.doi.org/10.1111/imm.12972] [PMID: 29908065]
[11]
Wight, T.N.; Kang, I.; Evanko, S.P.; Harten, I.A.; Chang, M.Y.; Pearce, O.M.T.; Allen, C.E.; Frevert, C.W. Versican—a critical extracellular matrix regulator of immunity and inflammation. Front. Immunol., 2020, 11, 512.
[http://dx.doi.org/10.3389/fimmu.2020.00512] [PMID: 32265939]
[12]
Johansson, A.; Hamzah, J.; Ganss, R. More than a scaffold: Stromal modulation of tumor immunity. Biochim. Biophys. Acta, 2016, 1865(1), 3-13.
[http://dx.doi.org/10.1016/j.bbcan.2015.06.001]
[13]
Pan, X.; Zheng, L. Epigenetics in modulating immune functions of stromal and immune cells in the tumor microenvironment. Cell. Mol. Immunol., 2020, 17(9), 940-953.
[http://dx.doi.org/10.1038/s41423-020-0505-9] [PMID: 32699350]
[14]
Zhao, J.; Xiao, Z.; Li, T.; Chen, H.; Yuan, Y.; Wang, Y.A.; Hsiao, C-H.; Chow, D.S.; Overwijk, W.W.; Li, C. Stromal modulation reverses primary resistance to immune checkpoint blockade in pancreatic cancer. ACS Nano, 2018, 12(10), 9881-9893.
[http://dx.doi.org/10.1021/acsnano.8b02481] [PMID: 30231203]
[15]
Tjomsland, V.; Niklasson, L.; Sandström, P.; Borch, K.; Druid, H.; Bratthäll, C.; Messmer, D.; Larsson, M.; Spångeus, A. The desmoplastic stroma plays an essential role in the accumulation and modulation of infiltrated immune cells in pancreatic adenocarcinoma. Clin. Dev. Immunol., 2011, 212810.
[http://dx.doi.org/10.1155/2011/212810]
[16]
Loike, J.D.; Cao, L.; Budhu, S.; Hoffman, S.; Silverstein, S.C. Blockade of α 5 β 1 integrins reverses the inhibitory effect of tenascin on chemotaxis of human monocytes and polymorphonuclear leukocytes through three-dimensional gels of extracellular matrix proteins. J. Immunol., 2001, 166(12), 7534-7542.
[http://dx.doi.org/10.4049/jimmunol.166.12.7534] [PMID: 11390508]
[17]
Wang, Y.; Zhao, M.; Zhang, Y. Identification of fibronectin 1 (FN1) and complement component 3 (C3) as immune infiltration-related biomarkers for diabetic nephropathy using integrated bioinformatic analysis. Bioengineered, 2021, 12(1), 5386-5401.
[http://dx.doi.org/10.1080/21655979.2021.1960766] [PMID: 34424825]
[18]
Amin, A.; Mokhdomi, T.A.; Bukhari, S.; Wani, Z.; Chikan, N.A.; Shah, B.A.; Koul, A.M.; Majeed, U.; Farooq, F.; Qadri, A.; Qadri, R.A. Lung cancer cell-derived EDA-containing fibronectin induces an inflammatory response from monocytes and promotes metastatic tumor microenvironment. J. Cell. Biochem., 2021, 122(5), 562-576.
[http://dx.doi.org/10.1002/jcb.29883] [PMID: 33393138]
[19]
Silzle, T.; Kreutz, M.; Dobler, M.A.; Brockhoff, G.; Knuechel, R.; Kunz-Schughart, L.A. Tumor-associated fibroblasts recruit blood monocytes into tumor tissue. Eur. J. Immunol., 2003, 33(5), 1311-1320.
[http://dx.doi.org/10.1002/eji.200323057] [PMID: 12731056]
[20]
Silzle, T.; Randolph, G.J.; Kreutz, M.; Kunz-Schughart, L.A. The fibroblast: Sentinel cell and local immune modulator in tumor tissue. Int. J. Cancer, 2004, 108(2), 173-180.
[http://dx.doi.org/10.1002/ijc.11542] [PMID: 14639599]
[21]
Wen, Y.; Wang, C.T.; Ma, T.T.; Li, Z.Y.; Zhou, L.N.; Mu, B.; Leng, F.; Shi, H.S.; Li, Y.O.; Wei, Y.Q. Immunotherapy targeting fibroblast activation protein inhibits tumor growth and increases survival in a murine colon cancer model. Cancer Sci., 2010, 101(11), 2325-2332.
[http://dx.doi.org/10.1111/j.1349-7006.2010.01695.x] [PMID: 20804499]
[22]
Patten, J.; Wang, K. Fibronectin in development and wound healing. Adv. Drug Deliv. Rev., 2021, 170, 353-368.
[http://dx.doi.org/10.1016/j.addr.2020.09.005] [PMID: 32961203]
[23]
Ji, T.; Ding, Y.; Zhao, Y.; Wang, J.; Qin, H.; Liu, X.; Lang, J.; Zhao, R.; Zhang, Y.; Shi, J.; Tao, N.; Qin, Z.; Nie, G. Peptide assembly integration of fibroblast-targeting and cell-penetration features for enhanced antitumor drug delivery. Adv. Mater., 2015, 27(11), 1865-1873.
[http://dx.doi.org/10.1002/adma.201404715] [PMID: 25651789]
[24]
Dallas, S.L.; Chen, Q.; Sivakumar, P. Dynamics of assembly and reorganization of extracellular matrix proteins. Curr. Top. Dev. Biol., 2006, 75, 1-24.
[http://dx.doi.org/10.1016/S0070-2153(06)75001-3]
[25]
Ingham, K.C.; Brew, S.A.; Erickson, H.P. Localization of a cryptic binding site for tenascin on fibronectin. J. Biol. Chem., 2004, 279(27), 28132-28135.
[http://dx.doi.org/10.1074/jbc.M312785200] [PMID: 15123658]
[26]
Schwarzbauer, J.E.; DeSimone, D.W. Fibronectins, their fibrillogenesis, and in vivo functions. Cold Spring Harb. Perspect. Biol., 2011, 3(7), a005041.
[http://dx.doi.org/10.1101/cshperspect.a005041] [PMID: 21576254]
[27]
Sottile, J.; Hocking, D.C. Fibronectin polymerization regulates the composition and stability of extracellular matrix fibrils and cell-matrix adhesions. Mol. Biol. Cell, 2002, 13(10), 3546-3559.
[http://dx.doi.org/10.1091/mbc.e02-01-0048] [PMID: 12388756]
[28]
Sabatier, L.; Djokic, J.; Fagotto-Kaufmann, C.; Chen, M.; Annis, D.S.; Mosher, D.F.; Reinhardt, D.P. Complex contributions of fibronectin to initiation and maturation of microfibrils. Biochem. J., 2013, 456(2), 283-295.
[http://dx.doi.org/10.1042/BJ20130699] [PMID: 24070235]
[29]
Efthymiou, G.; Saint, A.; Ruff, M.; Rekad, Z.; Ciais, D.; Van Obberghen-Schilling, E. Shaping up the tumor microenvironment with cellular fibronectin. Front. Oncol., 2020, 10, 641.
[http://dx.doi.org/10.3389/fonc.2020.00641] [PMID: 32426283]
[30]
Zollinger, A.J.; Smith, M.L. Fibronectin, the extracellular glue. Matrix Biol., 2017, 60-61, 27-37.
[http://dx.doi.org/10.1016/j.matbio.2016.07.011] [PMID: 27496349]
[31]
Dalton, C.J.; Lemmon, C.A. Fibronectin: Molecular structure, fibrillar structure and mechanochemical signaling. Cells, 2021, 10(9), 2443.
[http://dx.doi.org/10.3390/cells10092443] [PMID: 34572092]
[32]
Pankov, R.; Yamada, K.M. Fibronectin at a glance. J. Cell Sci., 2002, 115(Pt 20), 3861-3863.
[http://dx.doi.org/10.1242/jcs.00059] [PMID: 12244123]
[33]
Lin, T-C.; Yang, C-H.; Cheng, L-H.; Chang, W-T.; Lin, Y-R.; Cheng, H-C. Fibronectin in cancer: Friend or foe. Cells, 2019, 9(1), 27.
[http://dx.doi.org/10.3390/cells9010027] [PMID: 31861892]
[34]
Singh, P.; Carraher, C.; Schwarzbauer, J.E. Assembly of fibronectin extracellular matrix. Annu. Rev. Cell Dev. Biol., 2010, 26(1), 397-419.
[http://dx.doi.org/10.1146/annurev-cellbio-100109-104020] [PMID: 20690820]
[35]
White, E.S.; Baralle, F.E.; Muro, A.F. New insights into form and function of fibronectin splice variants. J. Pathol., 2008, 216(1), 1-14.
[http://dx.doi.org/10.1002/path.2388]
[36]
Nicolò, G.; Salvi, S.; Oliveri, G.; Borsi, L.; Castellani, P.; Zardi, L. Expression of tenascin and of the ED-B containing oncofetal fibronectin isoform in human cancer. Cell Differ. Dev., 1990, 32(3), 401-408.
[http://dx.doi.org/10.1016/0922-3371(90)90056-3] [PMID: 1711919]
[37]
Loridon-Rosa, B.; Vielh, P.; Matsuura, H.; Clausen, H.; Cuadrado, C.; Burtin, P. Distribution of oncofetal fibronectin in human mammary tumors: Immunofluorescence study on histological sections. Cancer Res., 1990, 50(5), 1608-1612.
[PMID: 2406016]
[38]
Fei, D.; Meng, X.; Yu, W.; Yang, S.; Song, N.; Cao, Y.; Jin, S.; Dong, L.; Pan, S.; Zhao, M. Fibronectin (FN) cooperated with TLR2/TLR4 receptor to promote innate immune responses of macrophages via binding to integrin β1. Virulence, 2018, 9(1), 1588-1600.
[http://dx.doi.org/10.1080/21505594.2018.1528841] [PMID: 30272511]
[39]
Freire-de-Lima, L.; Gelfenbeyn, K.; Ding, Y.; Mandel, U.; Clausen, H.; Handa, K.; Hakomori, S.I. Involvement of O-glycosylation defining oncofetal fibronectin in epithelial-mesenchymal transition process. Proc. Natl. Acad. Sci. USA, 2011, 108(43), 17690-17695.
[http://dx.doi.org/10.1073/pnas.1115191108] [PMID: 22006308]
[40]
Park, J.; Schwarzbauer, J.E. Mammary epithelial cell interactions with fibronectin stimulate epithelial-mesenchymal transition. Oncogene, 2014, 33(13), 1649-1657.
[http://dx.doi.org/10.1038/onc.2013.118] [PMID: 23624917]
[41]
Mansilla, C.; Berraondo, P.; Durantez, M.; Martínez, M.; Casares, N.; Arribillaga, L.; Rudilla, F.; Fioravanti, J.; Lozano, T.; Villanueva, L.; Sarobe, P.; Borrás, F.; Leclerc, C.; Prieto, J.; Lasarte, J.J. Eradication of large tumors expressing human papillomavirus E7 protein by therapeutic vaccination with E7 fused to the extra domain a from fibronectin. Int. J. Cancer, 2012, 131(3), 641-651.
[http://dx.doi.org/10.1002/ijc.26412] [PMID: 21898393]
[42]
Mansilla, C.; Gorraiz, M.; Martinez, M.; Casares, N.; Arribillaga, L.; Rudilla, F.; Echeverria, I.; Riezu-Boj, J.I.; Sarobe, P.; Borrás-Cuesta, F.; Prieto, J.; Lasarte, J.J. Immunization against hepatitis C virus with a fusion protein containing the extra domain A from fibronectin and the hepatitis C virus NS3 protein. J. Hepatol., 2009, 51(3), 520-527.
[http://dx.doi.org/10.1016/j.jhep.2009.06.005] [PMID: 19596480]
[43]
Moon, C.; Han, J.R.; Park, H-J.; Hah, J.S.; Kang, J.L. Synthetic RGDS peptide attenuates lipopolysaccharide-induced pulmonary inflammation by inhibiting integrin signaled MAP kinase pathways. Respir. Res., 2009, 10(1), 18.
[http://dx.doi.org/10.1186/1465-9921-10-18] [PMID: 19272161]
[44]
Mezu-Ndubuisi, O.J.; Maheshwari, A. The role of integrins in inflammation and angiogenesis. Pediatr. Res., 2021, 89(7), 1619-1626.
[http://dx.doi.org/10.1038/s41390-020-01177-9] [PMID: 33027803]
[45]
Zhang, K.; Gao, H.; Deng, R.; Li, J. Emerging applications of nanotechnology for controlling cell-surface receptor clustering. Angew. Chem. Int. Ed. Engl., 2019, 58(15), 4790-4799.
[http://dx.doi.org/10.1002/anie.201809006] [PMID: 30328227]
[46]
Mukhopadhyay, S.; Malik, P.; Arora, S.K.; Mukherjee, T.K. Role of β1 integrins in the complication and drug resistance against lung cancer: Targeting β1 integrins to eradicate lung cancer. In: Molecular mechanisms of tumor cell resistance to chemotherapy; Springer: New York, 2013; pp. 89-108.
[http://dx.doi.org/10.1007/978-1-4614-7070-0_5]
[47]
Ishikawa, T.; Kokura, S.; Enoki, T.; Sakamoto, N.; Okayama, T.; Ideno, M.; Mineno, J.; Uno, K.; Yoshida, N.; Kamada, K.; Katada, K.; Uchiyama, K.; Handa, O.; Takagi, T.; Konishi, H.; Yagi, N.; Naito, Y.; Itoh, Y.; Yoshikawa, T. Phase I clinical trial of fibronectin CH296-stimulated T cell therapy in patients with advanced cancer. PLoS One, 2014, 9(1), e83786.
[http://dx.doi.org/10.1371/journal.pone.0083786] [PMID: 24497917]
[48]
Vaure, C.; Liu, Y. A comparative review of toll-like receptor 4 expression and functionality in different animal species. Front. Immunol., 2014, 5, 316-316.
[http://dx.doi.org/10.3389/fimmu.2014.00316] [PMID: 25071777]
[49]
Okamura, Y.; Watari, M.; Jerud, E.S.; Young, D.W.; Ishizaka, S.T.; Rose, J.; Chow, J.C.; Strauss, J.F., III The extra domain A of fibronectin activates Toll-like receptor 4. J. Biol. Chem., 2001, 276(13), 10229-10233.
[http://dx.doi.org/10.1074/jbc.M100099200] [PMID: 11150311]
[50]
Rudilla, F.; Fayolle, C.; Casares, N.; Durantez, M.; Arribillaga, L.; Lozano, T.; Villanueva, L.; Pio, R.; Sarobe, P.; Leclerc, C.; Prieto, J.; Lasarte, J.J. Combination of a TLR4 ligand and anaphylatoxin C5a for the induction of antigen-specific cytotoxic T cell responses. Vaccine, 2012, 30(18), 2848-2858.
[http://dx.doi.org/10.1016/j.vaccine.2012.02.052] [PMID: 22387222]
[51]
Malara, A.; Gruppi, C.; Abbonante, V.; Cattaneo, D.; De Marco, L.; Massa, M.; Iurlo, A.; Gianelli, U.; Balduini, C.L.; Tira, M.E.; Muro, A.F.; Chauhan, A.K.; Rosti, V.; Barosi, G.; Balduini, A. EDA fibronectin-TLR4 axis sustains megakaryocyte expansion and inflammation in bone marrow fibrosis. J. Exp. Med., 2019, 216(3), 587-604.
[http://dx.doi.org/10.1084/jem.20181074] [PMID: 30733282]
[52]
Zhu, Q.; Zou, L.; Jagavelu, K.; Simonetto, D.A.; Huebert, R.C.; Jiang, Z-D.; DuPont, H.L.; Shah, V.H. Intestinal decontamination inhibits TLR4 dependent fibronectin-mediated cross-talk between stellate cells and endothelial cells in liver fibrosis in mice. J. Hepatol., 2012, 56(4), 893-899.
[http://dx.doi.org/10.1016/j.jhep.2011.11.013] [PMID: 22173161]
[53]
Zheng, M.; Ambesi, A.; McKeown-Longo, P.J.; McKeown-Longo, P. Role of TLR4 receptor complex in the regulation of the innate immune response by Fibronectin. Cells, 2020, 9(1), 216.
[http://dx.doi.org/10.3390/cells9010216] [PMID: 31952223]
[54]
Julier, Z.; Martino, M.M.; de Titta, A.; Jeanbart, L.; Hubbell, J.A. The TLR4 agonist fibronectin extra domain A is cryptic, exposed by elastase-2; use in a fibrin matrix cancer vaccine. Sci. Rep., 2015, 5(1), 8569.
[http://dx.doi.org/10.1038/srep08569] [PMID: 25708982]
[55]
Zhang, L.; Yan, H.; Tai, Y.; Xue, Y.; Wei, Y.; Wang, K.; Zhao, Q.; Wang, S.; Kong, D.; Midgley, A.C. design and evaluation of a polypeptide that mimics the integrin binding site for eda fibronectin to block profibrotic cell activity. Int. J. Mol. Sci., 2021, 22(4), 1575.
[http://dx.doi.org/10.3390/ijms22041575] [PMID: 33557232]
[56]
Rossnagl, S.; Altrock, E.; Sens, C.; Kraft, S.; Rau, K.; Milsom, M.D.; Giese, T.; Samstag, Y.; Nakchbandi, I.A. EDA-fibronectin originating from osteoblasts inhibits the immune response against cancer. PLoS Biol., 2016, 14(9), e1002562.
[http://dx.doi.org/10.1371/journal.pbio.1002562] [PMID: 27653627]
[57]
Caldwell, R.B.; Toque, H.A.; Narayanan, S.P.; Caldwell, R.W. Arginase: An old enzyme with new tricks. Trends Pharmacol. Sci., 2015, 36(6), 395-405.
[http://dx.doi.org/10.1016/j.tips.2015.03.006] [PMID: 25930708]
[58]
Munder, M. Arginase: An emerging key player in the mammalian immune system. Br. J. Pharmacol., 2009, 158(3), 638-651.
[http://dx.doi.org/10.1111/j.1476-5381.2009.00291.x] [PMID: 19764983]
[59]
Grzywa, T.M.; Sosnowska, A.; Matryba, P.; Rydzynska, Z.; Jasinski, M.; Nowis, D.; Golab, J. Myeloid cell-derived arginase in cancer immune response. Front. Immunol., 2020, 11, 938.
[http://dx.doi.org/10.3389/fimmu.2020.00938] [PMID: 32499785]
[60]
Singh, L.; Muise, E.S.; Bhattacharya, A.; Grein, J.; Javaid, S.; Stivers, P.; Zhang, J.; Qu, Y.; Joyce-Shaikh, B.; Loboda, A.; Zhang, C.; Meehl, M.; Chiang, D.Y.; Ranganath, S.H.; Rosenzweig, M.; Brandish, P.E. ILT3 (LILRB4) promotes the immunosuppressive function of tumor-educated human monocytic myeloid-derived suppressor cells. Mol. Cancer Res., 2021, 19(4), 702-716.
[http://dx.doi.org/10.1158/1541-7786.MCR-20-0622] [PMID: 33372059]
[61]
de Goeje, P.L.; Bezemer, K.; Heuvers, M.E.; Dingemans, A.C.; Groen, H.J.; Smit, E.F.; Hoogsteden, H.C.; Hendriks, R.W.; Aerts, J.G.; Hegmans, J.P. Immunoglobulin-like transcript 3 is expressed by myeloid-derived suppressor cells and correlates with survival in patients with non-small cell lung cancer. OncoImmunology, 2015, 4(7), e1014242.
[http://dx.doi.org/10.1080/2162402X.2015.1014242] [PMID: 26140237]
[62]
Paavola, K.J.; Roda, J.M.; Lin, V.Y.; Chen, P.; O’Hollaren, K.P.; Ventura, R.; Crawley, S.C.; Li, B.; Chen, H.H.; Malmersjö, S.; Sharkov, N.A.; Horner, G.; Guo, W.; Kutach, A.K.; Mondal, K.; Zhang, Z.; Lichtman, J.S.; Song, C.; Rivera, L.B.; Liu, W.; Luo, J.; Wang, Y.; Solloway, M.J.; Allan, B.B.; Kekatpure, A.; Starck, S.R.; Haldankar, R.; Fan, B.; Chu, C.; Tang, J.; Molgora, M.; Colonna, M.; Kaplan, D.D.; Hsu, J.Y. The fibronectin-ILT3 interaction functions as a stromal checkpoint that suppresses myeloid cells. Cancer Immunol. Res., 2021, 9(11), 1283-1297.
[http://dx.doi.org/10.1158/2326-6066.CIR-21-0240] [PMID: 34426457]
[63]
Yoshida, S.; Asanoma, K.; Yagi, H.; Onoyama, I.; Hori, E.; Matsumura, Y.; Okugawa, K.; Yahata, H.; Kato, K. Fibronectin mediates activation of stromal fibroblasts by SPARC in endometrial cancer cells. BMC Cancer, 2021, 21(1), 156.
[http://dx.doi.org/10.1186/s12885-021-07875-9] [PMID: 33579227]
[64]
Munasinghe, A.; Malik, K.; Mohamedi, F.; Moaraf, S.; Kocher, H.; Jones, L.; Hill, N.J. Fibronectin acts as a molecular switch to determine SPARC function in pancreatic cancer. Cancer Lett., 2020, 477, 88-96.
[http://dx.doi.org/10.1016/j.canlet.2020.02.031] [PMID: 32113990]
[65]
Sakai, T.; Johnson, K.J.; Murozono, M.; Sakai, K.; Magnuson, M.A.; Wieloch, T.; Cronberg, T.; Isshiki, A.; Erickson, H.P.; Fässler, R. Plasma fibronectin supports neuronal survival and reduces brain injury following transient focal cerebral ischemia but is not essential for skin-wound healing and hemostasis. Nat. Med., 2001, 7(3), 324-330.
[http://dx.doi.org/10.1038/85471] [PMID: 11231631]
[66]
Jara, C.P.; Wang, O.; Paulino do Prado, T.; Ismail, A.; Fabian, F.M.; Li, H.; Velloso, L.A.; Carlson, M.A.; Burgess, W.; Lei, Y.; Velander, W.H.; Araújo, E.P. Novel fibrin-fibronectin matrix accelerates mice skin wound healing. Bioact. Mater., 2020, 5(4), 949-962.
[http://dx.doi.org/10.1016/j.bioactmat.2020.06.015] [PMID: 32671290]
[67]
Malik, G.; Knowles, L.M.; Dhir, R.; Xu, S.; Yang, S.; Ruoslahti, E.; Pilch, J. Plasma fibronectin promotes lung metastasis by contributions to fibrin clots and tumor cell invasion. Cancer Res., 2010, 70(11), 4327-4334.
[http://dx.doi.org/10.1158/0008-5472.CAN-09-3312] [PMID: 20501851]
[68]
Knowles, L.M.; Gurski, L.A.; Engel, C.; Gnarra, J.R.; Maranchie, J.K.; Pilch, J. Integrin αvβ3 and fibronectin upregulate Slug in cancer cells to promote clot invasion and metastasis. Cancer Res., 2013, 73(20), 6175-6184.
[http://dx.doi.org/10.1158/0008-5472.CAN-13-0602] [PMID: 23966293]
[69]
Frisch, S.M.; Screaton, R.A. Anoikis mechanisms. Curr. Opin. Cell Biol., 2001, 13(5), 555-562.
[http://dx.doi.org/10.1016/S0955-0674(00)00251-9] [PMID: 11544023]
[70]
Han, H.J.; Sung, J.Y.; Kim, S-H.; Yun, U-J.; Kim, H.; Jang, E-J.; Yoo, H-E.; Hong, E.K.; Goh, S-H.; Moon, A.; Lee, J.S.; Ye, S.K.; Shim, J.; Kim, Y.N. Fibronectin regulates anoikis resistance via cell aggregate formation. Cancer Lett., 2021, 508, 59-72.
[http://dx.doi.org/10.1016/j.canlet.2021.03.011] [PMID: 33771684]
[71]
Hanahan, D.; Weinberg, R.A. Hallmarks of cancer: the next generation. Cell, 2011, 144(5), 646-674.
[http://dx.doi.org/10.1016/j.cell.2011.02.013] [PMID: 21376230]
[72]
Pietras, K.; Östman, A. Hallmarks of cancer: Interactions with the tumor stroma. Exp. Cell Res., 2010, 316(8), 1324-1331.
[http://dx.doi.org/10.1016/j.yexcr.2010.02.045] [PMID: 20211171]
[73]
Vaidya, A.; Wang, H.; Qian, V.; Gilmore, H.; Lu, Z-R. Overexpression of extradomain-B fibronectin is associated with invasion of breast cancer cells. Cells, 2020, 9(8), 1826.
[http://dx.doi.org/10.3390/cells9081826] [PMID: 32756405]
[74]
Xie, J.; Sun, M.; Zhang, D.; Chen, C.; Lin, S.; Zhang, G. Fibronectin enhances tumor metastasis through B7-H3 in clear cell renal cell carcinoma. FEBS Open Bio, 2021, 11(11), 2977-2987.
[http://dx.doi.org/10.1002/2211-5463.13280] [PMID: 34431237]
[75]
Flem-Karlsen, K.; Fodstad, Ø.; Tan, M.; Nunes-Xavier, C.E. B7-H3 in cancer–beyond immune regulation. Trends Cancer, 2018, 4(6), 401-404.
[http://dx.doi.org/10.1016/j.trecan.2018.03.010] [PMID: 29860983]
[76]
Bomken, S.; Fišer, K.; Heidenreich, O.; Vormoor, J. Understanding the cancer stem cell. Br. J. Cancer, 2010, 103(4), 439-445.
[http://dx.doi.org/10.1038/sj.bjc.6605821] [PMID: 20664590]
[77]
Zhong, C.; Tao, B.; Tang, F.; Yang, X.; Peng, T.; You, J.; Xia, K.; Xia, X.; Chen, L.; Peng, L. Remodeling cancer stemness by collagen/fibronectin via the AKT and CDC42 signaling pathway crosstalk in glioma. Theranostics, 2021, 11(4), 1991-2005.
[http://dx.doi.org/10.7150/thno.50613] [PMID: 33408794]
[78]
Lukjanenko, L.; Jung, M.J.; Hegde, N.; Perruisseau-Carrier, C.; Migliavacca, E.; Rozo, M.; Karaz, S.; Jacot, G.; Schmidt, M.; Li, L.; Metairon, S.; Raymond, F.; Lee, U.; Sizzano, F.; Wilson, D.H.; Dumont, N.A.; Palini, A.; Fässler, R.; Steiner, P.; Descombes, P.; Rudnicki, M.A.; Fan, C.M.; von Maltzahn, J.; Feige, J.N.; Bentzinger, C.F. Loss of fibronectin from the aged stem cell niche affects the regenerative capacity of skeletal muscle in mice. Nat. Med., 2016, 22(8), 897-905.
[http://dx.doi.org/10.1038/nm.4126] [PMID: 27376579]
[79]
Sun, M.; Xie, J.; Zhang, D.; Chen, C.; Lin, S.; Chen, Y.; Zhang, G. B7-H3 inhibits apoptosis of gastric cancer cell by interacting with Fibronectin. J. Cancer, 2021, 12(24), 7518-7526.
[http://dx.doi.org/10.7150/jca.59263] [PMID: 35003371]
[80]
Ghura, H.; Keimer, M.; von Au, A.; Hackl, N.; Klemis, V.; Nakchbandi, I.A. Inhibition of fibronectin accumulation suppresses tumor growth. Neoplasia, 2021, 23(9), 837-850.
[http://dx.doi.org/10.1016/j.neo.2021.06.012] [PMID: 34298233]
[81]
Mahvi, D.A.; Liu, R.; Grinstaff, M.W.; Colson, Y.L.; Raut, C.P. Local cancer recurrence: the realities, challenges, and opportunities for new therapies. CA Cancer J. Clin., 2018, 68(6), 488-505.
[http://dx.doi.org/10.3322/caac.21498] [PMID: 30328620]
[82]
Sosa, M.S.; Bragado, P.; Aguirre-Ghiso, J.A. Mechanisms of disseminated cancer cell dormancy: An awakening field. Nat. Rev. Cancer, 2014, 14(9), 611-622.
[http://dx.doi.org/10.1038/nrc3793] [PMID: 25118602]
[83]
Barney, L.E.; Hall, C.L.; Schwartz, A.D.; Parks, A.N.; Sparages, C.; Galarza, S.; Platt, M.O.; Mercurio, A.M.; Peyton, S.R. Tumor cell-organized fibronectin maintenance of a dormant breast cancer population. Sci. Adv., 2020, 6(11), eaaz4157.
[http://dx.doi.org/10.1126/sciadv.aaz4157] [PMID: 32195352]
[84]
Hanahan, D.; Weinberg, R.A. The hallmarks of cancer. Cell, 2000, 100(1), 57-70.
[http://dx.doi.org/10.1016/S0092-8674(00)81683-9] [PMID: 10647931]
[85]
Wang, K.; Andresen Eguiluz, R.C.; Wu, F.; Seo, B.R.; Fischbach, C.; Gourdon, D. Stiffening and unfolding of early deposited-fibronectin increase proangiogenic factor secretion by breast cancer-associated stromal cells. Biomaterials, 2015, 54, 63-71.
[http://dx.doi.org/10.1016/j.biomaterials.2015.03.019] [PMID: 25907040]
[86]
El-Emir, E.; Dearling, J.L.; Huhalov, A.; Robson, M.P.; Boxer, G.; Neri, D.; van Dongen, G.A.; Trachsel, E.; Begent, R.H.; Pedley, R.B. Characterisation and radioimmunotherapy of L19-SIP, an anti-angiogenic antibody against the extra domain B of fibronectin, in colorectal tumour models. Br. J. Cancer, 2007, 96(12), 1862-1870.
[http://dx.doi.org/10.1038/sj.bjc.6603806] [PMID: 17519905]
[87]
Senthebane, D.A.; Jonker, T.; Rowe, A.; Thomford, N.E.; Munro, D.; Dandara, C.; Wonkam, A.; Govender, D.; Calder, B.; Soares, N.C.; Blackburn, J.M.; Parker, M.I.; Dzobo, K. The role of tumor microenvironment in chemoresistance: 3D extracellular matrices as accomplices. Int. J. Mol. Sci., 2018, 19(10), 2861.
[http://dx.doi.org/10.3390/ijms19102861] [PMID: 30241395]
[88]
Arzumanyan, A.; Reis, H.M.; Feitelson, M.A. Pathogenic mechanisms in HBV- and HCV-associated hepatocellular carcinoma. Nat. Rev. Cancer, 2013, 13(2), 123-135.
[http://dx.doi.org/10.1038/nrc3449] [PMID: 23344543]
[89]
Norton, P.A.; Reis, H.M.; Prince, S.; Larkin, J.; Pan, J.; Liu, J.; Gong, Q.; Zhu, M.; Feitelson, M.A. Activation of fibronectin gene expression by hepatitis B virus x antigen. J. Viral Hepat., 2004, 11(4), 332-341.
[http://dx.doi.org/10.1111/j.1365-2893.2004.00555.x] [PMID: 15230856]
[90]
Yang, J.; Wang, F.; Tian, L.; Su, J.; Zhu, X.; Lin, L.; Ding, X.; Wang, X.; Wang, S. Fibronectin and asialoglyprotein receptor mediate hepatitis B surface antigen binding to the cell surface. Arch. Virol., 2010, 155(6), 881-888.
[http://dx.doi.org/10.1007/s00705-010-0657-5] [PMID: 20364278]
[91]
Ren, S.; Wang, J.; Chen, T-L.; Li, H-Y.; Wan, Y-S.; Peng, N-F.; Gui, X-E.; Zhu, Y. Hepatitis B virus stimulated fibronectin facilitates viral maintenance and replication through two distinct mechanisms. PLoS One, 2016, 11(3), e0152721.
[http://dx.doi.org/10.1371/journal.pone.0152721] [PMID: 27023403]
[92]
Huijbers, E.J.M.; Ringvall, M.; Femel, J.; Kalamajski, S.; Lukinius, A.; Åbrink, M.; Hellman, L.; Olsson, A-K. Vaccination against the extra domain-B of fibronectin as a novel tumor therapy. FASEB J., 2010, 24(11), 4535-4544.
[http://dx.doi.org/10.1096/fj.10-163022] [PMID: 20634349]
[93]
Femel, J.; Huijbers, E.J.; Saupe, F.; Cedervall, J.; Zhang, L.; Roswall, P.; Larsson, E.; Olofsson, H.; Pietras, K.; Dimberg, A.; Hellman, L.; Olsson, A.K. Therapeutic vaccination against fibronectin ED-A attenuates progression of metastatic breast cancer. Oncotarget, 2014, 5(23), 12418-12427.
[http://dx.doi.org/10.18632/oncotarget.2628] [PMID: 25360764]
[94]
Sasaki, S.; Okuda, K. The use of conventional immunologic adjuvants in DNA vaccine preparations. Methods Mol. Med., 2000, 29, 241-249.
[PMID: 21374324]
[95]
Li, W.; Joshi, M.D.; Singhania, S.; Ramsey, K.H.; Murthy, A.K. Peptide vaccine: Progress and challenges. Vaccines (Basel), 2014, 2(3), 515-536.
[http://dx.doi.org/10.3390/vaccines2030515] [PMID: 26344743]
[96]
Mehanny, M.; Lehr, C-M.; Fuhrmann, G. Extracellular vesicles as antigen carriers for novel vaccination avenues. Adv. Drug Deliv. Rev., 2021, 173, 164-180.
[http://dx.doi.org/10.1016/j.addr.2021.03.016] [PMID: 33775707]
[97]
Lasarte, J.J.; Casares, N.; Gorraiz, M.; Hervás-Stubbs, S.; Arribillaga, L.; Mansilla, C.; Durantez, M.; Llopiz, D.; Sarobe, P.; Borrás-Cuesta, F.; Prieto, J.; Leclerc, C. The extra domain A from fibronectin targets antigens to TLR4-expressing cells and induces cytotoxic T cell responses in vivo. J. Immunol., 2007, 178(2), 748-756.
[http://dx.doi.org/10.4049/jimmunol.178.2.748] [PMID: 17202335]
[98]
Ludewig, B. Dendritic cell vaccination and viral infection—animal models. Curr. Top. Microbiol. Immunol., 2003, 276, 199-214.
[http://dx.doi.org/10.1007/978-3-662-06508-2_9]
[99]
Vanneman, M.; Dranoff, G. Combining immunotherapy and targeted therapies in cancer treatment. Nat. Rev. Cancer, 2012, 12(4), 237-251.
[http://dx.doi.org/10.1038/nrc3237] [PMID: 22437869]
[100]
Kujawa, K.A. Zembala-Nożyńska, E.; Cortez, A.J.; Kujawa, T.; Kupryjańczyk, J.; Lisowska, K.M. Fibronectin and periostin as prognostic markers in ovarian cancer. Cells, 2020, 9(1), 149.
[http://dx.doi.org/10.3390/cells9010149] [PMID: 31936272]
[101]
Rick, J.W.; Chandra, A.; Dalle Ore, C.; Nguyen, A.T.; Yagnik, G.; Aghi, M.K. Fibronectin in malignancy: Cancer-specific alterations, protumoral effects, and therapeutic implications. In: Seminars in oncology: 2019; Elsevier, 2019; pp. 284-290.
[http://dx.doi.org/10.1053/j.seminoncol.2019.08.002]
[102]
Ventura, E.; Weller, M.; Macnair, W.; Eschbach, K.; Beisel, C.; Cordazzo, C.; Claassen, M.; Zardi, L.; Burghardt, I. TGF-β induces oncofetal fibronectin that, in turn, modulates TGF-β superfamily signaling in endothelial cells. J. Cell Sci., 2018, 131(1), jcs209619.
[PMID: 29158223]
[103]
Rybak, J.N.; Roesli, C.; Kaspar, M.; Villa, A.; Neri, D. The extra-domain A of fibronectin is a vascular marker of solid tumors and metastases. Cancer Res., 2007, 67(22), 10948-10957.
[http://dx.doi.org/10.1158/0008-5472.CAN-07-1436] [PMID: 18006840]
[104]
Frey, K.; Schliemann, C.; Schwager, K.; Giavazzi, R.; Johannsen, M.; Neri, D. The immunocytokine F8-IL2 improves the therapeutic performance of sunitinib in a mouse model of renal cell carcinoma. J. Urol., 2010, 184(6), 2540-2548.
[http://dx.doi.org/10.1016/j.juro.2010.07.030] [PMID: 21030045]
[105]
Borsi, L.; Balza, E.; Bestagno, M.; Castellani, P.; Carnemolla, B.; Biro, A.; Leprini, A.; Sepulveda, J.; Burrone, O.; Neri, D.; Zardi, L. Selective targeting of tumoral vasculature: comparison of different formats of an antibody (L19) to the ED-B domain of fibronectin. Int. J. Cancer, 2002, 102(1), 75-85.
[http://dx.doi.org/10.1002/ijc.10662] [PMID: 12353237]
[106]
Mortara, L.; Balza, E.; Bruno, A.; Poggi, A.; Orecchia, P.; Carnemolla, B. Anti-cancer therapies employing IL-2 cytokine tumor targeting: Contribution of innate, adaptive and immunosuppressive cells in the anti-tumor efficacy. Front. Immunol., 2018, 9, 2905-2905.
[http://dx.doi.org/10.3389/fimmu.2018.02905] [PMID: 30619269]
[107]
Moschetta, M.; Pretto, F.; Berndt, A.; Galler, K.; Richter, P.; Bassi, A.; Oliva, P.; Micotti, E.; Valbusa, G.; Schwager, K.; Kaspar, M.; Trachsel, E.; Kosmehl, H.; Bani, M.R.; Neri, D.; Giavazzi, R. Paclitaxel enhances therapeutic efficacy of the F8-IL2 immunocytokine to EDA-fibronectin-positive metastatic human melanoma xenografts. Cancer Res., 2012, 72(7), 1814-1824.
[http://dx.doi.org/10.1158/0008-5472.CAN-11-1919] [PMID: 22392081]
[108]
Fercher, C.; Keshvari, S.; McGuckin, M.A.; Barnard, R.T. Evolution of the magic bullet: Single chain antibody fragments for the targeted delivery of immunomodulatory proteins. Exp. Biol. Med. (Maywood), 2018, 243(2), 166-183.
[http://dx.doi.org/10.1177/1535370217748575] [PMID: 29256259]
[109]
Robl, B.; Botter, S.M.; Boro, A.; Meier, D.; Neri, D.; Fuchs, B. Evaluation of F8-TNF-α in models of early and progressive metastatic Osteosarcoma. Transl. Oncol., 2017, 10(3), 419-430.
[http://dx.doi.org/10.1016/j.tranon.2017.02.005] [PMID: 28448958]
[110]
Rosini, E.; Volpi, N.A.; Ziffels, B.; Grimaldi, A.; Sacchi, S.; Neri, D.; Pollegioni, L. An antibody-based enzymatic therapy for cancer treatment: The selective localization of D-amino acid oxidase to EDA fibronectin. Nanomedicine, 2021, 36, 102424.
[http://dx.doi.org/10.1016/j.nano.2021.102424] [PMID: 34174417]
[111]
Tijink, B.M.; Neri, D.; Leemans, C.R.; Budde, M.; Dinkelborg, L.M.; Stigter-van Walsum, M.; Zardi, L.; van Dongen, G.A. Radioimmunotherapy of head and neck cancer xenografts using 131I-labeled antibody L19-SIP for selective targeting of tumor vasculature. J. Nucl. Med., 2006, 47(7), 1127-1135.
[PMID: 16818947]
[112]
White, E.S.; Muro, A.F. Fibronectin splice variants: Understanding their multiple roles in health and disease using engineered mouse models. IUBMB Life, 2011, 63(7), 538-546.
[http://dx.doi.org/10.1002/iub.493] [PMID: 21698758]
[113]
Saito, S.; Yamaji, N.; Yasunaga, K.; Saito, T.; Matsumoto, S.; Katoh, M.; Kobayashi, S.; Masuho, Y. The fibronectin extra domain A activates matrix metalloproteinase gene expression by an interleukin-1-dependent mechanism. J. Biol. Chem., 1999, 274(43), 30756-30763.
[http://dx.doi.org/10.1074/jbc.274.43.30756] [PMID: 10521465]
[114]
Rick, J.W.; Chandra, A.; Dalle Ore, C.; Nguyen, A.T.; Yagnik, G.; Aghi, M.K. Fibronectin in malignancy: Cancer-specific alterations, protumoral effects, and therapeutic implications. Semin. Oncol., 2019, 46(3), 284-290.
[http://dx.doi.org/10.1053/j.seminoncol.2019.08.002] [PMID: 31488338]
[115]
Wagner, J.; Wickman, E.; Shaw, T.I.; Anido, A.A.; Langfitt, D.; Zhang, J.; Porter, S.N.; Pruett-Miller, S.M.; Tillman, H.; Krenciute, G.; Gottschalk, S. Antitumor effects of CAR T cells redirected to the EDB splice variant of fibronectin. Cancer Immunol. Res., 2021, 9(3), 279-290.
[http://dx.doi.org/10.1158/2326-6066.CIR-20-0280] [PMID: 33355188]
[116]
Lo, K-M.; Lan, Y.; Lauder, S.; Zhang, J.; Brunkhorst, B.; Qin, G.; Verma, R.; Courtenay-Luck, N.; Gillies, S.D. huBC1-IL12, an immunocytokine which targets EDB-containing oncofetal fibronectin in tumors and tumor vasculature, shows potent anti-tumor activity in human tumor models. Cancer Immunol. Immunother., 2007, 56(4), 447-457.
[http://dx.doi.org/10.1007/s00262-006-0203-1] [PMID: 16874486]
[117]
Xie, Y.J.; Dougan, M.; Jailkhani, N.; Ingram, J.; Fang, T.; Kummer, L.; Momin, N.; Pishesha, N.; Rickelt, S.; Hynes, R.O.; Ploegh, H. Nanobody-based CAR T cells that target the tumor microenvironment inhibit the growth of solid tumors in immunocompetent mice. Proc. Natl. Acad. Sci. USA, 2019, 116(16), 7624-7631.
[http://dx.doi.org/10.1073/pnas.1817147116] [PMID: 30936321]
[118]
Shaw, T.I.; Wagner, J.; Wickman, E.; Tian, L.; Li, D.; Poudel, S.; Stewart, E.; Li, Y.; Wang, H.; Niu, M. Mining cancer-specific isoforms as CAR T-cell therapy targets for pediatric solid and brain tumors Cancer Res., 2021, 81(13-Suppl.), 1543.

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