Targeting all transforming growth factor-β isoforms with an Fc chimeric receptor impairs tumor growth and angiogenesis of oral squamous cell cancer

Abstract

Tumor progression is governed by various growth factors and cytokines in the tumor microenvironment (TME). Among these, transforming growth factor-β (TGF-β) is secreted by various cell types residing in the TME and promotes tumor progression by inducing the epithelial-to-mesenchymal transition (EMT) of cancer cells and tumor angiogenesis. TGF-β comprises three isoforms, TGF-β1, -β2, and -β3, and transduces intracellular signals via TGF-β type I receptor (TβRI) and TGF-β type II receptor (TβRII). For the purpose of designing ligand traps that reduce oncogenic signaling in the TME, chimeric proteins comprising the ligand-interacting ectodomains of receptors fused with the Fc portion of immunoglobulin are often used. For example, chimeric soluble TβRII (TβRII-Fc) has been developed as an effective therapeutic strategy for targeting TGF-β ligands, but several lines of evidence indicate that TβRII-Fc more effectively traps TGF-β1 and TGF-β3 than TGF-β2, whose expression is elevated in multiple cancer types. In the present study, we developed a chimeric TGF-β receptor containing both TβRI and TβRII (TβRI-TβRII-Fc) and found that TβRI-TβRII-Fc trapped all TGF-β isoforms, leading to inhibition of both the TGF-β signal and TGF-β–induced EMT of oral cancer cells, whereas TβRII-Fc failed to trap TGF-β2. Furthermore, we found that TβRI-TβRII-Fc suppresses tumor growth and angiogenesis more effectively than TβRII-Fc in a subcutaneous xenograft model of oral cancer cells with high TGF-β expression. These results suggest that TβRI-TβRII-Fc may be a promising tool for targeting all TGF-β isoforms in the TME. Tumor progression is governed by various growth factors and cytokines in the tumor microenvironment (TME). Among these, transforming growth factor-β (TGF-β) is secreted by various cell types residing in the TME and promotes tumor progression by inducing the epithelial-to-mesenchymal transition (EMT) of cancer cells and tumor angiogenesis. TGF-β comprises three isoforms, TGF-β1, -β2, and -β3, and transduces intracellular signals via TGF-β type I receptor (TβRI) and TGF-β type II receptor (TβRII). For the purpose of designing ligand traps that reduce oncogenic signaling in the TME, chimeric proteins comprising the ligand-interacting ectodomains of receptors fused with the Fc portion of immunoglobulin are often used. For example, chimeric soluble TβRII (TβRII-Fc) has been developed as an effective therapeutic strategy for targeting TGF-β ligands, but several lines of evidence indicate that TβRII-Fc more effectively traps TGF-β1 and TGF-β3 than TGF-β2, whose expression is elevated in multiple cancer types. In the present study, we developed a chimeric TGF-β receptor containing both TβRI and TβRII (TβRI-TβRII-Fc) and found that TβRI-TβRII-Fc trapped all TGF-β isoforms, leading to inhibition of both the TGF-β signal and TGF-β–induced EMT of oral cancer cells, whereas TβRII-Fc failed to trap TGF-β2. Furthermore, we found that TβRI-TβRII-Fc suppresses tumor growth and angiogenesis more effectively than TβRII-Fc in a subcutaneous xenograft model of oral cancer cells with high TGF-β expression. These results suggest that TβRI-TβRII-Fc may be a promising tool for targeting all TGF-β isoforms in the TME. The tumor microenvironment (TME) is a complex system comprising tumor cells, stromal cells, endothelial cells, immune cells, and the extracellular matrix. The TME plays important roles during tumor progression via growth regulation and metastasis of cancer cells (1Hanahan D. Weinberg R.A. Hallmarks of cancer: the next generation.Cell. 2011; 144 (21376230): 646-67410.1016/j.cell.2011.02.013Abstract Full Text Full Text PDF PubMed Scopus (42748) Google Scholar). Recent lines of evidence have revealed that the TME composition changes during tumor progression in response to oncogenic signals from tumor cells; therefore, effective anti-tumor therapies should target not only cancer cells but also other TME components. Cells in the TME secrete various growth factors and cytokines to create a microenvironment favoring tumorigenesis. Among these factors, transforming growth factor-β (TGF-β) is secreted by various cell types residing in the TME. The pleiotropic functions of TGF-β, including not only the regulation of cell growth, differentiation, and apoptosis but also cell motility and invasion, have been widely studied (2Morikawa M. Derynck R. Miyazono K. TGF-β and the TGF-β family: context-dependent roles in cell and tissue physiology.Cold Spring Harb. Perspect. Biol. 2016; 8 (27141051): a02187310.1101/cshperspect.a021873Crossref PubMed Scopus (636) Google Scholar). Although TGF-β can function as an early-stage tumor suppressor, it may also act as a tumor promoter (3Miyazono K. Katsuno Y. Koinuma D. Ehata S. Morikawa M. Intracellular and extracellular TGF-β signaling in cancer: some recent topics.Front. Med. 2018; 12 (30043220): 387-41110.1007/s11684-018-0646-8Crossref PubMed Scopus (85) Google Scholar). TGF-β appears to create a favorable TME for cancer cells, stimulating cancer metastasis (3Miyazono K. Katsuno Y. Koinuma D. Ehata S. Morikawa M. Intracellular and extracellular TGF-β signaling in cancer: some recent topics.Front. Med. 2018; 12 (30043220): 387-41110.1007/s11684-018-0646-8Crossref PubMed Scopus (85) Google Scholar). These dual roles in tumorigenesis likely depend on an increased level of active TGF-β within the TME as well as dysregulation of TGF-β signaling pathways that leads to the reprogramming of the cellular signals that drive tumorigenesis. TGF-β comprises three isoforms, TGF-β1, -β2, and -β3. All three isoforms share high sequence similarity and essentially signal through the same receptors; however, their effects on tumorigenesis may depend on the cellular context and differences in their temporal and spatial expressions (4Heldin C.-H. Moustakas A. Signaling receptors for TGF-β family members.Cold Spring Harb. Perspect. Biol. 2016; 8 (27481709): a02205310.1101/cshperspect.a022053Crossref PubMed Scopus (351) Google Scholar). The canonical TGF-β signaling pathway relies on the activation of Smad transcription factors upon binding of TGF-βs to their transmembrane receptors: TGF-β type I receptor (TβRI) and TGF-β type II receptor (TβRII). Binding of TGF-β to TβRII stimulates phosphorylation of TβRI, leading to the activation of Smad transcription factors and expression of direct target genes (5Derynck R. Budi E.H. Specificity, versatility, and control of TGF-β family signaling.Sci. Signal. 2019; 12 (30808818): eaav518310.1126/scisignal.aav5183Crossref PubMed Scopus (313) Google Scholar). TGF-β1 and TGF-β3 bind with the high affinity to TβRII dimers in the absence of TβRI; however, TGF-β2 exhibits lower affinity for dimers formed by either TβRI or TβRII (6Baardsnes J. Hinck C.S. Hinck A.P. O'Connor-McCourt M.D. TβR-II discriminates the high- and low-affinity TGF-β isoforms via two hydrogen-bonded ion pairs.Biochemistry. 2009; 48 (19161338): 2146-215510.1021/bi8019004Crossref PubMed Scopus (43) Google Scholar, 7Ehrlich M. Gutman O. Knaus P. Henis Y.I. Oligomeric interactions of TGF-β and BMP receptors.FEBS Lett. 2012; 586 (22293501): 1885-189610.1016/j.febslet.2012.01.040Crossref PubMed Scopus (60) Google Scholar), suggesting that binding of TGF-β2 requires the of a complex the two types of these Although increased expression of all three active TGF-β isoforms has been in various including cancer Y. S. M. Y. P. tumor microenvironment via and TGF-β2 to in S. A. 2018; PubMed Scopus Google Scholar), cancer M. S. expression of isoforms in cancer roles during cancer Biol. 2018; PubMed Scopus Google Scholar), and K. M. regulation of by signaling in PubMed Scopus Google Scholar), TGF-β2 expression to be with the progression of multiple types of cancer M. A. P. K. M. 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O. of in expression of 2018; 8 PubMed Scopus Google of multiple cancer by that TGF-β2 but not TGF-β1 or TGF-β3 with of with and cell cell is a tumor of the and the cancer in the with and of oral J. 8 Google Scholar). the of with has not in recent has a to to the or other TGF-β expression has been in from with oral cancer cells to R. K. K. K. A. growth factor-β by stromal cells and cancer cells in by oral cell PubMed Scopus Google Scholar). we that TGF-β signals oral cancer cell K. Y. J. of transforming growth factor-β signals in the and tumor of cells, an oral cell 2018; Scholar), suggesting the important of TGF-β in oral cancer TGF-β the and of cancer cells via inducing a during cells their more and by to cells R.A. 2016; Full Text Full Text PDF PubMed Scopus Google Scholar). TGF-β signals the expression of various transcription factors, in expression of proteins in cell and of the cell is by increased expression of multiple genes or that results in of cell and a and in cancer cells A. C.-H. of Med. 2016; PubMed Scopus Google Scholar). targeting the TGF-β signals have been to effective anti-tumor with several P. on the of TGF-β for cancer 2019; PubMed Scopus Google Scholar). on the of targeting TGF-β to binding to a all TGF-β isoforms, has been in the of cell M. I of a growth factor-β in with or cell PubMed Scopus Google and cancer P. S. S. S. and in 2018; PubMed Scopus Google Scholar). have also been developed to TGF-β signaling by targeting the of TGF-β Among is in the of for the of and J. J. D. of a transforming growth factor-β receptor type I 2018; PubMed Scopus Google Scholar). a including cancer cell lines with TGF-β2 for the of are also in J. M. R. R. M. C.S. of an cell as for cell J. Full Text Full Text PDF PubMed Scopus Google Scholar). promising some of therapeutic or and S. P. TGF-β signaling in Full Text Full Text PDF PubMed Scopus Google Scholar). have been to ligand traps are chimeric proteins comprising the ligand-interacting ectodomains of receptors fused with Fc traps are promising that can be to reduce the of in the extracellular chimeric proteins of TGF-β have been and their for of TGF-β family in R. transforming growth factor-β ligand trap J. Med. 2016; PubMed Scopus Google Scholar, J. Y. R. of cancer and by leads to Full Text Full Text PDF PubMed Scopus Google however, their therapeutic is as trap TGF-β1 and TGF-β3 but not TGF-β2 R. transforming growth factor-β ligand trap J. Med. 2016; PubMed Scopus Google Scholar). high TGF-β2 expression is with the progression or of multiple Y. S. M. Y. P. tumor microenvironment via and TGF-β2 to in S. A. 2018; PubMed Scopus Google Scholar, M. A. P. K. M. TGF-β isoforms in cancer: expression and in tumor types with a of and PubMed Scopus Google Scholar), is a to an effective strategy to all three TGF-β TGF-β2 signaling requires the of a complex TβRI and TβRII M. Gutman O. Knaus P. Henis Y.I. Oligomeric interactions of TGF-β and BMP receptors.FEBS Lett. 2012; 586 (22293501): 1885-189610.1016/j.febslet.2012.01.040Crossref PubMed Scopus (60) Google Scholar). A. In the absence of type the transforming growth type receptor requires the type I receptor to bind Biol. Full Text Full Text PDF PubMed Scopus Google that the of cells, to a of the soluble of and TβRII-Fc TGF-β2 suggesting ligand via a of to in the effective of both ligand traps and differences in the of TGF-β receptor may not be for in these in the present study, we developed a ligand a chimeric that with all TGF-β also effective in to TGF-β signals and in to tumor growth of oral cancer cells, the chimeric Fc trap as a promising tool for the of effective that the soluble extracellular of the TGF-β type II receptor fused to the Fc portion of (TβRII-Fc) the of TGF-β1 and TGF-β3 but not TGF-β2 A. In the absence of type the transforming growth type receptor requires the type I receptor to bind Biol. Full Text Full Text PDF PubMed Scopus Google Scholar). the effects of TβRII-Fc by the of the soluble TGF-β type I receptor A. In the absence of type the transforming growth type receptor requires the type I receptor to bind Biol. Full Text Full Text PDF PubMed Scopus Google Scholar). these we expression and Fc as a control The chimeric proteins in cells and secreted as in with chimeric proteins are to trap TGF-β chimeric not with of TGF-β isoforms as with the other TβRII-Fc chimeric with TGF-β1 and TGF-β3 but not with TGF-β2. we the of various Fc chimeric proteins to TGF-β signals TGF-β The TGF-β system direct of TGF-β signaling by of secreted is the control of TGF-β cells with of the three TGF-β isoforms, TGF-β1, -β2, or -β3, the TGF-β signal as revealed by increased of TGF-βs with of cells or not the level of the TGF-β signal Although TβRII-Fc chimeric the signal by TGF-β1 and it not signals in response to the TGF-β2 results also for the of both chimeric and to TGF-β1 and TGF-β3 but not TGF-β2 signals target all TGF-β isoforms, we Fc chimeric receptors containing both TGF-β type I and II receptors and and found that the TβRI-TβRII-Fc chimeric not only with TGF-β1 and TGF-β3 but also with TGF-β2 with these TβRI-TβRII-Fc effectively the signals by all three isoforms we that of TβRI-TβRII-Fc chimeric the signals by all TGF-β isoforms, of TβRI-TβRII-Fc and not of effectively TGF-β2 but both TGF-β1 and TGF-β3 suggesting the of chimeric The also for TβRII-Fc chimeric TGF-β1 and ligands, with on TGF-β2 the that only TβRI-TβRII-Fc chimeric traps all of next studied the of the of a of the TGF-β to type I and II receptors that are from TGF-β it also signals in TGF-β be by an of TGF-β and type I receptors In of the Fc trapped suggesting that TβRI-TβRII-Fc can trap all TGF-β isoforms but not A. TGF-β2 expression is with and cancer as by we cells, an cell to TGF-β be to the extracellular of cancer cells and their response to TGF-β present in the extracellular the of chimeric proteins on TGF-β signaling in cells in from cells Fc chimeric proteins in the absence or of TGF-β1, -β2, or -β3, by an of the expression of transmembrane a direct target of TGF-β, by in increased expression in control cells with either TGF-β the of expression to the control level with the results in the TGF-β not in cells with TGF-β in the of either or the The TβRII-Fc chimeric expression by either TGF-β1 or TGF-β3 and on cells with the TGF-β2 The inhibition of signals upon with of the three isoforms only in the of the TβRI-TβRII-Fc chimeric suggesting that only TβRI-TβRII-Fc is a of all three TGF-β The of TβRI-TβRII-Fc on all three TGF-β isoforms by the of by of by of the three TGF-β isoforms only in the of TβRI-TβRII-Fc chimeric and not the other chimeric or TβRII-Fc the in oral cancer cells, we cell of and in the of TGF-β2 only upon in from cells TβRI-TβRII-Fc but not the other chimeric These results suggest that TβRI-TβRII-Fc chimeric effectively the signals by all TGF-β isoforms in multiple types of cells, whereas TβRII-Fc to TGF-β is a of EMT in various types of cancer A. C.-H. of Med. 2016; PubMed Scopus Google Scholar, Y. S. Derynck R. TGF-β signaling and transition in cancer PubMed Scopus Google Scholar), we next with of the TGF-β isoforms EMT in oral cancer cells with TGF-β or for and the expression of various and by in cells with of the three TGF-β isoforms expression of genes the and and by increased expression of the cell and suggesting that cells EMT in response to TGF-β In inhibition of TGF-β signals with increased the expression of the and the expression of and and The effects of TGF-β isoforms on the expression of and essentially the level by and and we the same of in All TGF-β isoforms the expression of The expression of by TGF-β1 and -β2, but not by TGF-β3 All TGF-β isoforms the expression of and as revealed by and essentially by and also that TGF-β–induced EMT increased the of cells, with a S. Derynck R. and in to transition is by activation of the Biol. PubMed Scopus Google Scholar). the effects of TGF-β isoforms and on the expression of and and cells, to the differences in cellular the results suggest that all TGF-β isoforms are of inducing EMT in multiple types of that all three TGF-β isoforms EMT of and oral cancer cells and we next ligand traps the EMT of oral cells by TGF-β cells or with TGF-β1, -β2, or in the of from cells or TβRI-TβRII-Fc and for the expression of and and and cells with TGF-β in containing either or proteins and expression and by of all and suggesting that chimeric the EMT of Although TβRII-Fc chimeric or EMT by changes in the expression of and and in cells, it not the EMT of cells by TGF-β2 In cells with of the three TGF-β isoforms in from cells TβRI-TβRII-Fc chimeric not with of the and and with in the control inhibition of EMT by TβRI-TβRII-Fc chimeric also by of the changes in and expression in response to various TGF-βs in the absence or of chimeric proteins with the the of expression by the of as revealed in two The of TβRII-Fc only the changes by TGF-β1 and TGF-β3 but not TGF-β2 from the TβRI-TβRII-Fc chimeric to inhibition of EMT by all TGF-β isoforms The of the TβRI-TβRII-Fc chimeric in changes in and expression also both and in the EMT of cells by of the three TGF-β isoforms only in the of the TβRI-TβRII-Fc suggesting that the TβRI-TβRII-Fc the EMT of oral cancer cells by all TGF-β TGF-β signals tumor progression in multiple types of including oral to the of TβRI-TβRII-Fc on tumor growth in we a subcutaneous xenograft model of oral cancer cells a high level of cells and TβRI-TβRII-Fc chimeric These ligand traps in cells and secreted the the of TβRI-TβRII-Fc lower than that of The of ligand traps in with the in cell suggesting that the soluble receptor traps may have via through the pathway as TGF-β receptors K. A. P. C.-H. of the in the and of J. PubMed Scopus Google Scholar). we the ligand traps with TGF-βs from the TGF-β cells in the of the cells in the absence or of and that cells secrete a level of TGF-βs whose signals are by or TβRII-Fc from the cells not to the TGF-β TGF-β signals in the of from cells the TβRI-TβRII-Fc chimeric suggesting that only the TβRI-TβRII-Fc chimeric effectively trapped TGF-β also studied the expression of TGF-β isoforms in the cells various ligand traps and found that their expression not have that TGF-β has an on cell growth Y. TGF-β family signaling in the control of cell and Spring Harb. Perspect. Biol. PubMed Scopus Google Scholar). with these we also that cells to all TGF-β isoforms and with cells cell growth the of Fc chimeric proteins by cells their cell growth by the present in the extracellular of the cell lines Fc chimeric proteins changes in with the cells the cells the Fc chimeric we their on the growth of oral in cells and TβRI-TβRII-Fc chimeric proteins the of and the to for 8 in tumor formed from cells or cells TβRII-Fc or TβRI-TβRII-Fc chimeric proteins formed with for other chimeric proteins Furthermore, the that developed from cells TβRI-TβRII-Fc with formed by cells TβRII-Fc that the level of secreted TβRI-TβRII-Fc proteins lower than that of TβRII-Fc these results suggest that TβRI-TβRII-Fc the tumor growth effectively via TGF-βs present in the TME. next to the by the TβRII-Fc and TβRI-TβRII-Fc chimeric proteins tumor in of cells not by TβRII-Fc or TβRI-TβRII-Fc inhibition of in tumor growth not from the of cancer not only cancer cells but also other stromal including tumor that cancer cells with and to tumor TGF-β signals have been in angiogenesis (3Miyazono K. Katsuno Y. Koinuma D. Ehata S. Morikawa M. Intracellular and extracellular TGF-β signaling in cancer: some recent topics.Front. Med. 2018; 12 (30043220): 387-41110.1007/s11684-018-0646-8Crossref PubMed Scopus (85) Google Scholar), we in from cells chimeric endothelial and endothelial cell and in we the of tumor that for both and in the formed by cells either or of with revealed that in formed by cells not from that of the other we a in the of tumor formed by cells TβRII-Fc as with Furthermore, the of tumor in TβRI-TβRII-Fc lower than that of TβRII-Fc is with the results of tumor These results suggest that the ligand traps in the extracellular may the response of endothelial cells within the TME, leading to the in tumor The roles of TGF-β in various of oncogenic have increased the to effective therapeutic targeting TGF-β In the present study, we developed a TβRI-TβRII-Fc chimeric that effectively trapped all TGF-β isoforms to the TGF-β also that the chimeric the EMT of oral cancer in in oral cancer cells and effects on the TME suggesting that TβRI-TβRII-Fc may be a promising tool for the of effective of the of TGF-β signaling in have to increased to effective P. on the of TGF-β for cancer 2019; PubMed Scopus Google Scholar). 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Full Text PDF PubMed Google Scholar). affinity in cells promotes the of the signaling complex with TGF-β2 J. ligand to the signaling Full Text PDF PubMed Scopus Google Scholar). and A. In the absence of type the transforming growth type receptor requires the type I receptor to bind Biol. Full Text Full Text PDF PubMed Scopus Google that the of TGF-β2 not by TβRII-Fc but by the of two and that the of and TβRII-Fc not trap TGF-β2 may the in affinity of TGF-β2 to both and TβRII-Fc are the two chimeric proteins have is a for effective Furthermore, by type I and II receptors in TβRI-TβRII-Fc can trap TGF-β more effectively than two Fc chimeric to two receptors in a Fc chimeric the same of both receptors and the of leading to more effective TGF-β2 is in various cancer including O. M. of TGF-β isoforms, TGF-β and of J. PubMed Scopus Google and cancer Y. M. M. M. expression of transforming growth isoforms in cancer with Full Text PDF PubMed Scopus Google Scholar), and expression is also with tumor have to target TGF-β2 in tumor TGF-β2 has been not only in cancer but also in other Recent that increased TGF-β2 with and A. R. M. A. growth in the PubMed Scopus Google Scholar, S. M. in with increased and TGF-β2 2016; PubMed Scopus Google Scholar). TβRI-TβRII-Fc may be a promising tool for the and of by TGF-β2. The oral cell from the and cells from TGF-β cells from The cells in with and The for cells also with TGF-β1, -β2, and from and of or on the from and a of from and of or on the The by the of and the the Fc of fused to the signal from the and the and of the For of the other ligand and the the extracellular of TβRI and TβRII from TβRI and TβRII with The to the of TβRI and TβRII and Fc to and The for as and the TβRI-TβRII-Fc the of TβRII a signal sequence with the of and The and the and of to the on both to the of the to and TβRII-Fc and TβRI-TβRII-Fc the expression from by the and for either cell to Fc proteins or as cells tissue and with Fc chimeric to the the with and the cells for 48 to of Fc chimeric The of Fc chimeric in the by with the to the of to for and and and The and The for with a of TGF-β ligand -β2, or in The with and with for The or TβRI-TβRII-Fc to ligand and The with by the of is to and for of Fc chimeric proteins with The by the of an of The of Fc chimeric proteins trapped by ligand a model The of Fc chimeric proteins on signal activation by TGF-β family -β2, and and TGF-β cells and in The next the with of and the cells for of Fc chimeric to the cells, by for The Fc chimeric formed as to of or TβRI-TβRII-Fc from with with to a of by the of TGF-β family ligand TGF-β1, -β2, or or and for of and in as a control for inhibition of TGF-β The activation of signals the for The of the by the a the of the from cells Fc chimeric cells in for 48 of to TGF-β cells and the cells in for The cells for an and signals as or cells and in The next the with of The Fc chimeric by the from cells Fc chimeric proteins of Fc chimeric proteins in of with TGF-β1, -β2, or -β3, and for to of the chimeric of and in as a control for TGF-β signal The chimeric to or The cells with chimeric for or on the and to expression by or I and The on a system All expression to the expression of The genes and are in as K. Y. Miyazono K. K. effects of on type I Biol. Full Text Full Text PDF PubMed Scopus Google Scholar). to Signaling and for the of Binding of and with a system or cells on tissue and with TGF-β1, -β2, or in the or absence of Fc chimeric proteins for The cells with an of for on and with by with Signaling and The proteins with and Signaling for with a by cells with the expression or and and The 48 and for a The to in tissue Cells and for the by cell to the The in The by the and of and and to the of the of and cells cells in of the Fc chimeric proteins and the of Tumor growth the by and from the and the with to tumor to the of the tumor and to the of the tumor of oral cancer as Y. Y. K. Miyazono K. of multiple types of endothelial cells in and in PubMed Scopus Google Scholar). formed in with cells, cells, cells, or cells on The in and in a the of in the the tumor xenograft a of a with with and with and The with to and to and Signaling for the of for tumor from with cells of for of for TβRII-Fc and of for TβRI-TβRII-Fc an with a of for the of All and to for The the of in are as or differences for All are within the for the for and the of the of of the of and the of of and for and with with tumor microenvironment transforming growth factor-β TGF-β type I receptor TGF-β type II receptor epithelial-to-mesenchymal transition oral cell secreted transmembrane and endothelial cell extracellular

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