Exploring the CXCR4/CXCR7/CXCL12 Axis in Primary Desmoid Tumors


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Abstract

Background: Desmoid tumors have an extremely variable natural history. The uncertainty behind desmoid behavior reflects the complexity, which subtends its development and non-linear advancement. Apart from Wnt- βcatenin mutation, estrogen receptors, and COX-2 overexpression, little is known about the ability of desmoids to grow and recur while being unable to metastasize. Several tumors have been shown to express the CXCR4/CXCR7/CXCL12 axis, whose functions are essential for tumoral development.

Aims:This study aimed to investigate the expression of the CXCR4/CXCR7/CXCL12 axis in primary desmoid tumors and discuss the potential role of this key-signaling as an antiangiogenic therapeutic strategy.

Method:In this study, 3 µm-thick consecutive sections from each formalin-fixed and paraffin-embedded tissue block were treated with mouse monoclonal antibodies developed against CD34, CXCR4, CXCR7, and CXCL12.

Results: Two distinct vessel populations: CXCR4+ and CXCR4- vessels, have been found. Similarly, chemokine receptor CXCR7 expression in the entire desmoid tumor series positively stained a portion of tumor-associated vessels, identifying two distinct subpopulations of vessels: CXCR7+ and CXCR7- vessels. All 8 neoplastic tissue samples expressed CXCL12. Immunohistochemical positivity was identified in both stromal and endothelial vascular cells. Compared to CXCR4 and CXCR7, the vast majority of tumor-associated vessels were found to express this chemokine.

Conclusion: It is the first time, as per our knowledge, that CXCR4/CXCR7/CXCL12 axis expression has been identified in a desmoid type-fibromatosis series. CXCL12 expression by neoplastic cells, together with CXCR4 and CXCR7 expression by a subgroup of tumor-associated vessels, was detected in all desmoid tumor tissue samples examined. Since chemokines are known contributors to neovascularization, CXCR4/CXCR7/CXCL12 axis may play a role in angiogenesis in this soft-tissue tumor histotype, thereby supporting its growth.

About the authors

Edoardo Baccalini

Sarcoma, Melanoma and Rare Tumors Surgery Unit, IRCCS Humanitas Research Hospital

Email: info@benthamscience.net

Salvatore Renne

Department of Pathology, IRCCS Humanitas Research Hospital

Email: info@benthamscience.net

Piergiuseppe Colombo

Department of Pathology, RCCS Humanitas Research Hospital

Email: info@benthamscience.net

Fabio Pasqualini

Department of Biomedical Sciences, Humanitas University

Email: info@benthamscience.net

Vittorio Quagliuolo

Sarcoma, Melanoma and Rare Tumors Surgery Unit, IRCCS Humanitas Research Hospital

Email: info@benthamscience.net

Ferdinando Cananzi

Sarcoma, Melanoma and Rare Tumors Surgery Unit, IRCCS Humanitas Research Hospital

Email: info@benthamscience.net

Fabio Grizzi

Department of Biomedical Sciences, Humanitas University

Author for correspondence.
Email: info@benthamscience.net

Elena Borroni

Department of Immunology and Inflammation, IRCCS Humanitas Research Hospital

Email: info@benthamscience.net

References

  1. Wu, C.; Nik-Amini, S.; Nadesan, P.; Stanford, W.L.; Alman, B.A. Aggressive fibromatosis (desmoid tumor) is derived from mesenchymal progenitor cells. Cancer Res., 2010, 70(19), 7690-7698. doi: 10.1158/0008-5472.CAN-10-1656 PMID: 20841474
  2. Zheng, C.; Fang, J.; Wang, Y.; Zhou, Y.; Tu, C.; Min, L. Efficacy and safety of apatinib for patients with advanced extremity desmoid fibromatosis: A retrospective study. J. Cancer Res. Clin. Oncol., 2021, 147(7), 2127-2135. doi: 10.1007/s00432-020-03498-y PMID: 33452581
  3. Pandrowala, S.; Jones, R.L.; Gupta, S.; Gulia, A. Desmoid fibromatosis: Is the current picture changing? Future Oncol., 2021, 17(25), 3397-3408. doi: 10.2217/fon-2021-0003 PMID: 34227399
  4. Reitamo, J.J.; Häyry, P.; Nykyri, E.; Saxén, E. The desmoid tumor. I. Incidence, sex-, age- and anatomical distribution in the Finnish population. Am. J. Clin. Pathol., 1982, 77(6), 665-673. doi: 10.1093/ajcp/77.6.665 PMID: 7091046
  5. Nieuwenhuis, M.H.; Casparie, M.; Mathus-Vliegen, L.M.H.; Dekkers, O.M.; Hogendoorn, P.C.W.; Vasen, H.F.A. A nation-wide study comparing sporadic and familial adenomatous polyposis-related desmoid-type fibromatoses. Int. J. Cancer, 2011, 129(1), 256-261. doi: 10.1002/ijc.25664 PMID: 20830713
  6. Crago, A.M.; Chmielecki, J.; Rosenberg, M.; O'Connor, R.; Byrne, C.; Wilder, F.G.; Thorn, K.; Agius, P.; Kuk, D.; Socci, N.D.; Qin, L.X.; Meyerson, M.; Hameed, M.; Singer, S. Near universal detection of alterations in CTNNB1 and Wnt pathway regulators in desmoid-type fibromatosis by whole-exome sequencing and genomic analysis. Genes Chromosomes Cancer, 2015, 54(10), 606-615. doi: 10.1002/gcc.22272 PMID: 26171757
  7. Penel, N.; Chibon, F.; Salas, S. Adult desmoid tumors: Biology, management and ongoing trials. Curr. Opin. Oncol., 2017, 29(4), 268-274. doi: 10.1097/CCO.0000000000000374 PMID: 28489620
  8. Zreik, R.T.; Fritchie, K.J. Morphologic spectrum of desmoid-type fibromatosis. Am. J. Clin. Pathol., 2016, 145(3), 332-340. doi: 10.1093/ajcp/aqv094 PMID: 27124915
  9. Rosenberg, A.E. WHO classification of soft tissue and bone. fourth edition: Summary and commentary. Curr. Opin. Oncol.,; , 2013, 25, pp. (5)571-3.
  10. Gounder, M.M.; Thomas, D.M.; Tap, W.D. Locally aggressive connective tissue tumors. J. Clin. Oncol., 2018, 36(2), 202-209. doi: 10.1200/JCO.2017.75.8482 PMID: 29220303
  11. Gounder, M.M.; Maddux, L.; Paty, J.; Atkinson, T.M. Prospective development of a patient‐reported outcomes instrument for desmoid tumors or aggressive fibromatosis. Cancer, 2020, 126(3), 531-539. doi: 10.1002/cncr.32555 PMID: 31691276
  12. Salas, S.; Dufresne, A.; Bui, B.; Blay, J.Y.; Terrier, P.; Ranchere-Vince, D.; Bonvalot, S.; Stoeckle, E.; Guillou, L.; Le Cesne, A.; Oberlin, O.; Brouste, V.; Coindre, J.M. Prognostic factors influencing progression-free survival determined from a series of sporadic desmoid tumors: A wait-and-see policy according to tumor presentation. J. Clin. Oncol., 2011, 29(26), 3553-3558. doi: 10.1200/JCO.2010.33.5489 PMID: 21844500
  13. Crago, A.M.; Denton, B.; Salas, S.; Dufresne, A.; Mezhir, J.J.; Hameed, M.; Gonen, M.; Singer, S.; Brennan, M.F. A prognostic nomogram for prediction of recurrence in desmoid fibromatosis. Ann. Surg., 2013, 258(2), 347-353. doi: 10.1097/SLA.0b013e31828c8a30 PMID: 23532110
  14. Fiore, M.; Crago, A.; Gladdy, R.; Kasper, B. The landmark series. Desmoid. Ann. Surg. Oncol., 2021, 28(3), 1682-1689. doi: 10.1245/s10434-020-09395-5 PMID: 33386543
  15. Nishida, Y.; Sakai, T.; Koike, H.; Ito, K. Pazopanib for progressive desmoid tumours: Children, persistant effects, and cost. Lancet Oncol., 2019, 20(10), e555. doi: 10.1016/S1470-2045(19)30543-1 PMID: 31578997
  16. Wilhelm, S.M.; Carter, C.; Tang, L.; Wilkie, D.; McNabola, A.; Rong, H.; Chen, C.; Zhang, X.; Vincent, P.; McHugh, M.; Cao, Y.; Shujath, J.; Gawlak, S.; Eveleigh, D.; Rowley, B.; Liu, L.; Adnane, L.; Lynch, M.; Auclair, D.; Taylor, I.; Gedrich, R.; Voznesensky, A.; Riedl, B.; Post, L.E.; Bollag, G.; Trail, P.A. BAY 43-9006 exhibits broad spectrum oral antitumor activity and targets the RAF/MEK/ERK pathway and receptor tyrosine kinases involved in tumor progression and angiogenesis. Cancer Res., 2004, 64(19), 7099-7109. doi: 10.1158/0008-5472.CAN-04-1443 PMID: 15466206
  17. Gounder, M.M.; Lefkowitz, R.A.; Keohan, M.L.; D'Adamo, D.R.; Hameed, M.; Antonescu, C.R.; Singer, S.; Stout, K.; Ahn, L.; Maki, R.G. Activity of Sorafenib against desmoid tumor/deep fibromatosis. Clin. Cancer Res., 2011, 17(12), 4082-4090. doi: 10.1158/1078-0432.CCR-10-3322 PMID: 21447727
  18. Gounder, M.M.; Mahoney, M.R.; Van Tine, B.A.; Ravi, V.; Attia, S.; Deshpande, H.A.; Gupta, A.A.; Milhem, M.M.; Conry, R.M.; Movva, S.; Pishvaian, M.J.; Riedel, R.F.; Sabagh, T.; Tap, W.D.; Horvat, N.; Basch, E.; Schwartz, L.H.; Maki, R.G.; Agaram, N.P.; Lefkowitz, R.A.; Mazaheri, Y.; Yamashita, R.; Wright, J.J.; Dueck, A.C.; Schwartz, G.K. Sorafenib for advanced and refractory desmoid tumors. N. Engl. J. Med., 2018, 379(25), 2417-2428. doi: 10.1056/NEJMoa1805052 PMID: 30575484
  19. Adnane, L.; Trail, P.A.; Taylor, I.; Wilhelm, S.M. Sorafenib (BAY 43-9006, Nexavar), a dual-action inhibitor that targets RAF/MEK/ERK pathway in tumor cells and tyrosine kinases VEGFR/PDGFR in tumor vasculature. Methods Enzymol., 2006, 407, 597-612. doi: 10.1016/S0076-6879(05)07047-3 PMID: 16757355
  20. Llovet, J.M.; Ricci, S.; Mazzaferro, V.; Hilgard, P.; Gane, E.; Blanc, J.F.; de Oliveira, A.C.; Santoro, A.; Raoul, J.L.; Forner, A.; Schwartz, M.; Porta, C.; Zeuzem, S.; Bolondi, L.; Greten, T.F.; Galle, P.R.; Seitz, J.F.; Borbath, I.; Häussinger, D.; Giannaris, T.; Shan, M.; Moscovici, M.; Voliotis, D.; Bruix, J. Sorafenib in advanced hepatocellular carcinoma. N. Engl. J. Med., 2008, 359(4), 378-390. doi: 10.1056/NEJMoa0708857 PMID: 18650514
  21. Escudier, B.; Eisen, T.; Stadler, W.M.; Szczylik, C.; Oudard, S.; Siebels, M.; Negrier, S.; Chevreau, C.; Solska, E.; Desai, A.A.; Rolland, F.; Demkow, T.; Hutson, T.E.; Gore, M.; Freeman, S.; Schwartz, B.; Shan, M.; Simantov, R.; Bukowski, R.M. Sorafenib in advanced clear-cell renal-cell carcinoma. N. Engl. J. Med., 2007, 356(2), 125-134. doi: 10.1056/NEJMoa060655 PMID: 17215530
  22. Fallahi, P.; Ferrari, S.M.; Santini, F.; Corrado, A.; Materazzi, G.; Ulisse, S.; Miccoli, P.; Antonelli, A. Sorafenib and thyroid cancer. BioDrugs, 2013, 27(6), 615-628. doi: 10.1007/s40259-013-0049-y PMID: 23818056
  23. Xu, J.; Liang, J.; Meng, Y.M.; Yan, J.; Yu, X.J.; Liu, C.Q.; Xu, L.; Zhuang, S.M.; Zheng, L. Vascular CXCR4 expression promotes vessel sprouting and sensitivity to sorafenib treatment in hepatocellular carcinoma. Clin. Cancer Res., 2017, 23(15), 4482-4492. doi: 10.1158/1078-0432.CCR-16-2131 PMID: 28223275
  24. Zuazo-Gaztelu, I.; Casanovas, O. Unraveling the role of angiogenesis in cancer ecosystems. Front. Oncol., 2018, 8, 248. doi: 10.3389/fonc.2018.00248 PMID: 30013950
  25. Liang, Z.; Brooks, J.; Willard, M.; Liang, K.; Yoon, Y.; Kang, S.; Shim, H. CXCR4/CXCL12 axis promotes VEGF-mediated tumor angiogenesis through Akt signaling pathway. Biochem. Biophys. Res. Commun., 2007, 359(3), 716-722. doi: 10.1016/j.bbrc.2007.05.182 PMID: 17559806
  26. Mills, B.G.; Frausto, A.; Brien, E. Cytokines associated with the pathophysiology of aggressive fibromatosis. J. Orthop. Res., 2000, 18(4), 655-662. doi: 10.1002/jor.1100180419 PMID: 11052503
  27. Egeblad, M.; Nakasone, E.S.; Werb, Z. Tumors as organs: Complex tissues that interface with the entire organism. Dev. Cell, 2010, 18(6), 884-901. doi: 10.1016/j.devcel.2010.05.012 PMID: 20627072
  28. Hanahan, D.; Weinberg, R.A. Hallmarks of cancer: The next generation. Cell, 2011, 144(5), 646-674. doi: 10.1016/j.cell.2011.02.013 PMID: 21376230
  29. Guo, F.; Wang, Y.; Liu, J.; Mok, S.C.; Xue, F.; Zhang, W. CXCL12/CXCR4: A symbiotic bridge linking cancer cells and their stromal neighbors in oncogenic communication networks. Oncogene, 2016, 35(7), 816-826. doi: 10.1038/onc.2015.139 PMID: 25961926
  30. Ehnman, M.; Chaabane, W.; Haglund, F.; Tsagkozis, P. The tumor microenvironment of pediatric sarcoma: Mesenchymal mechanisms regulating cell migration and metastasis. Curr. Oncol. Rep., 2019, 21(10), 90. doi: 10.1007/s11912-019-0839-6 PMID: 31418125
  31. Ceradini, D.J.; Kulkarni, A.R.; Callaghan, M.J.; Tepper, O.M.; Bastidas, N.; Kleinman, M.E.; Capla, J.M.; Galiano, R.D.; Levine, J.P.; Gurtner, G.C. Progenitor cell trafficking is regulated by hypoxic gradients through HIF-1 induction of SDF-1. Nat. Med., 2004, 10(8), 858-864. doi: 10.1038/nm1075 PMID: 15235597
  32. Schioppa, T.; Uranchimeg, B.; Saccani, A.; Biswas, S.K.; Doni, A.; Rapisarda, A.; Bernasconi, S.; Saccani, S.; Nebuloni, M.; Vago, L.; Mantovani, A.; Melillo, G.; Sica, A. Regulation of the chemokine receptor CXCR4 by hypoxia. J. Exp. Med., 2003, 198(9), 1391-1402. doi: 10.1084/jem.20030267 PMID: 14597738
  33. Salcedo, R.; Oppenheim, J.J. Role of chemokines in angiogenesis: CXCL12/SDF-1 and CXCR4 interaction, a key regulator of endothelial cell responses. Microcirculation, 2003, 10(3-4), 359-370. doi: 10.1080/mic.10.3-4.359.370 PMID: 12851652
  34. Alman, B.; Attia, S.; Baumgarten, C.; Benson, C.; Blay, J-Y.; Bonvalot, S.; Breuing, J.; Cardona, K.; Casali, P.G.; van Coevorden, F.; Colombo, C.; Dei Tos, A.P.; Dileo, P.; Ferrari, A.; Fiore, M.; Frezza, A.M.; Garcia, J.; Gladdy, R.; Gounder, M.; Gronchi, A.; Haas, R.; Hackett, S.; Haller, F.; Hohenberger, P.; Husson, O.; Jones, R.L.; Judson, I.; Kasper, B.; Kawai, A.; Kogosov, V.; Lazar, A.J.; Maki, R.; Mathes, T.; Messiou, C.; Navid, F.; Nishida, Y.; Palassini, E.; Penel, N.; Pollock, R.; Pieper, D.; Portnoy, M.; Raut, C.P.; Roets, E.; Sandrucci, S.; Sbaraglia, M.; Stacchiotti, S.; Thornton, K.A.; van der Graaf, W.; van der Zande, K.; van Houdt, W.J.; Villalobos, V.; Wagner, A.J.; Wardelmann, E.; Wartenberg, M.; Watson, S.; Weiss, A.; Zafiropoulos, N. The management of desmoid tumours: A joint global consensus-based guideline approach for adult and paediatric patients. Eur. J. Cancer, 2020, 127, 96-107. doi: 10.1016/j.ejca.2019.11.013 PMID: 32004793
  35. Cho, N.L.; Carothers, A.M.; Rizvi, H.; Hasson, R.M.; Redston, M.; Bertagnolli, M.M. Immunohistochemical and molecular analysis of tyrosine kinase activity in desmoid tumors. J. Surg. Res., 2012, 173(2), 320-326. doi: 10.1016/j.jss.2010.10.037 PMID: 21195420
  36. Liu, L.; Cao, Y.; Chen, C.; Zhang, X.; McNabola, A.; Wilkie, D.; Wilhelm, S.; Lynch, M.; Carter, C. Sorafenib blocks the RAF/MEK/ERK pathway, inhibits tumor angiogenesis, and induces tumor cell apoptosis in hepatocellular carcinoma model PLC/PRF/5. Cancer Res., 2006, 66(24), 11851-11858. doi: 10.1158/0008-5472.CAN-06-1377 PMID: 17178882
  37. Kim, S.; Yazici, Y.D.; Calzada, G.; Wang, Z.Y.; Younes, M.N.; Jasser, S.A.; El-Naggar, A.K.; Myers, J.N. Sorafenib inhibits the angiogenesis and growth of orthotopic anaplastic thyroid carcinoma xenografts in nude mice. Mol. Cancer Ther., 2007, 6(6), 1785-1792. doi: 10.1158/1535-7163.MCT-06-0595 PMID: 17575107
  38. Liu, L.; Ho, R.L.K.; Chen, G.G.; Lai, P.B.S. Sorafenib inhibits hypoxia-inducible factor-1α synthesis: Implications for antiangiogenic activity in hepatocellular carcinoma. Clin. Cancer Res., 2012, 18(20), 5662-5671. doi: 10.1158/1078-0432.CCR-12-0552 PMID: 22929805
  39. Shi, Y.; Riese, D.J., II; Shen, J. The role of the CXCL12/CXCR4/CXCR7 chemokine axis in cancer. Front. Pharmacol., 2020, 11, 574667. doi: 10.3389/fphar.2020.574667 PMID: 33363463
  40. Zheng, N.; Liu, W.; Chen, J.; Li, B.; Liu, J.; Wang, J.; Gao, Y.; Shao, J.; Jia, L. CXCR7 is not obligatory for CXCL12‐CXCR4‐induced epithelial‐mesenchymal transition in human ovarian cancer. Mol. Carcinog., 2019, 58(1), 144-155. doi: 10.1002/mc.22916 PMID: 30259564

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