Anti-angiogenic therapy in head and neck squamous cell carcinoma - current limitations and future directions

Abstract

Angiogenesis, the formation of new blood vessels, plays a crucial role in the progression and metastasis of various cancers, including head and neck squamous cell carcinoma (HNSCC). HNSCCs are characterized by altered levels of angiogenesis-related factors, including the overexpression of pro-angiogenic factors such as vascular endothelial growth factor (VEGF) and platelet-derived growth factor (PDGF), as well as the dysregulation of angiogenesis inhibitors. Together, these factors drive the formation of new blood vessels within the tumor microenvironment and are considered therapeutic targets in HNSCC. Although preclinical studies are promising, challenges have emerged in the clinical use of anti-angiogenic agents in the clinic, including treatment-related toxicities and the development of resistance to therapy. There is an unmet need for further research to elucidate the molecular pathways involved in HNSCC angiogenesis, identify novel therapeutic targets, and discover predictive biomarkers to improve patient selection.

Keywords

Head and neck squamous cell carcinoma / HNSCC / oral squamous cell carcinoma / OSCC / anti-angiogenic therapy / tumor angiogenesis

References

[1] Johnson DE,Leemans CR,Bauman JE.Head and neck squamous cell carcinoma.Nat Rev Dis Primers2020;6:92 PMCID:PMC7944998

[2] Ferlay J,Soerjomataram I.Estimating the global cancer incidence and mortality in 2018: GLOBOCAN sources and methods.Int J Cancer2019;144:1941-53

[3] Bray F,Soerjomataram I,Torre LA.Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries.CA A Cancer J Clin2018;68:394-424

[4] Curry JM,Cognetti D.Tumor microenvironment in head and neck squamous cell carcinoma.Semin Oncol2014;41:217-34

[5] Longo DL.Head and neck cancer.N Engl J Med2020;382:60-72

[6] Ernani V.Oral cavity cancer: risk factors, pathology, and management.Oncology2015;89:187-95

[7] Brouwer AF,Chinn SB.Time-varying survival effects for squamous cell carcinomas at oropharyngeal and nonoropharyngeal head and neck sites in the United States, 1973-2015.Cancer2020;126:5137-46 PMCID:PMC7869108

[8] Hashibe M,Chuang S.Interaction between tobacco and alcohol use and the risk of head and neck cancer: pooled analysis in the international head and neck cancer epidemiology consortium.Cancer Epidemiol Biomarkers Prev2009;18:541-50

[9] von Witzleben A, Wang C, Laban S, Savelyeva N, Ottensmeier CH. HNSCC: tumour antigens and their targeting by immunotherapy.Cells2020;9:2103 PMCID:PMC7564543

[10] Chamoli A,Shirwadkar UP.Overview of oral cavity squamous cell carcinoma: risk factors, mechanisms, and diagnostics.Oral Oncol2021;121:105451

[11] Walsh T,Brocklehurst P.Clinical assessment to screen for the detection of oral cavity cancer and potentially malignant disorders in apparently healthy adults.Cochrane Database Syst Rev2013;2013:Cd010173 PMCID:PMC7087434

[12] Fitzhugh VA,Gurudutt VV,Chen H.Fine-needle aspiration biopsy of granular cell tumor of the tongue: a technique for the aspiration of oral lesions.Diagn Cytopathol2009;37:839-42

[13] Wang H,Zhang Y.Immunotherapy advances in locally advanced and recurrent/metastatic head and neck squamous cell carcinoma and its relationship with human papillomavirus.Front Immunol2021;12:652054 PMCID:PMC8296140

[14] Chaturvedi AK,Pfeiffer RM.Human papillomavirus and rising oropharyngeal cancer incidence in the United States.J Clin Oncol2011;29:4294-301 PMCID:PMC3221528

[15] Hanahan D.Hallmarks of cancer: the next generation.Cell2011;144:646-74

[16] Micaily I,Argiris A.An update on angiogenesis targeting in head and neck squamous cell carcinoma.Cancers Head Neck2020;5:5 PMCID:PMC7132887

[17] Schito L.Bridging angiogenesis and immune evasion in the hypoxic tumor microenvironment.Am J Physiol Regul Integr Comp Physiol2018;315:R1072-84

[18] Dudley AC.Pathological angiogenesis: mechanisms and therapeutic strategies.Angiogenesis2023;26:313-47 PMCID:PMC10105163

[19] Udan RS,Dickinson ME.Understanding vascular development.Wiley Interdiscip Rev Dev Biol2013;2:327-46 PMCID:PMC4146572

[20] Hillen F.Tumour vascularization: sprouting angiogenesis and beyond.Cancer Metastasis Rev2007;26:489-502 PMCID:PMC2797856

[21] Gerhardt H,Fruttiger M.VEGF guides angiogenic sprouting utilizing endothelial tip cell filopodia.J Cell Biol2003;161:1163-77 PMCID:PMC2172999

[22] Ackermann M,Plucinski E.The role of vasculature and angiogenesis in respiratory diseases. Angiogenesis 2024:1-18.

[23] Baum O,Gerber B.VEGF-A promotes intussusceptive angiogenesis in the developing chicken chorioallantoic membrane.Microcirculation2010;17:447-57

[24] Saravanan S,Pavani K,Sumantran VN.Intussusceptive angiogenesis as a key therapeutic target for cancer therapy.Life Sci2020;252:117670

[25] Nitzsche B,Goede A.Coalescent angiogenesis-evidence for a novel concept of vascular network maturation.Angiogenesis2022;25:35-45 PMCID:PMC8669669

[26] Zhang Y,Dudley AC.Models and molecular mechanisms of blood vessel co-option by cancer cells.Angiogenesis2020;23:17-25 PMCID:PMC7018564

[27] Wagenblast E,Gutiérrez-ángel S.A model of breast cancer heterogeneity reveals vascular mimicry as a driver of metastasis.Nature2015;520:358-62 PMCID:PMC4634366

[28] Carmeliet P.Principles and mechanisms of vessel normalization for cancer and other angiogenic diseases.Nat Rev Drug Discov2011;10:417-27

[29] Jain RK.Normalization of tumor vasculature: an emerging concept in antiangiogenic therapy.Science2005;307:58-62

[30] Datta M,Nishikawa H,Jain RK.Reprogramming the tumor microenvironment to improve immunotherapy: emerging strategies and combination therapies.Am Soc Clin Oncol Educ Book2019;39:165-74 PMCID:PMC6596289

[31] Carmeliet P.Molecular mechanisms and clinical applications of angiogenesis.Nature2011;473:298-307 PMCID:PMC4049445

[32] Dong Y,Liu Y,Liu L.Prognostic value of microvessel density in head and neck squamous cell carcinoma: a meta-analysis.Dis Markers2020;2020:1-11 PMCID:PMC7539077

[33] Evans M,Magliocca KR.Prognostic implications of peritumoral vasculature in head and neck cancer.Cancer Med2019;8:147-54 PMCID:PMC6346230

[34] Bielenberg DR.The contribution of angiogenesis to the process of metastasis.Cancer J2015;21:267-73 PMCID:PMC4670555

[35] Clambey ET,Westrich JA.Hypoxia-inducible factor-1 alpha-dependent induction of FoxP3 drives regulatory T-cell abundance and function during inflammatory hypoxia of the mucosa.Proc Natl Acad Sci USA2012;109:E2784-93 PMCID:PMC3478644

[36] Corzo CA,Lu L.HIF-1α regulates function and differentiation of myeloid-derived suppressor cells in the tumor microenvironment.J Exp Med2010;207:2439-53 PMCID:PMC2964584

[37] Doedens AL,Rubinstein MP.Macrophage expression of hypoxia-inducible factor-1α suppresses T-cell function and promotes tumor progression.Cancer Res2010;70:7465-75 PMCID:PMC2948598

[38] Zhang H,Xiang L.HIF-1 regulates CD47 expression in breast cancer cells to promote evasion of phagocytosis and maintenance of cancer stem cells.Proc Natl Acad Sci USA2015;112:E6215-23 PMCID:PMC4653179

[39] Burke B,Corke KP.Expression of HIF-1α by human macrophages: implications for the use of macrophages in hypoxia-regulated cancer gene therapy.J Pathol2002;196:204-12

[40] Ohm JE,Sempowski GD.VEGF inhibits T-cell development and may contribute to tumor-induced immune suppression.Blood2003;101:4878-86

[41] Gabrilovich DI,Girgis KR.Production of vascular endothelial growth factor by human tumors inhibits the functional maturation of dendritic cells.Nat Med1996;2:1096-103

[42] Zang J,Zhao L.Prognostic value of vascular endothelial growth factor in patients with head and neck cancer: a meta-analysis.Head Neck2013;35:1507-14

[43] Kyzas PA,Ioannidis JP.Prognostic significance of vascular endothelial growth factor immunohistochemical expression in head and neck squamous cell carcinoma: a meta-analysis.Clin Cancer Res2005;11:1434-40

[44] Hoang T,Armstrong E,Harari PM.Enhancement of radiation response with bevacizumab.J Exp Clin Cancer Res2012;31:37 PMCID:PMC3537546

[45] Shih T.Bevacizumab: an angiogenesis inhibitor for the treatment of solid malignancies.Clin Ther2006;28:1779-802

[46] Salem A,Al-samadi A.Editorial: angiogenesis and angiogenesis inhibitors in oral cancer.Front Oral Health2021;2:816963 PMCID:PMC8757880

[47] Argiris A,Savvides P.Phase III randomized trial of chemotherapy with or without bevacizumab in patients with recurrent or metastatic head and neck cancer.J Clin Oncol2019;37:3266-74

[48] Yoo DS,Craciunescu O.Prospective trial of synchronous bevacizumab, erlotinib, and concurrent chemoradiation in locally advanced head and neck cancer.Clin Cancer Res2012;18:1404-14

[49] Hyytiäinen A,Väyrynen O.Angiogenesis inhibitors for head and neck squamous cell carcinoma treatment: is there still hope?.Front Oncol2021;11:683570 PMCID:PMC8236814

[50] Cohen EE,Karrison TG.Erlotinib and bevacizumab in patients with recurrent or metastatic squamous-cell carcinoma of the head and neck: a phase I/II study.Lancet Oncol2009;10:247-57 PMCID:PMC2768532

[51] Rahma OE.The intersection between tumor angiogenesis and immune suppression.Clin Cancer Res2019;25:5449-57

[52] Yao J,Sheng J.Efficacy and safety of combined immunotherapy and antiangiogenic therapy for advanced non-small cell lung cancer: a two-center retrospective study.Int Immunopharmacol2020;89:107033

[53] Herbst RS,Santana-davila R.Ramucirumab plus pembrolizumab in patients with previously treated advanced non-small-cell lung cancer, gastro-oesophageal cancer, or urothelial carcinomas (JVDF): a multicohort, non-randomised, open-label, phase 1a/b trial.Lancet Oncol2019;20:1109-23

[54] Ju W,Zhu D.A pilot study of neoadjuvant combination of anti-PD-1 camrelizumab and VEGFR2 inhibitor apatinib for locally advanced resectable oral squamous cell carcinoma.Nat Commun2022;13:5378 PMCID:PMC9472189

[55] Liang D,Sang N.Effects of histone deacetylase inhibitors on HIF-1.Cell Cycle2006;5:2430-5 PMCID:PMC4505804

[56] Liang T,Elhassan RM.Targeting histone deacetylases for cancer therapy: trends and challenges.Acta Pharmaceutica Sinica B2023;13:2425-63 PMCID:PMC10326266

[57] Hao B,Xu J.Proteomics analysis of histone deacetylase inhibitor-resistant solid tumors reveals resistant signatures and potential drug combinations.Acta Pharmacol Sin2024;45:1305-15 PMCID:PMC11130134

[58] Schrenk C,Haist C.Synergistic interaction of the class IIa HDAC inhibitor CHDI0039 with bortezomib in head and neck cancer cells.IJMS2023;24:5553 PMCID:PMC10056166

[59] He L,Shay C,Lv F.Histone deacetylase inhibitors suppress aggressiveness of head and neck squamous cell carcinoma via histone acetylation-independent blockade of the EGFR-Arf1 axis.J Exp Clin Cancer Res2019;38:84 PMCID:PMC6379952

[60] Ye Z,Chen G.Extracellular vesicles in tumor angiogenesis and resistance to anti-angiogenic therapy.Cancer Sci2023;114:2739-49 PMCID:PMC10323098

[61] Kuczynski EA.Vessel co-option and resistance to anti-angiogenic therapy.Angiogenesis2020;23:55-74

[62] Becker A,Weiss JM,Peinado H.Extracellular vesicles in cancer: cell-to-cell mediators of metastasis.Cancer Cell2016;30:836-48 PMCID:PMC5157696

[63] Yu Z,Wu M.Untouched isolation enables targeted functional analysis of tumour-cell-derived extracellular vesicles from tumour tissues.J Extracell Vesicle2022;11:e12214 PMCID:PMC9014807

[64] Ludwig N,Azambuja JH.TGFβ⁺ small extracellular vesicles from head and neck squamous cell carcinoma cells reprogram macrophages towards a pro-angiogenic phenotype.J Extracell Vesicle2022;11:12294 PMCID:PMC9764108

[65] Ludwig N,Harasymczuk M.TGFβ carrying exosomes in plasma: potential biomarkers of cancer progression in patients with head and neck squamous cell carcinoma.Br J Cancer2023;128:1733-41 PMCID:PMC10133391

[66] Ludwig N,Whiteside TL.Role of exosome-associated adenosine in promoting angiogenesis.Vessel Plus2020;4:8 PMCID:PMC7266301

[67] Ludwig N,Azambuja JH.Tumor-derived exosomes promote angiogenesis via adenosine A_2B receptor signaling.Angiogenesis2020;23:599-610 PMCID:PMC7529853

[68] Jeong H,Liao S.Investigation of the lack of angiogenesis in the formation of lymph node metastases.J Natl Cancer Inst2015;107:djv155 PMCID:PMC4651102

[69] Frentzas S,Bridgeman VL.Vessel co-option mediates resistance to anti-angiogenic therapy in liver metastases.Nat Med2016;22:1294-302 PMCID:PMC5104270

[70] Chan LS,Christophi C.Selective targeting of the tumour vasculature*.ANZ J Surg2008;78:955-67

[71] Nguyen L,Malcontenti-wilson C.Spatial morphological and molecular differences within solid tumors may contribute to the failure of vascular disruptive agent treatments.BMC Cancer2012;12:522 PMCID:PMC3583184

[72] Nguyen L,Christophi C.Vascular disruptive agent OXi4503 and anti-angiogenic agent Sunitinib combination treatment prolong survival of mice with CRC liver metastasis.BMC Cancer2016;16:533 PMCID:PMC4962549

[73] Garcia V, Basu B, Molife LR, Kaye SB. Combining antiangiogenics to overcome resistance: rationale and clinical experience.Clin Cancer Res2012;18:3750-61

[74] Siemann DW.Efficacy of combined antiangiogenic and vascular disrupting agents in treatment of solid tumors.Int J Rad Oncol Biol Phys2004;60:1233-40

[75] Sauter ER,Watson JC,Litwin S. Vascular endothelial growth factor is a marker of tumor invasion and metastasis in squamous cell carcinomas of the head and neck. Clin Cancer Res 1999;5:775-82. Available from: https://aacrjournals.org/clincancerres/article/5/4/775/287485/Vascular [Last accessed on 20 Jun 2024]

[76] Smith BD,Carter D,Haffty BG.Prognostic significance of vascular endothelial growth factor protein levels in oral and oropharyngeal squamous cell carcinoma.J Clin Oncol2000;18:2046-52

[77] Alessandrini L,Daloiso A.Diagnostic, prognostic, and therapeutic role for angiogenesis markers in head and neck squamous cell carcinoma: a narrative review.Int J Mol Sci2023;24:10733 PMCID:PMC10341715

[78] Schlesinger M.Vascular cell adhesion molecule-1 (VCAM-1)-An increasing insight into its role in tumorigenicity and metastasis.Int J Cancer2015;136:2504-14

[79] Ebeling S,Perez-vazquez D.Regulation of tumor angiogenesis by the crosstalk between innate immunity and endothelial cells.Front Oncol2023;13:1171794 PMCID:PMC10206118

[80] Chandler KB,Rahimi N.Glycosylation in the tumor microenvironment: implications for tumor angiogenesis and metastasis.Cells2019;8:544 PMCID:PMC6627046

[81] Vanheyst KA,Kingsley DT.Ectopic tumor VCAM-1 expression in cancer metastasis and therapy resistance.Cells2022;11:3922 PMCID:PMC9735769

[82] Lieder AM,Wood KJ.The relevance of adhesion molecules in the classification of squamous cell carcinoma of the head and neck.Anticancer Res2005;25:4141-7

[83] Haigentz M,Sarta C.Phase II trial of the histone deacetylase inhibitor romidepsin in patients with recurrent/metastatic head and neck cancer.Oral Oncol2012;48:1281-8 PMCID:PMC3465519

[84] Candelaria M,Arce C.A phase II study of epigenetic therapy with hydralazine and magnesium valproate to overcome chemotherapy resistance in refractory solid tumors.Ann Oncol2007;18:1529-38