Top

Published in:

Open Access 01-12-2021 | Research

Comprehensive analysis of angiogenesis subtype of squamous cell carcinoma

Authors: Fanglu Qin, Shenghua Lin, Kun Deng, Junqi Qin, Zhanyu Xu, Liqiang Yuan, Jiangbo Wei, Yu Sun, Tiaozhan Zheng, Shikang Li

Published in: World Journal of Surgical Oncology | Issue 1/2021

Abstract

Background

Squamous cell carcinoma (SCC) is a disease with distinct management complexities as it displays a remarkably heterogeneous molecular subtype. However, the landscape of angiogenesis for SCC is not fully investigated.

Method and materials

The angiogenesis-related subtypes of SCC were established by using the ConsensusClusterPlus package based on angiogenesis-related genes and TCGA data. We analyzed the alteration of genes and miRNAs as well as pathways associated with angiogenesis subtypes. Next, the regulation network, the correlation with genomic characteristics, immune microenvironment, and clinical features of the angiogenesis subtypes were further investigated. Finally, the prognostic impact of the angiogenesis-related subtypes for SCC was also analyzed.

Results

A total of 1368 SCC samples were included in this study. Two angiogenesis subtypes were then identified based on the one hundred and sixty-three angiogenesis-related genes with subtype1 (angiogenesis subtype) of 951 SCC patients and subtype2 (non-angiogenesis subtype) of 417 SCC. GSEA revealed that angiogenesis and epithelial-mesenchymal transition, inflammatory response, and hypoxia were enriched in the angiogenesis subtype. Eight of the 15 immune checkpoints (ADORA2A, BTLA, CD276, CYBB, HAVCR2, SIGLEC7, SIGLEC9, and VTCN1) were significantly upregulated while C10orf54 were significantly downregulated in the angiogenesis subtype. The survival analysis revealed that the patients in the angiogenesis subtype have poorer survival outcomes than those in the non-angiogenesis subtype (P = 0.017 for disease-free interval and P = 0.00013 for overall survival).

Conclusion

Our analysis revealed a novel angiogenesis subtype classification in SCC and provides new insights into a hallmark of SCC progression.

Dotto GP, Rustgi AK. Squamous cell cancers: a unified perspective on biology and genetics. Cancer Cell. 2016;29(5):622–37. https://doi.org/10.1016/j.ccell.2016.04.004.CrossRefPubMedPubMedCentral

Dotto GP. Multifocal epithelial tumors and field cancerization: stroma as a primary determinant. J Clin Invest. 2014;124(4):1446–53. https://doi.org/10.1172/JCI72589.CrossRefPubMedPubMedCentral

Parker JS, Mullins M, Cheang MC, Leung S, Voduc D, Vickery T, et al. Supervised risk predictor of breast cancer based on intrinsic subtypes. J Clin Oncol. 2009;27(8):1160–7. https://doi.org/10.1200/JCO.2008.18.1370.CrossRefPubMedPubMedCentral

Martínez E, Yoshihara K, Kim H, Mills GM, Treviño V, Verhaak RG. Comparison of gene expression patterns across 12 tumor types identifies a cancer supercluster characterized by TP53 mutations and cell cycle defects. Oncogene. 2015;34(21):2732–40. https://doi.org/10.1038/onc.2014.216.CrossRefPubMed

Pandey M, Kannepali KK, Dixit R, Kumar M. Effect of neoadjuvant chemotherapy and its correlation with HPV status, EGFR, Her-2-neu, and GADD45 expression in oral squamous cell carcinoma. World J Surg Oncol. 2018;16(1):20. https://doi.org/10.1186/s12957-018-1308-7.CrossRefPubMedPubMedCentral

Mo J, Hu X, Gu L, Chen B, Khadaroo PA, Shen Z, et al. Smokers or non-smokers: who benefits more from immune checkpoint inhibitors in treatment of malignancies? An up-to-date meta-analysis. World J Surg Oncol. 2020;18(1):15. https://doi.org/10.1186/s12957-020-1792-4.CrossRefPubMedPubMedCentral

Zhang R, Zhang TT, Zhai GQ, Guo XY, Qin Y, Gan TQ, et al. Evaluation of the HOXA11 level in patients with lung squamous cancer and insights into potential molecular pathways via bioinformatics analysis. World J Surg Oncol. 2018;16(1):109. https://doi.org/10.1186/s12957-018-1375-9.CrossRefPubMedPubMedCentral

Mao L, Wu X, Gong Z, Yu M, Huang Z. PDIA6 contributes to aerobic glycolysis and cancer progression in oral squamous cell carcinoma. World J Surg Oncol. 2021;19(1):88. https://doi.org/10.1186/s12957-021-02190-w.CrossRefPubMedPubMedCentral

Zheng Z, Tian R, Wang P. Roles of KAI1 and nm23 in lymphangiogenesis and lymph metastasis of laryngeal squamous cell carcinoma. World J Surg Oncol. 2017;15(1):211. https://doi.org/10.1186/s12957-017-1279-0.CrossRefPubMedPubMedCentral

10.

Tang J, Yang Z, Wang Z, Li Z, Li H, Yin J, et al. Foxp3 is correlated with VEGF-C expression and lymphangiogenesis in cervical cancer. World J Surg Oncol. 2017;15(1):173. https://doi.org/10.1186/s12957-017-1221-5.CrossRefPubMedPubMedCentral

11.

Luo J, Shi K, Yin SY, Tang RX, Chen WJ, Huang LZ, et al. Clinical value of miR-182-5p in lung squamous cell carcinoma: a study combining data from TCGA, GEO, and RT-qPCR validation. World J Surg Oncol. 2018;16(1):76. https://doi.org/10.1186/s12957-018-1378-6.CrossRefPubMedPubMedCentral

12.

He K, Zhu ZB, Shu R, Hong A. LncRNA NEAT1 mediates progression of oral squamous cell carcinoma via VEGF-A and Notch signaling pathway. World J Surg Oncol. 2020;18(1):261. https://doi.org/10.1186/s12957-020-02028-x.CrossRefPubMed

13.

Hoadley KA, Yau C, Hinoue T, Wolf DM, Lazar AJ, Drill E, et al. Cell-of-origin patterns dominate the molecular classification of 10,000 tumors from 33 types of cancer. Cell. 2018;173(2):291–304.e296.CrossRef

14.

Marla V, Hegde V, Shrestha A. Relationship of angiogenesis and oral squamous cell carcinoma. Kathmandu Univ Med J (KUMJ). 2015;13(50):178–85. https://doi.org/10.3126/kumj.v13i2.16796.CrossRef

15.

Kabiraj A, Jaiswal R, Singh A, Gupta J, Singh A, Samadi FM. Immunohistochemical evaluation of tumor angiogenesis and the role of mast cells in oral squamous cell carcinoma. J Cancer Res Ther. 2018;14(3):495–502. https://doi.org/10.4103/0973-1482.163693.CrossRefPubMed

16.

Folkman J. Fundamental concepts of the angiogenic process. Curr Mol Med. 2003;3(7):643–51. https://doi.org/10.2174/1566524033479465.CrossRefPubMed

17.

Ascani G, Balercia P, Messi M, Lupi L, Goteri G, Filosa A, et al. Angiogenesis in oral squamous cell carcinoma. Acta Otorhinolaryngol Ital. 2005;25(1):13–7.PubMedPubMedCentral

18.

Lingen MW. Angiogenesis in the development of head and neck cancer and its inhibition by chemopreventive agents. Crit Rev Oral Biol Med. 1999;10(2):153–64. https://doi.org/10.1177/10454411990100020301.CrossRefPubMed

19.

Subramanian A, Tamayo P, Mootha VK, Mukherjee S, Ebert BL, Gillette MA, et al. Gene set enrichment analysis: a knowledge-based approach for interpreting genome-wide expression profiles. Proc Natl Acad Sci U S A. 2005;102(43):15545–50. https://doi.org/10.1073/pnas.0506580102.CrossRefPubMedPubMedCentral

20.

Thorsson V, Gibbs DL, Brown SD, Wolf D, Bortone DS, Ou Yang TH, et al. The immune landscape of cancer. Immunity. 2018;48(4):812–830.e814.CrossRef

21.

Carter SL, Cibulskis K, Helman E, McKenna A, Shen H, Zack T, et al. Absolute quantification of somatic DNA alterations in human cancer. Nat Biotechnol. 2012;30(5):413–21. https://doi.org/10.1038/nbt.2203.CrossRefPubMedPubMedCentral

22.

Viallard C, Larrivée B. Tumor angiogenesis and vascular normalization: alternative therapeutic targets. Angiogenesis. 2017;20(4):409–26. https://doi.org/10.1007/s10456-017-9562-9.CrossRefPubMed

23.

Newman AM, Liu CL, Green MR, Gentles AJ, Feng W, Xu Y, et al. Robust enumeration of cell subsets from tissue expression profiles. Nat Methods. 2015;12(5):453–7. https://doi.org/10.1038/nmeth.3337.CrossRefPubMedPubMedCentral

24.

Chen B, Khodadoust MS, Liu CL, Newman AM, Alizadeh AA. Profiling tumor infiltrating immune cells with CIBERSORT. Methods Mol Biol. 2018;1711:243–59.CrossRef

25.

Yoshihara K, Shahmoradgoli M, Martínez E, Vegesna R, Kim H, Torres-Garcia W, et al. Inferring tumour purity and stromal and immune cell admixture from expression data. Nat Commun. 2013;4(1):2612. https://doi.org/10.1038/ncomms3612.CrossRefPubMed

26.

Li B, Cui Y, Nambiar DK, Sunwoo JB, Li R. The immune subtypes and landscape of squamous cell carcinoma. Clin Cancer Res. 2019;25(12):3528–37. https://doi.org/10.1158/1078-0432.CCR-18-4085.CrossRefPubMedPubMedCentral

27.

Kahn BM, Lucas A, Alur RG, Wengyn MD, Schwartz GW, Li J, Sun K, Maurer HC, Olive KP, Faryabi RB, Stanger BZ. The vascular landscape of human cancer. J Clin Invest. 2021:131.

28.

Nowak-Sliwinska P, Alitalo K, Allen E, Anisimov A, Aplin AC, Auerbach R, et al. Consensus guidelines for the use and interpretation of angiogenesis assays. Angiogenesis. 2018;21(3):425–532. https://doi.org/10.1007/s10456-018-9613-x.CrossRefPubMedPubMedCentral

29.

Hawighorst T. Angiogenesis, lymphangiogenesis, and tumor progression. Zentralbl Gynakol. 2002;124(11):497–505. https://doi.org/10.1055/s-2002-39653.CrossRefPubMed

30.

Lamouille S, Xu J, Derynck R. Molecular mechanisms of epithelial-mesenchymal transition. Nat Rev Mol Cell Biol. 2014;15(3):178–96. https://doi.org/10.1038/nrm3758.CrossRefPubMedPubMedCentral

31.

Zhang Z, Dong Z, Lauxen IS, Filho MS, Nör JE. Endothelial cell-secreted EGF induces epithelial to mesenchymal transition and endows head and neck cancer cells with stem-like phenotype. Cancer Res. 2014;74(10):2869–81. https://doi.org/10.1158/0008-5472.CAN-13-2032.CrossRefPubMedPubMedCentral

32.

Mantovani A, Allavena P, Sica A, Balkwill F. Cancer-related inflammation. Nature. 2008;454(7203):436–44. https://doi.org/10.1038/nature07205.CrossRefPubMed

33.

An X, Xu G, Yang L, Wang Y, Li Y, McHepange UO, et al. Expression of hypoxia-inducible factor-1α, vascular endothelial growth factor and prolyl hydroxylase domain protein 2 in cutaneous squamous cell carcinoma and precursor lesions and their relationship with histological stages and clinical features. J Dermatol. 2014;41(1):76–83. https://doi.org/10.1111/1346-8138.12314.CrossRefPubMed

34.

De Felice F, Marchetti C, Palaia I, Ostuni R, Muzii L, Tombolini V, et al. Immune check-point in cervical cancer. Crit Rev Oncol Hematol. 2018;129:40–3. https://doi.org/10.1016/j.critrevonc.2018.06.006.CrossRefPubMed

35.

Pardoll DM. The blockade of immune checkpoints in cancer immunotherapy. Nat Rev Cancer. 2012;12(4):252–64. https://doi.org/10.1038/nrc3239.CrossRefPubMedPubMedCentral

36.

De Felice F, Marchetti C, Palaia I, Musio D, Muzii L, Tombolini V, et al. Immunotherapy of ovarian cancer: the role of checkpoint inhibitors. J Immunol Res. 2015;2015:191832.CrossRef

37.

La-Beck NM, Jean GW, Huynh C, Alzghari SK, Lowe DB. Immune Checkpoint Inhibitors: New Insights and Current Place in Cancer Therapy. Pharmacotherapy. 2015;35:963–76.

Title: Comprehensive analysis of angiogenesis subtype of squamous cell carcinoma
Authors: Fanglu Qin
Shenghua Lin
Kun Deng
Junqi Qin
Zhanyu Xu
Liqiang Yuan
Jiangbo Wei
Yu Sun
Tiaozhan Zheng
Shikang Li
Publication date: 01-12-2021
Publisher: BioMed Central
Published in: World Journal of Surgical Oncology / Issue 1/2021
Electronic ISSN: 1477-7819
DOI: https://doi.org/10.1186/s12957-021-02367-3

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Comprehensive analysis of angiogenesis subtype of squamous cell carcinoma

Abstract

Background

Method and materials

Results

Conclusion

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Background

Method and materials

Results

Conclusion

Please log in to get access to this content

Other articles of this Issue 1/2021

In silico analysis of differentially expressed genesets in metastatic breast cancer identifies potential prognostic biomarkers

The role of FOLFIRINOX in metastatic pancreatic cancer: a meta-analysis

Secondarily estimated cure fraction and five-year recurrence-free conditional survival probabilities among patients undergoing surgical resection for hepatocellular carcinoma presenting with minor gross vascular invasion

Pre-colectomy location and TNM staging of colon cancer by the computed tomography colonography: a diagnostic performance study

Potential role of chimeric genes in pathway-related gene co-expression modules

Total laparoscopic transabdominal-transdiaphragmatic approach for treating Siewert II tumors: a prospective analysis of a case series