Anaplastic transition within the cancer microenvironment in early-stage oral tongue squamous cell carcinoma is associated with local recurrence

  • Authors:
    • Kohei Okuyama
    • Keiji Suzuki
    • Souichi Yanamoto
    • Tomofumi Naruse
    • Hiroki Tsuchihashi
    • Shunichi Yamashita
    • Masahiro Umeda
  • View Affiliations

  • Published online on: August 6, 2018     https://doi.org/10.3892/ijo.2018.4515
  • Pages: 1713-1720
Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )
Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )


Abstract

The cancer microenvironment (CME) promotes malignant progression of cancer cells by stimulating cell growth, migration and invasion. Cancer-associated fibroblasts (CAFs), prominent features of the CME, interact directly with cancer cells and facilitate epithelial-mesenchymal transition (EMT). The present study examined the spatial distribution of CAFs and EMT on cancer cells in patients with early-stage tongue squamous cell carcinoma (TSCC) and their association with local recurrence. The present study included 14 patients with early-stage TSCC who had undergone glossectomy between 2006 and 2015, of which 7 experienced local recurrence (LR group) and 7 did not (control group). Multiple immunofluorescent analysis (MIA) of PCNA, αSMA, vimentin, E-cadherin and cytokeratin 14 (CK14) was performed on slides obtained from surgical specimens to identify the expression of various cell-specific markers. The number of CAFs in the CME was significantly increased in the LR group (P=0.001). Furthermore, the neighbouring cancer cells were positive for vimentin expression, indicating EMT. However, the present study also identified concurrent expression of CK14 in all vimentin-positive cancer cells, whilst epithelial markers, including E-cadherin, were expressed in certain vimentin-positive cancer cells. Concurrent expression of CK14 and vimentin is not defined as EMT or partial EMT. Therefore, the present study proposed a novel mechanism of anaplastic transition (APT), in which epithelial cancer cells concurrently develop mesenchymal features, which is achieved by pathways other than EMT. APT is characterized such that epithelial cancer cells differentiate into more primitive states, which is different from EMT or partial EMT, and it may be associated with LR. The concept aids in improving knowledge regarding tumor recurrence in patients with early-stage TSCC.

References

1 

Lin NN, Wang P, Zhao D, Zhang FJ, Yang K and Chen R: Significance of oral cancer-associated fibroblasts in angiogenesis, lymphangiogenesis, and tumor invasion in oral squamous cell carcinoma. J Oral Pathol Med. 46:21–30. 2017. View Article : Google Scholar

2 

Haddad RI and Shin DM: Recent advances in head and neck cancer. N Engl J Med. 359:1143–1154. 2008. View Article : Google Scholar : PubMed/NCBI

3 

Döbrossy L: Epidemiology of head and neck cancer: Magnitude of the problem. Cancer Metastasis Rev. 24:9–17. 2005. View Article : Google Scholar : PubMed/NCBI

4 

Rodrigues-Lisoni FC, Peitl P Jr, Vidotto A, Polachini GM, Maniglia JV, Carmona-Raphe J, Cunha BR, Henrique T, Souza CF, Teixeira RA, et al Head and Neck Genome Project GENCAPO: Genomics and proteomics approaches to the study of cancer-stroma interactions. BMC Med Genomics. 3:142010. View Article : Google Scholar : PubMed/NCBI

5 

Kalluri R and Zeisberg M: Fibroblasts in cancer. Nat Rev Cancer. 6:392–401. 2006. View Article : Google Scholar : PubMed/NCBI

6 

Hanna E, Quick J and Libutti SK: The tumour microenvironment: A novel target for cancer therapy. Oral Dis. 15:8–17. 2009. View Article : Google Scholar

7 

Zhou B, Chen WL, Wang YY, Lin ZY, Zhang DM, Fan S and Li JS: A role for cancer-associated fibroblasts in inducing the epithelial-to-mesenchymal transition in human tongue squamous cell carcinoma. J Oral Pathol Med. 43:585–592. 2014. View Article : Google Scholar : PubMed/NCBI

8 

Vered M, Dayan D, Yahalom R, Dobriyan A, Barshack I, Bello IO, Kantola S and Salo T: Cancer-associated fibroblasts and epithelial-mesenchymal transition in metastatic oral tongue squamous cell carcinoma. Int J Cancer. 127:1356–1362. 2010. View Article : Google Scholar : PubMed/NCBI

9 

Li H, Zhang J, Chen SW, Liu LL, Li L, Gao F, Zhuang SM, Wang LP, Li Y and Song M: Cancer-associated fibroblasts provide a suitable microenvironment for tumor development and progression in oral tongue squamous cancer. J Transl Med. 13:1982015. View Article : Google Scholar : PubMed/NCBI

10 

De Wever O and Mareel M: Role of tissue stroma in cancer cell invasion. J Pathol. 200:429–447. 2003. View Article : Google Scholar : PubMed/NCBI

11 

Jewett A, Head C and Cacalano NA: Emerging mechanisms of immunosuppression in oral cancers. J Dent Res. 85:1061–1073. 2006. View Article : Google Scholar : PubMed/NCBI

12 

De Wever O, Demetter P, Mareel M and Bracke M: Stromal myofibroblasts are drivers of invasive cancer growth. Int J Cancer. 123:2229–2238. 2008. View Article : Google Scholar : PubMed/NCBI

13 

Wheeler SE, Shi H, Lin F, Dasari S, Bednash J, Thorne S, Watkins S, Joshi R and Thomas SM: Enhancement of head and neck squamous cell carcinoma proliferation, invasion, and metastasis by tumor-associated fibroblasts in preclinical models. Head Neck. 36:385–392. 2014. View Article : Google Scholar

14 

Sappino AP, Skalli O, Jackson B, Schürch W and Gabbiani G: Smooth-muscle differentiation in stromal cells of malignant and non-malignant breast tissues. Int J Cancer. 41:707–712. 1988. View Article : Google Scholar : PubMed/NCBI

15 

Lazard D, Sastre X, Frid MG, Glukhova MA, Thiery JP and Koteliansky VE: Expression of smooth muscle-specific proteins in myoepithelium and stromal myofibroblasts of normal and malignant human breast tissue. Proc Natl Acad Sci USA. 90:999–1003. 1993. View Article : Google Scholar : PubMed/NCBI

16 

Mueller MM and Fusenig NE: Friends or foes - bipolar effects of the tumour stroma in cancer. Nat Rev Cancer. 4:839–849. 2004. View Article : Google Scholar : PubMed/NCBI

17 

Rønnov-Jessen L, Petersen OW and Bissell MJ: Cellular changes involved in conversion of normal to malignant breast: Importance of the stromal reaction. Physiol Rev. 76:69–125. 1996. View Article : Google Scholar : PubMed/NCBI

18 

el-Naggar AK, Lai S, Luna MA, Zhou XD, Weber RS, Goepfert H and Batsakis JG: Sequential p53 mutation analysis of pre-invasive and invasive head and neck squamous carcinoma. Int J Cancer. 64:196–201. 1995. View Article : Google Scholar : PubMed/NCBI

19 

Kellermann MG, Sobral LM, da Silva SD, Zecchin KG, Graner E, Lopes MA, Kowalski LP and Coletta RD: Mutual paracrine effects of oral squamous cell carcinoma cells and normal oral fibroblasts: Induction of fibroblast to myofibroblast transdifferentiation and modulation of tumor cell proliferation. Oral Oncol. 44:509–517. 2008. View Article : Google Scholar

20 

Daly AJ, McIlreavey L and Irwin CR: Regulation of HGF and SDF-1 expression by oral fibroblasts–implications for invasion of oral cancer. Oral Oncol. 44:646–651. 2008. View Article : Google Scholar

21 

Thiery JP, Acloque H, Huang RY and Nieto MA: Epithelial-mesenchymal transitions in development and disease. Cell. 139:871–890. 2009. View Article : Google Scholar : PubMed/NCBI

22 

Potenta S, Zeisberg E and Kalluri R: The role of endothelial-to-mesenchymal transition in cancer progression. Br J Cancer. 99:1375–1379. 2008. View Article : Google Scholar : PubMed/NCBI

23 

Kalluri R and Weinberg RA: The basics of epithelial-mesenchymal transition. J Clin Invest. 119:1420–1428. 2009. View Article : Google Scholar : PubMed/NCBI

24 

Chen C, Zimmermann M, Tinhofer I, Kaufmann AM and Albers AE: Epithelial-to-mesenchymal transition and cancer stem(-like) cells in head and neck squamous cell carcinoma. Cancer Lett. 338:47–56. 2013. View Article : Google Scholar

25 

Lee JM, Dedhar S, Kalluri R and Thompson EW: The epithelial-mesenchymal transition: New insights in signaling, development, and disease. J Cell Biol. 172:973–981. 2006. View Article : Google Scholar : PubMed/NCBI

26 

Yang J, Mani SA, Donaher JL, Ramaswamy S, Itzykson RA, Come C, Savagner P, Gitelman I, Richardson A and Weinberg RA: Twist, a master regulator of morphogenesis, plays an essential role in tumor metastasis. Cell. 117:927–939. 2004. View Article : Google Scholar : PubMed/NCBI

27 

Wang C, Huang H, Huang Z, Wang A, Chen X, Huang L, Zhou X and Liu X: Tumor budding correlates with poor prognosis and epithelial-mesenchymal transition in tongue squamous cell carcinoma. J Oral Pathol Med. 40:545–551. 2011. View Article : Google Scholar : PubMed/NCBI

28 

Lydiatt WM, Patel SG, O'Sullivan B, Brandwein MS, Ridge JA, Migliacci JC, Loomis AM and Shah JP: Head and neck cancers-major changes in the American Joint Committee on cancer eighth edition cancer staging manual. CA Cancer J Clin. 67:122–37. 2017. View Article : Google Scholar : PubMed/NCBI

29 

Brierley JD, Gospodarowicz MK and Wittekind C: TNM Classification of Malignant Tumours. 8th edition. Wiley-Blackwell; Chichester: 2017

30 

Lim KP, Cirillo N, Hassona Y, Wei W, Thurlow JK, Cheong SC, Pitiyage G, Parkinson EK and Prime SS: Fibroblast gene expression profile reflects the stage of tumour progression in oral squamous cell carcinoma. J Pathol. 223:459–469. 2011. View Article : Google Scholar : PubMed/NCBI

31 

Kawashiri S, Tanaka A, Noguchi N, Hase T, Nakaya H, Ohara T, Kato K and Yamamoto E: Significance of stromal desmoplasia and myofibroblast appearance at the invasive front in squamous cell carcinoma of the oral cavity. Head Neck. 31:1346–1353. 2009. View Article : Google Scholar : PubMed/NCBI

32 

Wang J, Min A, Gao S and Tang Z: Genetic regulation and potentially therapeutic application of cancer-associated fibroblasts in oral cancer. J Oral Pathol Med. 43:323–334. 2014. View Article : Google Scholar

33 

Olumi AF, Grossfeld GD, Hayward SW, Carroll PR, Tlsty TD and Cunha GR: Carcinoma-associated fibroblasts direct tumor progression of initiated human prostatic epithelium. Cancer Res. 59:5002–5011. 1999.PubMed/NCBI

34 

Takahashi H, Sakakura K, Kudo T, Toyoda M, Kaira K, Oyama T and Chikamatsu K: Cancer-associated fibroblasts promote an immunosuppressive microenvironment through the induction and accumulation of protumoral macrophages. Oncotarget. 8:8633–8647. 2017. View Article : Google Scholar : PubMed/NCBI

35 

Johansson AC, Ansell A, Jerhammar F, Lindh MB, Grénman R, Munck-Wikland E, Östman A and Roberg K: Cancer-associated fibroblasts induce matrix metalloproteinase-mediated cetuximab resistance in head and neck squamous cell carcinoma cells. Mol Cancer Res. 10:1158–1168. 2012. View Article : Google Scholar : PubMed/NCBI

36 

Sinha N, Mukhopadhyay S, Das DN, Panda PK and Bhutia SK: Relevance of cancer initiating/stem cells in carcinogenesis and therapy resistance in oral cancer. Oral Oncol. 49:854–862. 2013. View Article : Google Scholar : PubMed/NCBI

37 

Matsushita Y, Yanamoto S, Takahashi H, Yamada S, Naruse T, Sakamoto Y, Ikeda H, Shiraishi T, Fujita S, Ikeda T, et al: A clinicopathological study of perineural invasion and vascular invasion in oral tongue squamous cell carcinoma. Int J Oral Maxillofac Surg. 44:543–548. 2015. View Article : Google Scholar : PubMed/NCBI

38 

Velez-delValle C, Marsch-Moreno M, Castro-Muñozledo F, Galván-Mendoza IJ and Kuri-Harcuch W: Epithelial cell migration requires the interaction between the vimentin and keratin intermediate filaments. Sci Rep. 6:243892016. View Article : Google Scholar : PubMed/NCBI

39 

Ramaekers FC, Haag D, Kant A, Moesker O, Jap PH and Vooijs GP: Coexpression of keratin- and vimentin-type intermediate filaments in human metastatic carcinoma cells. Proc Natl Acad Sci USA. 80:2618–2622. 1983. View Article : Google Scholar : PubMed/NCBI

40 

Pagan R, Martín I, Alonso A, Llobera M and Vilaró S: Vimentin filaments follow the preexisting cytokeratin network during epithelial-mesenchymal transition of cultured neonatal rat hepatocytes. Exp Cell Res. 222:333–344. 1996. View Article : Google Scholar : PubMed/NCBI

41 

Grigore AD, Jolly MK, Jia D, Farach-Carson MC and Levine H: Tumor Budding: The Name is EMT. Partial EMT J Clin Med. 5:E512016. View Article : Google Scholar

42 

Pradella D, Naro C, Sette C and Ghigna C: EMT and stemness: Flexible processes tuned by alternative splicing in development and cancer progression. Mol Cancer. 16:82017. View Article : Google Scholar : PubMed/NCBI

Related Articles

Journal Cover

October 2018
Volume 53 Issue 4

Print ISSN: 1019-6439
Online ISSN:1791-2423

Sign up for eToc alerts

Recommend to Library

Copy and paste a formatted citation
APA
Okuyama, K., Suzuki, K., Yanamoto, S., Naruse, T., Tsuchihashi, H., Yamashita, S., & Umeda, M. (2018). Anaplastic transition within the cancer microenvironment in early-stage oral tongue squamous cell carcinoma is associated with local recurrence. International Journal of Oncology, 53, 1713-1720. https://doi.org/10.3892/ijo.2018.4515
MLA
Okuyama, K., Suzuki, K., Yanamoto, S., Naruse, T., Tsuchihashi, H., Yamashita, S., Umeda, M."Anaplastic transition within the cancer microenvironment in early-stage oral tongue squamous cell carcinoma is associated with local recurrence". International Journal of Oncology 53.4 (2018): 1713-1720.
Chicago
Okuyama, K., Suzuki, K., Yanamoto, S., Naruse, T., Tsuchihashi, H., Yamashita, S., Umeda, M."Anaplastic transition within the cancer microenvironment in early-stage oral tongue squamous cell carcinoma is associated with local recurrence". International Journal of Oncology 53, no. 4 (2018): 1713-1720. https://doi.org/10.3892/ijo.2018.4515