Cancer-associated fibroblasts provide a suitable microenvironment for tumor development and progression in oral tongue squamous cancer

Journal of Translational Medicine

Ming Song³  Yan Li²  Li-ping Wang⁵  Shi-Min Zhuang¹  Fan Gao³  Lei Li²  Lu-lu Liu²  Shu-Wei Chen³  Ji Zhang³  Huan Li⁴ 

[1] Department of Otolaryngology-Head & Neck Surgery, The Third Affiliated Hospital of Sun Yat-sen University, Guangzhou, People’s Republic of China;Department of Experimental Research, Sun Yat-sen University Cancer Center, Guangzhou, People’s Republic of China;Department of Head and Neck Surgery, Sun Yat-sen University Cancer Center, Guangzhou, People’s Republic of China;Department of Intensive Care, Sun Yat-sen University Cancer Center, Guangzhou, People’s Republic of China;The People’s Hospital of Bao’an District Shenzhen, Shenzhen, People’s Republic of China

关键词: Progression;    Cancer-associated fibroblast;    Microenvironment;    Oral tongue squamous cell cancer;   

Others  :  1228113
DOI  :  10.1186/s12967-015-0551-8

 received in 2014-11-24, accepted in 2015-05-27,  发布年份 2015

【 摘 要 】

Background

Oral tongue squamous cell carcinoma (OTSCC) is still associated with a poor prognosis due to local recurrence and metastasis. Cancer-associated fibroblasts (CAFs) play an important role in the complex processes of cancer stroma interaction and tumorigenesis. This study aims to determine the role of CAFs in the development and progression of OTSCC.

Methods

Immunohistochemistry was performed to evaluate the frequency and distribution of CAFs in 178 paraffin specimens from patients with OTSCC. Immunofluorescence, a cell proliferation assay, flow cytometry, migration and invasion assays and western blot analysis were used to study the effects of CAFs and the corresponding conditioned medium (CM) on the proliferation and invasion of OTSCC cell lines.

Results

Statistical analysis showed a strong correlation between the frequency and distribution of CAFs and the clinicopathological characteristics of patients with cN0 OTSCC, including pathological stage (P = 0.001), T classification (P = 0.001), and N classification (P = 0.009). Survival analysis demonstrated a negative correlation of the frequency and distribution of CAFs with the overall survival and disease-free survival of patients with cN0 tongue squamous cell cancer (P = 0.009, 0.002, respectively); Cox regression analysis showed that the presence of CAFs (relative risk: 2.113, CI 1.461–3.015, P = 0.023) is an independent prognostic factor. A functional study demonstrated that CAFs and CM from CAFs could promote the growth, proliferation, mobility, invasion and even Epithelial Mesenchymal Transition (EMT) of OTSCC cells compared with NFs and CM from NFs.

Conclusions

CAFs were an independent prognostic factor for patients with OTSCC. Compared with NFs, CAFs and their CM have the ability to promote the growth, proliferation, metastasis and even EMT of OTSCC cells.

【 授权许可】

   
2015 Li et al.

【 图 表 】

Figure1.

Figure2.

Figure3.

Figure4.

Figure5.

【 参考文献 】

• [1]Jemal A, Bray F, Center MM, Ferlay J, Ward E, Forman D. Global cancer statistics. CA Cancer J Clin. 2011; 61:69-90.
• [2]Moore SR, Johnson NW, Pierce AM, Wilson DF. The epidemiology of tongue cancer: a review of global incidence. Oral Dis. 2000; 6:75-84.
• [3]Jemal A, Clegg LX, Ward E, Ries LA, Wu X, Jamison PM et al.. Annual report to the nation on the status of cancer, 1975–2001, with a special feature regarding survival. Cancer. 2004; 101:3-27.
• [4]Rodrigues-Lisoni FC, Peitl PJ, Vidotto A, Polachini GM, Maniglia JV, Carmona-Raphe J et al.. Genomics and proteomics approaches to the study of cancer-stroma interactions. BMC Med Genomics. 2010; 3:14. BioMed Central Full Text
• [5]Kalluri R, Zeisberg M. Fibroblasts in cancer. Nat Rev Cancer. 2006; 6:392-401.
• [6]Plzak J, Lacina L, Chovanec M, Dvorankova B, Szabo P, Cada Z et al.. Epithelial-stromal interaction in squamous cell epithelium-derived tumors: an important new player in the control of tumor biological properties. Anticancer Res. 2010; 30:455-462.
• [7]Polyak K, Haviv I, Campbell IG. Co-evolution of tumor cells and their microenvironment. Trends Genet. 2009; 25:30-38.
• [8]Eck SM, Cote AL, Winkelman WD, Brinckerhoff CE. CXCR4 and matrix metalloproteinase-1 are elevated in breast carcinoma-associated fibroblasts and in normal mammary fibroblasts exposed to factors secreted by breast cancer cells. Mol Cancer Res. 2009; 7:1033-1044.
• [9]Gonda TA, Varro A, Wang TC, Tycko B. Molecular biology of cancer-associated fibroblasts: can these cells be targeted in anti-cancer therapy? Semin Cell Dev Biol. 2010; 21:2-10.
• [10]Sappino AP, Skalli O, Jackson B, Schurch W, Gabbiani G. Smooth-muscle differentiation in stromal cells of malignant and non-malignant breast tissues. Int J Cancer. 1988; 41:707-712.
• [11]Lazard D, Sastre X, Frid MG, Glukhova MA, Thiery JP, 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. 1993; 90:999-1003.
• [12]Mueller MM, Fusenig NE. Friends or foes—bipolar effects of the tumour stroma in cancer. Nat Rev Cancer. 2004; 4:839-849.
• [13]Ronnov-Jessen L, Petersen OW, Bissell MJ. Cellular changes involved in conversion of normal to malignant breast: importance of the stromal reaction. Physiol Rev. 1996; 76:69-125.
• [14]De Wever O, Mareel M. Role of tissue stroma in cancer cell invasion. J Pathol. 2003; 200:429-447.
• [15]Jewett A, Head C, Cacalano NA. Emerging mechanisms of immunosuppression in oral cancers. J Dent Res. 2006; 85:1061-1073.
• [16]De Wever O, Demetter P, Mareel M, Bracke M. Stromal myofibroblasts are drivers of invasive cancer growth. Int J Cancer. 2008; 123:2229-2238.
• [17]Voulgari A, Pintzas A. Epithelial-mesenchymal transition in cancer metastasis: mechanisms, markers and strategies to overcome drug resistance in the clinic. Biochim Biophys Acta. 2009; 1796:75-90.
• [18]Thiery JP, Sleeman JP. Complex networks orchestrate epithelial-mesenchymal transitions. Nat Rev Mol Cell Biol. 2006; 7:131-142.
• [19]Nawshad A, Lagamba D, Polad A, Hay ED. Transforming growth factor-beta signaling during epithelial-mesenchymal transformation: implications for embryogenesis and tumor metastasis. Cells Tissues Organs. 2005; 179:11-23.
• [20]Vered M, Allon I, Buchner A, Dayan D. Stromal myofibroblasts accompany modifications in the epithelial phenotype of tongue dysplastic and malignant lesions. Cancer Microenviron. 2009; 2:49-57.
• [21]Friess H, Ding J, Kleeff J, Fenkell L, Rosinski JA, Guweidhi A et al.. Microarray-based identification of differentially expressed growth- and metastasis-associated genes in pancreatic cancer. Cell Mol Life Sci. 2003; 60:1180-1199.
• [22]Nakagawa H, Liyanarachchi S, Davuluri RV, Auer H, Martin EJ, de la Chapelle A et al.. Role of cancer-associated stromal fibroblasts in metastatic colon cancer to the liver and their expression profiles. Oncogene. 2004; 23:7366-7377.
• [23]Singer CF, Gschwantler-Kaulich D, Fink-Retter A, Haas C, Hudelist G, Czerwenka K et al.. Differential gene expression profile in breast cancer-derived stromal fibroblasts. Breast Cancer Res Treat. 2008; 110:273-281.
• [24]Micke P, Kappert K, Ohshima M, Sundquist C, Scheidl S, Lindahl P et al.. In situ identification of genes regulated specifically in fibroblasts of human basal cell carcinoma. J Invest Dermatol. 2007; 127:1516-1523.
• [25]Tlsty TD. Stromal cells can contribute oncogenic signals. Semin Cancer Biol. 2001; 11:97-104.
• [26]Elenbaas B, Weinberg RA. Heterotypic signaling between epithelial tumor cells and fibroblasts in carcinoma formation. Exp Cell Res. 2001; 264:169-184.
• [27]Nakayama H, Enzan H, Miyazaki E, Naruse K, Kiyoku H, Hiroi M. The role of myofibroblasts at the tumor border of invasive colorectal adenocarcinomas. Jpn J Clin Oncol. 1998; 28:615-620.
• [28]Tuxhorn JA, Ayala GE, Smith MJ, Smith VC, Dang TD, Rowley DR. Reactive stroma in human prostate cancer: induction of myofibroblast phenotype and extracellular matrix remodeling. Clin Cancer Res. 2002; 8:2912-2923.
• [29]Orimo A, Tomioka Y, Shimizu Y, Sato M, Oigawa S, Kamata K et al.. Cancer-associated myofibroblasts possess various factors to promote endometrial tumor progression. Clin Cancer Res. 2001; 7:3097-3105.
• [30]Nouraee N, Van Roosbroeck K, Vasei M, Semnani S, Samaei NM, Naghshvar F et al.. Expression, tissue distribution and function of miR-21 in esophageal squamous cell carcinoma. PLoS One. 2013; 8(9):e73009.
• [31]Thompson L. World Health Organization classification of tumours: pathology and genetics of head and neck tumours. Ear Nose Throat J. 2006; 85:74.
• [32]Vered M, Dobriyan A, Dayan D, Yahalom R, Talmi YP, Bedrin L et al.. Tumor-host histopathologic variables, stromal myofibroblasts and risk score, are significantly associated with recurrent disease in tongue cancer. Cancer Sci. 2010; 101:274-280.
• [33]D’Cruz AK, Siddachari RC, Walvekar RR, Pantvaidya GH, Chaukar DA, Deshpande MS et al.. Elective neck dissection for the management of the N0 neck in early cancer of the oral tongue: need for a randomized controlled trial. Head Neck. 2009; 31:618-624.
• [34]Hayry V, Makinen LK, Atula T, Sariola H, Makitie A, Leivo I et al.. Bmi-1 expression predicts prognosis in squamous cell carcinoma of the tongue. Br J Cancer. 2010; 102:892-897.
• [35]Manning BD, Cantley LC. AKT/PKB signaling: navigating downstream. Cell. 2007; 129:1261-1274.
• [36]Guarino M. Epithelial-mesenchymal transition and tumour invasion. Int J Biochem Cell Biol. 2007; 39:2153-2160.
• [37]Yang J, Weinberg RA. Epithelial-mesenchymal transition: at the crossroads of development and tumor metastasis. Dev Cell. 2008; 14:818-829.
• [38]Hugo H, Ackland ML, Blick T, Lawrence MG, Clements JA, Williams ED et al.. Epithelial–mesenchymal and mesenchymal–epithelial transitions in carcinoma progression. J Cell Physiol. 2007; 213:374-383.
• [39]Zhi K, Shen X, Zhang H, Bi J. Cancer-associated fibroblasts are positively correlated with metastatic potential of human gastric cancers. J Exp Clin Cancer Res. 2010; 29:66. BioMed Central Full Text
• [40]Ruotsalainen T, Joensuu H, Mattson K, Salven P. High pretreatment serum concentration of basic fibroblast growth factor is a predictor of poor prognosis in small cell lung cancer. Cancer Epidemiol Biomarkers Prev. 2002; 11:1492-1495.
• [41]Pardo OE, Wellbrock C, Khanzada UK, Aubert M, Arozarena I, Davidson S et al.. FGF-2 protects small cell lung cancer cells from apoptosis through a complex involving PKCepsilon, B-Raf and S6K2. EMBO J. 2006; 25:3078-3088.
• [42]Presta M, Dell’Era P, Mitola S, Moroni E, Ronca R, Rusnati M. Fibroblast growth factor/fibroblast growth factor receptor system in angiogenesis. Cytokine Growth Factor Rev. 2005; 16:159-178.
• [43]Birrer MJ, Johnson ME, Hao K, Wong KK, Park DC, Bell A et al.. Whole genome oligonucleotide-based array comparative genomic hybridization analysis identified fibroblast growth factor 1 as a prognostic marker for advanced-stage serous ovarian adenocarcinomas. J Clin Oncol. 2007; 25:2281-2287.