Fusion between cancer cells and myofibroblasts is involved in osteosarcoma

Yu,Ling; Guo,Weichun; Zhao,Shenghao; Wang,Fuan; Xu,Yong

doi:10.3892/ol.2011.363

Fusion between cancer cells and myofibroblasts is involved in osteosarcoma

Authors:
- Ling Yu
- Weichun Guo
- Shenghao Zhao
- Fuan Wang
- Yong Xu
View Affiliations

Affiliations: Department of Orthopedics, Renmin Hospital of Wuhan University, Wuhan, Hubei, P.R. China
Published online on: July 14, 2011 https://doi.org/10.3892/ol.2011.363
Pages: 1083-1087

Metrics: Total Views: 0 (Spandidos Publications: | PMC Statistics: )

Metrics: Total PDF Downloads: 0 (Spandidos Publications: | PMC Statistics: )

Cited By (CrossRef): 0 citations Loading Articles...

Abstract

Communication between cancer cells and the microenvironment appears to be an important determinant of disease prognosis. However, the detailed mechanisms of the interactions between cancer cells and surrounding cells have yet to be clarified. Recent studies on cell fusion have indicated this interaction to be one of the driving forces in cancer progression. Fibroblasts constitute a significant component of the carcinoma stromal compartment. Many of these fibroblasts are thought to differentiate into myofibroblasts, which are characterized by a positive expression of α-smooth muscle actin. Expression of α-smooth muscle actin in osteosarcoma was evaluated, and was observed to be excessive in the multinucleated osteoclast-like giant cells in osteosarcoma tissue, indicating the possibility of cell fusion between cancer cells and myofibroblasts. In order to test the above hypothesis, we first transformed the primary mouse embryonic fibroblast cells into activated myofibroblast cells. Osteosarcoma cells were then co-cultured with mouse myofibroblast cells, and cell fusion was investigated using species-specific chromosomal markers. Expression of α-smooth muscle actin was successfully induced in primary mouse embryonic fibroblast cells. Cells fused spontaneously with a fusion rate of approximately 1-2% and fusion between more than two cells was also observed. Our study demonstrated that fusion between cancer cells and myofibroblasts may contribute to the observed multinucleated giant cells in osteosarcoma. We posit that cell fusion is a novel mechanism for the interaction between cancer cells and the microenvironment.

View Figures

View References

1	Ottaviani G and Jaffe N: The epidemiology of osteosarcoma. Cancer Treat Res. 152:3–13. 2009. View Article : Google Scholar
2	Hansen MF, Koufos A, Gallie BL, et al: Osteosarcoma and retinoblastoma: a shared chromosomal mechanism revealing recessive predisposition. Proc Natl Acad Sci USA. 82:6216–6120. 1985. View Article : Google Scholar : PubMed/NCBI
3	Porter DE, Holden ST, Steel CM, Cohen BB, Wallace MR and Reid R: A significant proportion of patients with osteosarcoma may belong to Li-Fraumeni cancer families. J Bone Joint Surg Br. 74:883–886. 1992.PubMed/NCBI
4	Selvarajah S, Yoshimoto M, Ludkovski O, et al: Genomic signatures of chromosomal instability and osteosarcoma progression detected by high resolution array CGH and interphase FISH. Cytogenet Genome Res. 122:5–15. 2008. View Article : Google Scholar : PubMed/NCBI
5	Bayani J, Zielenska M, Pandita A, et al: Spectral karyotyping identifies recurrent complex rearrangements of chromosomes 8, 17, and 20 in osteosarcomas. Genes Chromosomes Cancer. 36:7–16. 2003. View Article : Google Scholar : PubMed/NCBI
6	Ogle BM, Cascalho M and Platt JL: Biological implications of cell fusion. Nat Rev Mol Cell Biol. 6:567–575. 2005. View Article : Google Scholar : PubMed/NCBI
7	Lu X and Kang Y: Cell fusion as a hidden force in tumor progression. Cancer Res. 69:8536–8539. 2009. View Article : Google Scholar : PubMed/NCBI
8	Orimo A, Tomioka Y, Shimizu Y, et al: Cancer-associated myofibroblasts possess various factors to promote endometrial tumor progression. Clin Cancer Res. 7:3097–3105. 2001.PubMed/NCBI
9	Garfield AS: Derivation of primary mouse embryonic fibroblast (PMEF) cultures. Methods Mol Biol. 633:19–27. 2010. View Article : Google Scholar : PubMed/NCBI
10	Meister P, Konrad E, Lob G, Janka G, Keyl W and Stürz H: Osteosarcoma: histological evaluation and grading. Arch Orthop Trauma Surg. 94:91–98. 1979. View Article : Google Scholar : PubMed/NCBI
11	Tsujino T, Seshimo I, Yamamoto H, et al: Stromal myofibroblasts predict disease recurrence for colorectal cancer. Clin Cancer Res. 13:2082–2090. 2007. View Article : Google Scholar : PubMed/NCBI
12	Henry LR, Lee HO, Lee JS, et al: Clinical implications of fibroblast activation protein in patients with colon cancer. Clin Cancer Res. 13:1736–1741. 2007. View Article : Google Scholar : PubMed/NCBI
13	Cohen SJ, Alpaugh RK, Palazzo I, et al: Fibroblast activation protein and its relationship to clinical outcome in pancreatic adenocarcinoma. Pancreas. 37:154–158. 2008. View Article : Google Scholar : PubMed/NCBI
14	Infante JR, Matsubayashi H, Sato N, et al: Peritumoral fibroblast SPARC expression and patient outcome with resectable pancreatic adenocarcinoma. J Clin Oncol. 25:319–325. 2007. View Article : Google Scholar : PubMed/NCBI
15	Sasaki T, Nakamura T, Rebhun RB, et al: Modification of the primary tumor microenvironment by transforming growth factor alpha-epidermal growth factor receptor signaling promotes metastasis in an orthotopic colon cancer model. Am J Pathol. 173:205–16. 2008. View Article : Google Scholar
16	Kalluri R and Zeisberg M: Fibroblasts in cancer. Nat Rev Cancer. 6:392–401. 2006. View Article : Google Scholar
17	Shekhar MP, Santner S, Carolin KA and Tait L: Direct involvement of breast tumor fibroblasts in the modulation of tamoxifen sensitivity. Am J Pathol. 170:1546–1560. 2007. View Article : Google Scholar : PubMed/NCBI
18	Koukourakis MI, Giatromanolaki A, Harris AL and Sivridis E: Comparison of metabolic pathways between cancer cells and stromal cells in colorectal carcinomas: a metabolic survival role for tumor-associated stroma. Cancer Res. 66:632–637. 2006. View Article : Google Scholar : PubMed/NCBI
19	Karnoub AE, Dash AB, Vo AP, et al: Mesenchymal stem cells within tumour stroma promote breast cancer metastasis. Nature. 449:557–563. 2007. View Article : Google Scholar : PubMed/NCBI
20	Ishii G, Sangai T, Oda T, et al: Bone-marrow-derived myofibroblasts contribute to the cancer-induced stromal reaction. Biochem Biophys Res Commun. 309:232–240. 2003. View Article : Google Scholar : PubMed/NCBI
21	Direkze NC, Hodivala-Dilke K, Jeffery R, et al: Bone marrow contribution to tumor-associated myofibroblasts and fibroblasts. Cancer Res. 64:8492–8495. 2004. View Article : Google Scholar : PubMed/NCBI
22	Radisky DC, Kenny PA and Bissell MJ: Fibrosis and cancer: do myofibroblasts come also from epithelial cells via EMT? J Cell Biochem. 101:830–839. 2007. View Article : Google Scholar : PubMed/NCBI
23	Zeisberg EM, Potenta S, Xie L, Zeisberg M and Kalluri R: Discovery of endothelial to mesenchymal transition as a source for carcinoma-associated fibroblasts. Cancer Res. 67:10123–10128. 2007.PubMed/NCBI
24	Mishra PJ, Mishra PJ, Humeniuk R, et al: Carcinoma-associated fibroblast-like differentiation of human mesenchymal stem cells. Cancer Res. 68:4331–4339. 2008. View Article : Google Scholar : PubMed/NCBI
25	Miller FR, McInerney D, Rogers C and Miller BE: Spontaneous fusion between metastatic mammary tumor subpopulations. J Cell Biochem. 36:129–136. 1988. View Article : Google Scholar : PubMed/NCBI
26	Duelli D and Lazebnik Y: Cell fusion: a hidden enemy? Cancer Cell. 3:445–448. 2003. View Article : Google Scholar : PubMed/NCBI
27	Andersen TL, Boissy P, Sondergaard TE, et al: Osteoclast nuclei of myeloma patients show chromosome translocations specific for the myeloma cell clone: a new type of cancer-host partnership? J Pathol. 211:10–17. 2007. View Article : Google Scholar : PubMed/NCBI
28	Mortensen K, Lichtenberg J, Thomsen PD and Larsson LI: Spontaneous fusion between cancer cells and endothelial cells. Cell Mol Life Sci. 61:2125–2131. 2004. View Article : Google Scholar : PubMed/NCBI