Differentiation and roles of bone marrow‑derived cells on the tumor microenvironment of oral squamous cell carcinoma

Anqi,Chang; Takabatake,Kiyofumi; Kawai,Hotaka; Oo,May  Wathone; Yoshida,Saori; Fujii,Masae; Omori,Haruka; Sukegawa,Shintaro; Nakano,Keisuke; Tsujigiwa,Hidetsugu; Jinhua,Zheng; Nagatsuka,Hitoshi

doi:10.3892/ol.2019.11045

Differentiation and roles of bone marrow‑derived cells on the tumor microenvironment of oral squamous cell carcinoma

Authors:
- Chang Anqi
- Kiyofumi Takabatake
- Hotaka Kawai
- May Wathone Oo
- Saori Yoshida
- Masae Fujii
- Haruka Omori
- Shintaro Sukegawa
- Keisuke Nakano
- Hidetsugu Tsujigiwa
- Zheng Jinhua
- Hitoshi Nagatsuka
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Affiliations: Department of Oral Pathology and Medicine, Graduate School of Medicine, Dentistry and Pharmaceutical Sciences, Okayama University, Okayama 700‑8525, Japan, Department of Anatomy, Basic Medical Science College, Harbin Medical University, Harbin, Heilongjiang 150081, P.R. China
Published online on: November 4, 2019 https://doi.org/10.3892/ol.2019.11045
Pages: 6628-6638
Copyright: © Anqi et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

The stroma affects the properties and dynamics of the tumor. Previous studies have demonstrated that bone marrow‑derived cells (BMDCs) possess the capability of differentiating into stromal cells. However, the characteristics and roles of BMDCs in oral squamous cell carcinoma remain unclear. The current study therefore investigated their locations and features by tracing green fluorescent protein (GFP)‑labeled BMDCs in a transplantation mouse model. After irradiation, BALB‑c nu‑nu mice were injected with bone marrow cells from C57BL/6‑BALB‑C‑nu/nu‑GFP transgenic mice. These recipient mice were then injected subcutaneously in the head with human squamous cell carcinoma‑2 cells. Immunohistochemistry for GFP, Vimentin, CD11b, CD31 and α‑smooth muscle actin (SMA), and double‑fluorescent immunohistochemistry for GFP‑Vimentin, GFP‑CD11b, GFP‑CD31 and GFP‑α‑SMA was subsequently performed. Many round‑shaped GFP‑positive cells were observed in the cancer stroma, which indicated that BMDCs served a predominant role in tumorigenesis. Vimentin(+) GFP(+) cells may also be a member of the cancer‑associated stroma, originating from bone marrow. Round or spindle‑shaped CD11b(+) GFP(+) cells identified in the present study may be macrophages derived from bone marrow. CD31(+)GFP(+) cells exhibited a high tendency towards bone marrow‑derived angioblasts. The results also indicated that spindle‑shaped α‑SMA(+) GFP(+) cells were not likely to represent bone marrow‑derived cancer‑associated fibroblasts. BMDCs gathering within the tumor microenvironment exhibited multilineage potency and participated in several important processes, such as tumorigenesis, tumor invasion and angiogenesis.

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1	Joyce JA and Pollard JW: Microenvironmental regulation of metastasis. Nat Rev Cancer. 9:239–252. 2009. View Article : Google Scholar : PubMed/NCBI
2	Yashiro M and Hirakawa K: Cancer-stromal interactions in scirrhous gastric carcinoma. Cancer Microenviron. 3:127–135. 2010. View Article : Google Scholar : PubMed/NCBI
3	Fuyuhiro Y, Yashiro M, Noda S, Matsuoka J, Hasegawa T, Kato Y, Sawada T and Hirakawa K: Cancer-associated orthotopic myofibroblasts stimulates the motility of gastric carcinoma cells. Cancer Sci. 103:797–805. 2012. View Article : Google Scholar : PubMed/NCBI
4	Tripathi M, Billet S and Bhowmick NA: Understanding the role of stromal fibroblasts in cancer progression. Cell Adhes Migr. 6:231–235. 2012. View Article : Google Scholar
5	Harper J and Sainson RC: Regulation of the anti-tumour immune response by cancer-associated fibroblasts. Semin Cancer Biol. 25:69–77. 2014. View Article : Google Scholar : PubMed/NCBI
6	Li H, Fan X and Houghton JM: Tumor microenvironment: The role of the tumor stroma in cancer. J Cell Biochem. 101:805–815. 2007. View Article : Google Scholar : PubMed/NCBI
7	Clark RAF: The molecular cell biology of wound repairPlenum Press New York. 3. pp. 501996
8	Desmoulière A, Geinoz A, Gabbiani F and Gabbiani G: Transforming growth factor-beta 1 induces alpha-smooth muscle actin expression in granulation tissue myofibroblasts and in quiescent and growing cultured fibroblasts. J Cell Biol. 122:103–111. 1993. View Article : Google Scholar : PubMed/NCBI
9	Roberts AB, Sporn MB, Assoian RK, Smith JM, Roche NS, Wakefield LM, Heine UI, Liotta LA, Falanga V, Kehrl JH, et al: Transforming growth factor type beta: Rapid induction of fibrosis and angiogenesis in vivo and stimulation of collagen formation in vitro. Proc Natl Acad Sci USA. 83:4167–4171. 1986. View Article : Google Scholar : PubMed/NCBI
10	Tjomsland V: Studies of the tumor microenvironment: Local and systemic effects exerted by the cross-talk between tumor and stroma cells in pancreatic cancer. PhD dissertation. Linköping UniversityPublication no. 1219. Linköping; Sweden: 2010
11	Bhowmick NA, Neilson EG and Moses HL: Stromal fibroblasts in cancer initiation and progression. Nature. 432:332–337. 2004. View Article : Google Scholar : PubMed/NCBI
12	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
13	Kalluri R and Zeisberg M: Fibroblasts in cancer. Nat Rev Cancer. 6:392–401. 2006. View Article : Google Scholar : PubMed/NCBI
14	Micke P and Ostman A: Exploring the tumour environment: Cancer-associated fibroblasts as targets in cancer therapy. Expert Opin Ther Targets. 9:1217–1233. 2005. View Article : Google Scholar : PubMed/NCBI
15	Bhowmick NA, Chytil A, Plieth D, Gorska AE, Dumont N, Shappell S, Washington MK, Neilson EG and Moses HL: TGF-beta signaling in fibroblasts modulates the oncogenic potential of adjacent epithelia. Science. 303:848–851. 2004. View Article : Google Scholar : PubMed/NCBI
16	Mbeunkui F and Johann DJ Jr: Cancer and the tumor microenvironment: A review of an essential relationship. Cancer Chemother Pharmacol. 63:571–582. 2009. View Article : Google Scholar : PubMed/NCBI
17	Costea DE, Hills A, Osman AH, Thurlow J, Kalna G, Huang X, Pena Murillo C, Parajuli H, Suliman S, Kulasekara KK, et al: Identification of two distinct carcinoma-associated fibroblast subtypes with differential tumor-promoting abilities in oral squamous cell carcinoma. Cancer Res. 73:3888–3901. 2013. View Article : Google Scholar : PubMed/NCBI
18	Routray S, Sunkavali A and Bari KA: Carcinoma-associated fibroblasts, its implication in head and neck squamous cell carcinoma: A mini review. Oral Dis. 20:246–253. 2014. View Article : Google Scholar : PubMed/NCBI
19	Kessenbrock K, Plaks V and Werb Z: Matrix metalloproteinases: Regulators of the tumor microenvironment. Cell. 141:52–67. 2010. View Article : Google Scholar : PubMed/NCBI
20	Naritani M, Inoue M, Raju R, Miyagi M, Oshima M and Matsuka Y: Analysis of Bone marrow-derived mesenchymal stem cell kinetics after short-term stimulation with tumor necrosis factor-α (TNF-α). J Hard Tissue Biol. 28:99–108. 2019. View Article : Google Scholar
21	Badiavas EV, Abedi M, Butmarc J, Falanga V and Quesenberry P: Participation of bone marrow derived cells in cutaneous wound healing. J Cell Physiol. 196:245–250. 2003. View Article : Google Scholar : PubMed/NCBI
22	Houghton J, Stoicov C, Nomura S, Rogers AB, Carlson J, Li H, Cai X, Fox JG, Goldenring JR and Wang TC: Gastric cancer originating from bone marrow-derived cells. Science. 306:1568–1571. 2004. View Article : Google Scholar : PubMed/NCBI
23	Pittenger MF, Mackay AM, Beck SC, Jaiswal RK, Douglas R, Mosca JD, Moorman MA, Simonetti DW, Craig S and Marshak DR: Multilineage potential of adult human mesenchymal stem cells. Science. 284:143–147. 1999. View Article : Google Scholar : PubMed/NCBI
24	Caplan AI: Mesenchymal stem cells. J Orthop Res. 9:641–650. 1991. View Article : Google Scholar : PubMed/NCBI
25	Krause DS, Theise ND, Collector MI, Henegariu O, Hwang S, Gardner R, Neutzel S and Sharkis SJ: Multi-organ, multi-lineage engraftment by a single bone marrow-derived stem cell. Cell. 105:369–377. 2001. View Article : Google Scholar : PubMed/NCBI
26	Tsujigiwa H, Nishizaki K, Teshima T, Takeda Y, Yoshinobu J, Takeuchi A, Orita Y, Sugata Y, Nagatsuka H and Nagai N: The engraftment of transplanted bone marrow-derived cells into the olfactory epithelium. Brain Res. 1052:10–15. 2005. View Article : Google Scholar : PubMed/NCBI
27	Aghi M and Chiocca EA: Contribution of bone marrow-derived cells to blood vessels in ischemic tissues and tumors. Mol Ther. 12:994–1005. 2005. View Article : Google Scholar : PubMed/NCBI
28	Lyden D, Hattori K, Dias S, Costa C, Blaikie P, Butros L, Chadburn A, Heissig B, Marks W, Witte L, et al: Impaired recruitment of bone-marrow-derived endothelial and hematopoietic precursor cells blocks tumor angiogenesis and growth. Nat Med. 7:1194–1201. 2001. View Article : Google Scholar : PubMed/NCBI
29	Bamba S, Lee CY, Brittan M, Preston SL, Direkze NC, Poulsom R, Alison MR, Wright NA and Otto WR: Bone marrow transplantation ameliorates pathology in interleukin-10 knockout colitic mice. J Pathol. 209:265–273. 2006. View Article : Google Scholar : PubMed/NCBI
30	Kawai H, Tsujigiwa H, Siar CH, Nakano K, Takabatake K, Fujii M, Hamada M, Tamamura R and Nagatsuka H: Characterization and potential roles of bone marrow-derived stromal cells in cancer development and metastasis. Int J Med Sci. 15:1406–1414. 2018. View Article : Google Scholar : PubMed/NCBI
31	Masui M, Okui T, Shimo T, Takabatake K, Fukazawa T, Matsumoto K, Kurio N, Ibaragi S, Naomoto Y, Nagatsuka H and Sasaki A: Novel midkine inhibitor iMDK inhibits tumor growth and angiogenesis in oral squamous cell carcinoma. Anticancer Res. 36:2775–2781. 2016.PubMed/NCBI
32	Mhawech-Fauceglia P, Wang D, Samrao D, Kim G, Lawrenson K, Meneses T, Liu S, Yessaian A and Pejovic T: Clinical implications of marker expression of carcinoma-associated fibroblasts (CAFs) in patients with epithelial ovarian carcinoma after treatment with neoadjuvant chemotherapy. Cancer Microenviron. 7:33–39. 2014. View Article : Google Scholar : PubMed/NCBI
33	Zajchowski DA, Bartholdi MF, Gong Y, Webster L, Liu HL, Munishkin A, Beauheim C, Harvey S, Ethier SP and Johnson PH: Identification of gene expression profiles that predict the aggressive behavior of breast cancer cells. Cancer Res. 61:5168–5178. 2001.PubMed/NCBI
34	Mellick AS, Day CJ, Weinstein SR, Griffiths LR and Morrison NA: Differential gene expression in breast cancer cell lines and stroma-tumor differences in microdissected breast cancer biopsies revealed by display array analysis. Int J Cancer. 100:172–180. 2002. View Article : Google Scholar : PubMed/NCBI
35	Peñuelas S, Noé V and Ciudad CJ: Modulation of IMPDH2, survivin, topoisomerase I and vimentin increases sensitivity to methotrexate in HT29 human colon cancer cells. FEBS J. 272:696–710. 2005. View Article : Google Scholar : PubMed/NCBI
36	Ngan CY, Yamamoto H, Seshimo I, Tsujino T, Man-i M, Ikeda JI, Konishi K, Takemasa I, Ikeda M, Sekimoto M, et al: Quantitative evaluation of vimentin expression in tumour stroma of colorectal cancer. Br J Cancer. 96:986–992. 2007. View Article : Google Scholar : PubMed/NCBI
37	Kasashima H, Yashiro M, Nakamae H, Masuda G, Kinoshita H, Morisaki T, Fukuoka T, Hasegawa T, Sakurai K, Toyokawa T, et al: Bone marrow-derived stromal cells are associated with gastric cancer progression. Br J Cancer. 113:443–452. 2015. View Article : Google Scholar : PubMed/NCBI
38	Ishii S, Tsuji S, Tsujii M, Kanazawa Y, Nishida T, Iijima H, Yasumaru M, Irie T, Yamamoto K, Tsutsui S, et al: Involvement of bone marrow-derived stromal cells in gastrointestinal cancer development and metastasis. J Gastroenterol Hepatol. 23 (Suppl 2):S242–S249. 2008. View Article : Google Scholar : PubMed/NCBI
39	Udagawa T, Puder M, Wood M, Schaefer BC and D'Amato RJ: Analysis of tumor-associated stromal cells using SCID GFP transgenic mice: Contribution of local and bone marrow-derived host cells. FASEB J. 20:95–102. 2006. View Article : Google Scholar : PubMed/NCBI
40	Colegio OR, Chu NQ, Szabo AL, Chu T, Rhebergen AM, Jairam V, Cyrus N, Brokowski CE, Eisenbarth SC, Phillips GM, et al: Functional polarization of tumour-associated macrophages by tumour-derived lactic acid. Nature. 513:559–563. 2014. View Article : Google Scholar : PubMed/NCBI
41	Komohara Y, Jinushi M and Takeya M: Clinical significance of macrophage heterogeneity in human malignant tumors. Cancer Sci. 105:1–8. 2014. View Article : Google Scholar : PubMed/NCBI
42	Asahara T, Murohara T, Sullivan A, Silver M, van der Zee R, Li T, Witzenbichler B, Schatteman G and Isner JM: Isolation of putative progenitor endothelial cells for angiogenesis. Science. 275:964–967. 1997. View Article : Google Scholar : PubMed/NCBI
43	Le Ricousse-Roussanne LS, Barateau V, Contreres JO, Boval B, Kraus-Berthier L and Tobelem G: Ex vivo differentiated endothelial and smooth muscle cells from human cord blood progenitors home to the angiogenic tumor vasculature. Cardiovasc Res. 62:176–184. 2004. View Article : Google Scholar : PubMed/NCBI
44	Orimo A, Gupta PB, Sgroi DC, Arenzana-Seisdedos F, Delaunay T, Naeem R, Carey VJ, Richardson AL and Weinberg RA: Stromal fibroblasts present in invasive human breast carcinomas promote tumor growth and angiogenesis through elevated SDF-1/CXCL12 secretion. Cell. 121:335–348. 2005. View Article : Google Scholar : PubMed/NCBI
45	Direkze NC, Forbes SJ, Brittan M, Hunt T, Jeffery R, Preston SL, Poulsom R, Hodivala-Dilke K, Alison MR and Wright NA: Multiple organ engraftment by bone-marrow-derived myofibroblasts and fibroblasts in bone-marrow-transplanted mice. Stem Cells. 21:514–520. 2003. View Article : Google Scholar : PubMed/NCBI
46	Karnoub AE, Dash AB, Vo AP, Sullivan A, Brooks MW, Bell GW, Richardson AL, Polyak K, Tubo R and Weinberg RA: Mesenchymal stem cells within tumour stroma promote breast cancer metastasis. Nature. 449:557–563. 2007. View Article : Google Scholar : PubMed/NCBI
47	Quante M, Tu SP, Tomita H, Gonda T, Wang SS, Takashi S, Baik GH, Shibata W, Diprete B, Betz KS, et al: Bone marrow-derived myofibroblasts contribute to the mesenchymal stem cell niche and promote tumor growth. Cancer Cell. 19:257–272. 2011. View Article : Google Scholar : PubMed/NCBI
48	Ohgushi H and Caplan AI: Stem cell technology and bioceramics: From cell to gene engineering. J Biomed Mater Res. 48:913–927. 1999. View Article : Google Scholar : PubMed/NCBI