Functional effects of SDF-1α on a CD44+ CXCR4+ squamous cell carcinoma cell line as a model for interactions in the cancer stem cell niche

Faber,Anne; Hoermann,Karl; Stern-Straeter,Jens; Schultz,David  Johannes; Goessler,Ulrich  Reinhart

doi:10.3892/or.2012.2171

Functional effects of SDF-1α on a CD44+ CXCR4+ squamous cell carcinoma cell line as a model for interactions in the cancer stem cell niche

Authors:
- Anne Faber
- Karl Hoermann
- Jens Stern-Straeter
- David Johannes Schultz
- Ulrich Reinhart Goessler
View Affiliations

Affiliations: Department of Otorhinolaryngology Head and Neck Surgery, University Medical Centre Mannheim, 68167 Mannheim, Germany
Published online on: December 10, 2012 https://doi.org/10.3892/or.2012.2171
Pages: 579-584

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

Stromal cell-derived factor-1α (SDF-1α), also known as CXCL12, has variable effects on a plurality of cells. It is known to have selective effects on cell migration, morphology, survival and cell homing. As such the SDF-1-CXCR4 axis is postulated to be a crucial key pathway in the interaction between (cancer) stem cells and their surrounding supportive cells, the so-called (cancer) stem cell niche. We evaluated the expression of CD44 as a cancer stem cell (CSC) marker and the expression of CXCR4 in the head and neck squamous cell carcinoma (HNSCC) cell line UM-SCC 11A. In addition, we monitored proliferation, formation of podia and migration of UM-SCC 11A cells under the influence of SDF-1α. Whereas SDF-1α induced the formation of podia of CD44+ CXCR4+ UM-SCC 11A cells in a dose-dependent manner and the maximum number of cells exhibiting the formation of podia was observed under the influence of 10 ng/ml SDF-1α (P=5.3x10-6), the highest number of migrating cells was noted using a concentration of 100 ng/ml (P=0.027). Proliferation and survival were not affected by SDF-1α. We showed that UM-SCC 11A cells could be a target for SDF-1α by CXCR4 expression and these cells also showed characteristics of HNSCC CSCs via CD44 expression. We demonstrated that SDF-1α is a chemoattractant for UM-SCC 11A cells, and a maximum directed migration was achieved under the influence of 100 ng/ml SDF-1α. Changes in cell morphology by presenting filopodia or a prominent uropod were noted following treatment of 10 ng/ml SDF-1α. The SDF-CXCR4 axis may play a crucial role in the interaction between CSCs and their supportive cells in the CSC niche. Understanding these interactions may help to gain further insight into the pathophysiology of the progression and recurrence of malignant diseases and thus help to develop novel strategies for therapy.

View Figures

View References

1	Vokes EE, Weichselbaum RR, Lippman SM and Hong WK: Head and neck cancer. N Engl J Med. 328:184–194. 1993. View Article : Google Scholar : PubMed/NCBI
2	Prince ME, Sivanandan R, Kaczorowski A, et al: Identification of a subpopulation of cells with cancer stem cell properties in head and neck squamous cell carcinoma. Proc Natl Acad Sci USA. 104:973–978. 2007. View Article : Google Scholar : PubMed/NCBI
3	Zhang P, Zuo H, Ozaki T, Nakagomi N and Kakudo K: Cancer stem cell hypothesis in thyroid cancer. Pathol Int. 56:485–489. 2006. View Article : Google Scholar : PubMed/NCBI
4	Franzmann EJ, Reategui EP, Pedroso F, et al: Soluble CD44 is a potential marker for the early detection of head and neck cancer. Cancer Epidemiol Biomarkers Prev. 16:1348–1355. 2007. View Article : Google Scholar : PubMed/NCBI
5	Saito H, Tsujitani S, Katano K, Ikeguchi M, Maeta M and Kaibara N: Serum concentration of CD44 variant 6 and its relation to prognosis in patients with gastric carcinoma. Cancer. 83:1094–1101. 1998. View Article : Google Scholar : PubMed/NCBI
6	Ponta H, Wainwright D and Herrlich P: The CD44 protein family. Int J Biochem Cell Biol. 30:299–305. 1998. View Article : Google Scholar
7	Screaton GR, Bell MV, Bell JI and Jackson DG: The identification of a new alternative exon with highly restricted tissue expression in transcripts encoding the mouse Pgp-1 (CD44) homing receptor. Comparison of all 10 variable exons between mouse, human, and rat. J Biol Chem. 268:12235–12238. 1993.
8	Screaton GR, Bell MV, Jackson DG, Cornelis FB, Gerth U and Bell JI: Genomic structure of DNA encoding the lymphocyte homing receptor CD44 reveals at least 12 alternatively spliced exons. Proc Natl Acad Sci USA. 89:12160–12164. 1992. View Article : Google Scholar : PubMed/NCBI
9	Picker LJ, Nakache M and Butcher EC: Monoclonal antibodies to human lymphocyte homing receptors define a novel class of adhesion molecules on diverse cell types. J Cell Biol. 109:927–937. 1989. View Article : Google Scholar : PubMed/NCBI
10	Stamenkovic I, Amiot M, Pesando JM and Seed B: A lymphocyte molecule implicated in lymph node homing is a member of the cartilage link protein family. Cell. 56:1057–1062. 1989. View Article : Google Scholar : PubMed/NCBI
11	Gunthert U, Hofmann M, Rudy W, et al: A new variant of glycoprotein CD44 confers metastatic potential to rat carcinoma cells. Cell. 65:13–24. 1991. View Article : Google Scholar : PubMed/NCBI
12	Hofmann M, Rudy W, Zoller M, et al: CD44 splice variants confer metastatic behavior in rats: homologous sequences are expressed in human tumor cell lines. Cancer Res. 51:5292–5297. 1991.PubMed/NCBI
13	Thenappan A, Li Y, Shetty K, Johnson L, Reddy EP and Mishra L: New therapeutics targeting colon cancer stem cells. Curr Colorectal Cancer Rep. 5:2092009. View Article : Google Scholar : PubMed/NCBI
14	Zlobec I, Gunthert U, Tornillo L, et al: Systematic assessment of the prognostic impact of membranous CD44v6 protein expression in colorectal cancer. Histopathology. 55:564–575. 2009. View Article : Google Scholar : PubMed/NCBI
15	Park SY, Lee HE, Li H, Shipitsin M, Gelman R and Polyak K: Heterogeneity for stem cell-related markers according to tumor subtype and histologic stage in breast cancer. Clin Cancer Res. 16:876–887. 2010. View Article : Google Scholar : PubMed/NCBI
16	Okayama H, Kumamoto K, Saitou K, et al: CD44v6, MMP-7 and nuclear Cdx2 are significant biomarkers for prediction of lymph node metastasis in primary gastric cancer. Oncol Rep. 22:745–755. 2009.PubMed/NCBI
17	Dar A, Goichberg P, Shinder V, et al: Chemokine receptor CXCR4-dependent internalization and resecretion of functional chemokine SDF-1 by bone marrow endothelial and stromal cells. Nat Immunol. 6:1038–1046. 2005. View Article : Google Scholar : PubMed/NCBI
18	Faber A, Roderburg C, Wein F, et al: The many facets of SDF-1alpha, CXCR4 agonists and antagonists on hematopoietic progenitor cells. J Biomed Biotechnol. 2007:260652007. View Article : Google Scholar : PubMed/NCBI
19	Imai K, Kobayashi M, Wang J, et al: Selective secretion of chemoattractants for haemopoietic progenitor cells by bone marrow endothelial cells: a possible role in homing of haemopoietic progenitor cells to bone marrow. Br J Haematol. 106:905–911. 1999. View Article : Google Scholar : PubMed/NCBI
20	De La Luz Sierra M, Yang F, Narazaki M, et al: Differential processing of stromal-derived factor-1alpha and stromal-derived factor-1beta explains functional diversity. Blood. 103:2452–2459. 2004.PubMed/NCBI
21	Shirozu M, Nakano T, Inazawa J, et al: Structure and chromosomal localization of the human stromal cell-derived factor 1 (SDF1) gene. Genomics. 28:495–500. 1995. View Article : Google Scholar : PubMed/NCBI
22	Kim CH and Broxmeyer HE: In vitro behavior of hematopoietic progenitor cells under the influence of chemoattractants: stromal cell-derived factor-1, steel factor, and the bone marrow environment. Blood. 91:100–110. 1998.PubMed/NCBI
23	Mohle R, Bautz F, Rafii S, Moore MA, Brugger W and Kanz L: The chemokine receptor CXCR-4 is expressed on CD34⁺ hematopoietic progenitors and leukemic cells and mediates transendothelial migration induced by stromal cell-derived factor-1. Blood. 91:4523–4530. 1998.PubMed/NCBI
24	Petit I, Goichberg P, Spiegel A, et al: Atypical PKC-zeta regulates SDF-1-mediated migration and development of human CD34⁺ progenitor cells. J Clin Invest. 115:168–176. 2005. View Article : Google Scholar : PubMed/NCBI
25	Chute JP: Stem cell homing. Curr Opin Hematol. 13:399–406. 2006. View Article : Google Scholar : PubMed/NCBI
26	Fruehauf S, Srbic K, Seggewiss R, Topaly J and Ho AD: Functional characterization of podia formation in normal and malignant hematopoietic cells. J Leukoc Biol. 71:425–432. 2002.PubMed/NCBI
27	Lataillade JJ, Clay D, Dupuy C, et al: Chemokine SDF-1 enhances circulating CD34(+) cell proliferation in synergy with cytokines: possible role in progenitor survival. Blood. 95:756–768. 2000.
28	Broxmeyer HE, Kohli L, Kim CH, et al: Stromal cell-derived factor-1/CXCL12 directly enhances survival/antiapoptosis of myeloid progenitor cells through CXCR4 and G(alpha)i proteins and enhances engraftment of competitive, repopulating stem cells. J Leukoc Biol. 73:630–638. 2003. View Article : Google Scholar
29	Kijowski J, Baj-Krzyworzeka M, Majka M, et al: The SDF-1-CXCR4 axis stimulates VEGF secretion and activates integrins but does not affect proliferation and survival in lymphohematopoietic cells. Stem Cells. 19:453–466. 2001. View Article : Google Scholar : PubMed/NCBI
30	Hattori K, Heissig B, Tashiro K, et al: Plasma elevation of stromal cell-derived factor-1 induces mobilization of mature and immature hematopoietic progenitor and stem cells. Blood. 97:3354–3360. 2001. View Article : Google Scholar : PubMed/NCBI
31	Goichberg P, Kalinkovich A, Borodovsky N, et al: cAMP-induced PKCzeta activation increases functional CXCR4 expression on human CD34⁺ hematopoietic progenitors. Blood. 107:870–879. 2006. View Article : Google Scholar : PubMed/NCBI
32	Tudan C, Willick GE, Chahal S, et al: C-terminal cyclization of an SDF-1 small peptide analogue dramatically increases receptor affinity and activation of the CXCR4 receptor. J Med Chem. 45:2024–2031. 2002. View Article : Google Scholar : PubMed/NCBI
33	Grenman R, Burk D, Virolainen E, Wagner JG, Lichter AS and Carey TE: Radiosensitivity of head and neck cancer cells in vitro. A 96-well plate clonogenic cell assay for squamous cell carcinoma. Arch Otolaryngol Head Neck Surg. 114:427–431. 1988. View Article : Google Scholar : PubMed/NCBI
34	Domanska UM, Kruizinga RC, Nagengast WB, et al: A review on CXCR4/CXCL12 axis in oncology: No place to hide. Eur J Cancer. June 8–2012.(Epub ahead of print).
35	Pries R, Wittkopf N, Hasselbacher K and Wollenberg B: Constitutive expression of the potential stem cell marker CD44 in permanent HNSCC cell lines. Hno. 56:461–466. 2008.(In German).
36	Wollenberg B: Implication of stem cells in the biology and therapy of head and neck cancer. Laryngorhinootologie. 90(Suppl 1): S110–S119. 2011.(In German).
37	Zhang Z, Filho MS and Nor JE: The biology of head and neck cancer stem cells. Oral Oncol. 48:1–9. 2012. View Article : Google Scholar : PubMed/NCBI
38	La Porta CA: Thoughts about cancer stem cells in solid tumors. World J Stem Cells. 4:17–20. 2012.PubMed/NCBI
39	Jaggupilli A and Elkord E: Significance of CD44 and CD24 as Cancer Stem Cell Markers: An Enduring Ambiguity. Clin Dev Immunol. 2012:7080362012. View Article : Google Scholar : PubMed/NCBI
40	Clay MR, Tabor M, Owen JH, et al: Single-marker identification of head and neck squamous cell carcinoma cancer stem cells with aldehyde dehydrogenase. Head Neck. 32:1195–1201. 2010. View Article : Google Scholar : PubMed/NCBI
41	Li KC, Huang YH, Ho CY, et al: The role of IL-8 in the SDF-1alpha/CXCR4-induced angiogenesis of laryngeal and hypopharyngeal squamous cell carcinoma. Oral Oncol. 48:507–515. 2012. View Article : Google Scholar : PubMed/NCBI
42	Teicher BA and Fricker SP: CXCL12 (SDF-1)/CXCR4 pathway in cancer. Clin Cancer Res. 16:2927–2931. 2010. View Article : Google Scholar : PubMed/NCBI
43	Stenvik J, Sletta H, Grimstad O, et al: Alginates induce differentiation and expression of CXCR7 and CXCL12/SDF-1 in human keratinocytes-The role of calcium. J Biomed Mater Res A. 100:2803–2812. 2012. View Article : Google Scholar : PubMed/NCBI
44	Gentilini A, Rombouts K, Galastri S, et al: Role of the stromal-derived factor-1 (SDF-1)-CXCR4 axis in the interaction between hepatic stellate cells and cholangiocarcinoma. J Hepatol. June 19–2012.(Epub ahead of print).
45	Chen J and Gallo KA: MLK3 regulates paxillin phosphorylation in chemokine-mediated breast cancer cell migration and invasion to drive metastasis. Cancer Res. 72:4130–4140. 2012. View Article : Google Scholar : PubMed/NCBI
46	Jin F, Brockmeier U, Otterbach F and Metzen E: New insight into the SDF-1/CXCR4 axis in a breast carcinoma model: Hypoxia-induced endothelial SDF-1 and tumor cell CXCR4 are required for tumor cell intravasation. Mol Cancer Res. 10:1021–1031. 2012. View Article : Google Scholar : PubMed/NCBI
47	Flores-Figueroa E, Varma S, Montgomery K, Greenberg PL and Gratzinger D: Distinctive contact between CD34⁺ hematopoietic progenitors and CXCL12⁺ CD271⁺ mesenchymal stromal cells in benign and myelodysplastic bone marrow. Lab Invest. 92:1330–1341. 2012.
48	Purizaca J, Meza I and Pelayo R: Early lymphoid development and microenvironmental cues in B-cell acute lymphoblastic leukemia. Arch Med Res. 43:89–101. 2012. View Article : Google Scholar : PubMed/NCBI
49	Juarez J, Dela Pena A, Baraz R, et al: CXCR4 antagonists mobilize childhood acute lymphoblastic leukemia cells into the peripheral blood and inhibit engraftment. Leukemia. 21:1249–1257. 2007. View Article : Google Scholar : PubMed/NCBI
50	Nervi B, Ramirez P, Rettig MP, et al: Chemosensitization of acute myeloid leukemia (AML) following mobilization by the CXCR4 antagonist AMD3100. Blood. 113:6206–6214. 2009. View Article : Google Scholar : PubMed/NCBI
51	Faber A, Barth C, Hormann K, et al: CD44 as a stem cell marker in head and neck squamous cell carcinoma. Oncol Rep. 26:321–326. 2011.PubMed/NCBI
52	Geutskens SB, Andrews WD, van Stalborch AM, et al: Control of human hematopoietic stem/progenitor cell migration by the extracellular matrix protein Slit3. Lab Invest. 92:1129–1139. 2012. View Article : Google Scholar : PubMed/NCBI
53	Ghosh MC, Makena PS, Gorantla V, Sinclair SE and Waters CM: CXCR4 regulates migration of lung alveolar epithelial cells through activation of Rac1 and matrix metalloproteinase-2. Am J Physiol Lung Cell Mol Physiol. 302:L846–L856. 2012. View Article : Google Scholar : PubMed/NCBI
54	Faber A, Sauter A, Hoedt S, et al: Alteration of MMP-2 and -14 expression by imatinib in HPV-positive and -negative squamous cell carcinoma. Oncol Rep. 28:172–178. 2012.PubMed/NCBI