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Role of Hyaluronan-Mediated CD44 Signaling in Head and Neck Squamous Cell Carcinoma Progression and Chemoresistance

2011; Elsevier BV; Volume: 178; Issue: 3 Linguagem: Inglês

10.1016/j.ajpath.2010.11.077

ISSN

1525-2191

Autores

Steven J. Wang, Lilly Bourguignon,

Tópico(s)

Fibroblast Growth Factor Research

Resumo

Head and neck squamous cell carcinoma (HNSCC) is an aggressive malignancy that may involve the oral cavity, pharynx, larynx, and paranasal sinuses. The mechanisms of tumor progression underlying the clinical behavior of HNSCC remain unclear. CD44 comprises a family of transmembrane receptors that can give rise to multiple CD44 variant isoforms. Hyaluronan (HA), a major extracellular matrix component is the primary ligand for CD44 receptors. HA and CD44 signaling play an important role in HNSCC progression. Several CD44 variant isoforms (including v3-, v6-, and v10-containing isoforms) are associated with advanced disease, possibly through unique growth factor interactions with binding domains in the inserted variant regions of the cytoplasmic domain of CD44. In HNSCC, HA mediates the formation of a complex including CD44 and the epidermal growth factor receptor (EGFR) which is overexpressed in a large proportion of HNSCCs. Downstream effectors under EGFR regulation are activated, promoting promote cell growth and tumor survival. The leukemia-associated Rho-guanine nucleotide exchange factor (LARG) also associates with CD44 and EGFR to promote several Ras and RhoA pathway effectors, leading to cell migration, growth, and tumor survival. The secretion of matrix metalloproteinases, necessary for tumor cell invasion, is also regulated by these HA/CD44-mediated pathways. Finally, EGFR-mediated pathways play major roles in the HA/CD44 promotion of chemoresistance in HNSCC. Understanding HA/CD44-mediated signaling pathways may lead to improved treatment of HNSCC. Head and neck squamous cell carcinoma (HNSCC) is an aggressive malignancy that may involve the oral cavity, pharynx, larynx, and paranasal sinuses. The mechanisms of tumor progression underlying the clinical behavior of HNSCC remain unclear. CD44 comprises a family of transmembrane receptors that can give rise to multiple CD44 variant isoforms. Hyaluronan (HA), a major extracellular matrix component is the primary ligand for CD44 receptors. HA and CD44 signaling play an important role in HNSCC progression. Several CD44 variant isoforms (including v3-, v6-, and v10-containing isoforms) are associated with advanced disease, possibly through unique growth factor interactions with binding domains in the inserted variant regions of the cytoplasmic domain of CD44. In HNSCC, HA mediates the formation of a complex including CD44 and the epidermal growth factor receptor (EGFR) which is overexpressed in a large proportion of HNSCCs. Downstream effectors under EGFR regulation are activated, promoting promote cell growth and tumor survival. The leukemia-associated Rho-guanine nucleotide exchange factor (LARG) also associates with CD44 and EGFR to promote several Ras and RhoA pathway effectors, leading to cell migration, growth, and tumor survival. The secretion of matrix metalloproteinases, necessary for tumor cell invasion, is also regulated by these HA/CD44-mediated pathways. Finally, EGFR-mediated pathways play major roles in the HA/CD44 promotion of chemoresistance in HNSCC. Understanding HA/CD44-mediated signaling pathways may lead to improved treatment of HNSCC. Head and neck squamous cell carcinoma (HNSCC) is a malignancy that may involve the oral cavity, pharynx, larynx, and paranasal sinuses. It is the sixth most common cancer worldwide.1Jemal A. Siegel R. Ward E. Hao Y. Xu J. Thun M.J. Cancer statistics, 2009.CA Cancer J Clin. 2009; 59: 225-249Crossref PubMed Scopus (9897) Google Scholar Advanced HNSCC is an aggressive disease, associated with major morbidity and mortality. The 3-year survival rate for patients with advanced-stage HNSCC treated with standard therapy is only 30%–50%.1Jemal A. Siegel R. Ward E. Hao Y. Xu J. Thun M.J. Cancer statistics, 2009.CA Cancer J Clin. 2009; 59: 225-249Crossref PubMed Scopus (9897) Google Scholar Resistance to standard therapy continues to be a limiting factor in the treatment of HNSCC. Nearly 40% to 60% of HNSCC patients subsequently develop locoregional recurrences or distant metastases.There is a great need to clarify the mechanisms of tumor progression underlying the clinical behavior of HNSCC. CD44 comprises a family of transmembrane receptors found on many different benign and malignant cells. The human gene (CD44) contains 19 exons.2Turley E.A. Noble P.W. Bourguignon L.Y. Signaling properties of hyaluronan receptors.J Biol Chem. 2002; 277: 4589-4592Crossref PubMed Scopus (876) Google Scholar Up to 10 exons (primarily exons 6 through 14) may be alternatively spliced to give rise to multiple variant CD44 isoforms (eg, CD44 v3, CD44 v6, CD44 v10, etc) that, along with standard CD44 (CD44s; ∼85-kDa isoform with no variable exons), make up the CD44 class of receptors. Alternative splicing and post-translational modifications are tightly regulated and permit expression of multiple different CD44 isoforms. The many splicing possibilities of the variable exons of CD44 could in theory give rise to a vast number of CD44 variants, although relatively few have been described to date. Various CD44 variant isoforms are differentially expressed in normal and malignant cells, and confirmation of CD44 isoform expression in HNSCC is well documented, in both tissue specimens and established cell lines.3Kawano T. Nakamura Y. Yanoma S. Kubota A. Furukawa M. Miyagi Y. Tsukuda M. Expression of E-cadherin, and CD44s and CD44v6 and its association with prognosis in head and neck cancer.Auris Nasus Larynx. 2004; 31: 35-41Abstract Full Text Full Text PDF PubMed Scopus (54) Google Scholar, 4Kanke M. Fujii M. Kameyama K. Kanzaki J. Tokumaru Y. Imanishi Y. Tomita T. Matsumura Y. Clinicopathological significance of expression of CD44 variants in head and neck squamous cell carcinoma.Jpn J Cancer Res. 2000; 91: 410-415Crossref PubMed Scopus (15) Google Scholar, 5Herold-Mende C. Seiter S. Born A.I. Patzelt E. Schupp M. Zöller J. Bosch F.X. Zöller M. Expression of CD44 splice variants in squamous epithelia and squamous cell carcinomas of the head and neck.J Pathol. 1996; 179: 66-73Crossref PubMed Scopus (91) Google Scholar, 6Van Hal N.L. van Dongen G.A. Stigter-Van Walsum M. Snow G.B. Brakenhoff R.H. Characterization of CD44v6 isoforms in head-and-neck squamous-cell carcinoma.Int J Cancer. 1999; 82: 837-845Crossref PubMed Scopus (37) Google Scholar All isoforms of the CD44 membrane receptor share a common ligand-binding region for hyaluronan (HA), a glycosaminoglycan component of the extracellular matrix (ECM).2Turley E.A. Noble P.W. Bourguignon L.Y. Signaling properties of hyaluronan receptors.J Biol Chem. 2002; 277: 4589-4592Crossref PubMed Scopus (876) Google Scholar Recently, HA has been studied with regard to its ability to promote various CD44-mediated signaling pathways.2Turley E.A. Noble P.W. Bourguignon L.Y. Signaling properties of hyaluronan receptors.J Biol Chem. 2002; 277: 4589-4592Crossref PubMed Scopus (876) Google Scholar, 7Toole B.P. Hyaluronan-CD44 interactions in cancer: paradoxes and possibilities.Clin Cancer Res. 2009; 15: 7462-7468Crossref PubMed Scopus (290) Google Scholar HA/CD44 signaling has been linked to solid tumor progression, including invasion, metastasis, and chemoresistance.7Toole B.P. Hyaluronan-CD44 interactions in cancer: paradoxes and possibilities.Clin Cancer Res. 2009; 15: 7462-7468Crossref PubMed Scopus (290) Google Scholar, 8Toole B.P. Slomiany M.G. Hyaluronan: a constitutive regulator of chemoresistance and malignancy in cancer cells.Semin Cancer Biol. 2008; 18: 244-250Crossref PubMed Scopus (181) Google Scholar In cancer cells, HA interaction with CD44 promotes multiple signaling pathways that influence tumor cell progression behaviors in a variety of solid tumors. Because all CD44 isoforms are capable of HA interaction, HA-mediated signaling may involve CD44s or variant isoforms. An accumulating body of evidence indicates that HA and CD44 signaling play an important role in HNSCC tumor progression and chemoresistance. Here we review the recent scientific literature regarding the role of HA-mediated CD44 signaling in HNSCC. All CD44 isoforms contain a conserved extracellular binding domain for HA, along with common cytoplasmic domains capable of interacting with cytoskeleton proteins to activate cell signaling pathways.9Singleton P.A. Bourguignon L.Y. CD44v10 interaction with Rho-kinase (ROK) activates inositol 1,4,5-triphosphate (IP3) receptor-mediated Ca2+ signaling during hyaluronan (HA)-induced endothelial cell migration.Cell Motil Cytoskeleton. 2002; 53: 293-316Crossref PubMed Scopus (71) Google Scholar The ability of CD44 receptors to provide a direct link between the ECM and the cytoskeleton, coupled with their ability to interact with a multitude of signaling kinases, explains how one family of molecules is able to mediate diverse cellular functions. CD44 isoforms are expressed to varying degrees in both normal and tumor cells, suggesting a normal cellular function for many of the different CD44 receptor isoforms. How the same CD44-mediated signaling pathways can promote both normal and malignant cellular behaviors could be explained by several different mechanisms. For example, the regulation of CD44 signaling includes variable N- or O-linked glycosylation of the CD44 extracellular domain that differentially modulates the interaction of cytoskeletal proteins such as ankyrin with the cytoplasmic domain.10Bourguignon L.Y. Hyaluronan-mediated CD44 activation of RhoGTPase signaling and cytoskeleton function promotes tumor progression.Semin Cancer Biol. 2008; 18: 251-259Crossref PubMed Scopus (238) Google Scholar It is thought, however, that the most important mechanism regulating CD44 signaling is through alternative exon splicing leading to expression of CD44 variant isoforms. In cancer cells, the exon-splicing mechanism can result in overexpression or novel expression of certain CD44 variant isoforms.11Franzmann E. Weed D.T. Civantos F. Goodwin W.J. Bourguignon L.Y. A novel CD44 v3 isoform is involved in head and neck squamous cell carcinoma progression.Otolaryngol Head Neck Surg. 2001; 124: 426-432Crossref PubMed Scopus (38) Google Scholar, 12Günthert U. Hofmann M. Rudy W. Reber S. Zöller M. Haussmann I. Matzku S. Wenzel A. Ponta H. Herrlich P. A new variant of glycoprotein CD44 confers metastatic potential to rat carcinoma cells.Cell. 1991; 65: 13-24Abstract Full Text PDF PubMed Scopus (1598) Google Scholar The insertion of variant exons into the extracellular component of the CD44 receptor has been shown to alter the signaling properties of the CD44 receptor by providing additional binding domains for molecules other than HA.11Franzmann E. Weed D.T. Civantos F. Goodwin W.J. Bourguignon L.Y. A novel CD44 v3 isoform is involved in head and neck squamous cell carcinoma progression.Otolaryngol Head Neck Surg. 2001; 124: 426-432Crossref PubMed Scopus (38) Google Scholar The insertion of variant exons may also result in changes to the HA-binding affinity of the CD44 isoform, further altering its signaling behavior. Overexpression of several CD44 variant isoforms has been associated with tumor progression, suggesting that these CD44 isoforms may have unique signaling properties. In colon cancer, CD44 v3 has been shown to promote invasion and resistance to apoptosis, and CD44 v6 has been associated with metastasis and shorter disease-free survival.13Kuniyasu H. Oue N. Tsutsumi M. Tahara E. Yasui W. Heparan sulfate enhances invasion by human colon carcinoma cell lines through expression of CD44 variant exon 3.Clin Cancer Res. 2001; 7: 4067-4072PubMed Google Scholar, 14Kuhn S. Koch M. Nübel T. Ladwein M. Antolovic D. Klingbeil P. Hildebrand D. Moldenhauer G. Langbein L. Franke W.W. Weitz J. Zöller M. A complex of EpCAM, claudin-7, CD44 variant isoforms, and tetraspanins promotes colorectal cancer progression.Mol Cancer Res. 2007; 5: 553-567Crossref PubMed Scopus (210) Google Scholar In lung cancer, there is preferential CD44 variant expression in squamous cell carcinoma and bronchioalveolar carcinoma, in which the v5 and v6 variants appear to promote metastasis.15Pirinen R. Hirvikoski P. Böhm J. Kellokoski J. Moisio K. Virén M. Johansson R. Hollmén S. Kosma V.M. Reduced expression of CD44v3 variant isoform is associated with unfavorable outcome in non-small cell lung carcinoma.Hum Pathol. 2000; 31: 1088-1095Abstract Full Text PDF PubMed Scopus (39) Google Scholar, 16Mizera-Nyczak E. Dyszkiewicz W. Heider K.H. Zeromski J. Isoform expression of CD44 adhesion molecules, Bcl-2, p53 and Ki-67 proteins in lung cancer.Tumour Biol. 2001; 22: 45-53Crossref PubMed Scopus (24) Google Scholar Numerous reports have shown that CD44 variants promote breast cancer progression, including the association of CD44 v3-containing isoforms and breast cancer metastasis.17Kalish E.D. Iida N. Moffat F.L. Bourguignon L.Y. A new CD44V3-containing isoform is involved in tumor cell growth and migration during human breast carcinoma progression.Front Biosci. 1999; 4: A1-A8Crossref PubMed Google Scholar Because of evidence linking CD44 variant isoform expression with tumor progression in a variety of solid malignancies, multiple groups have studied the role of CD44 variant isoforms in HNSCC. Nonetheless, the role of CD44 variant isoforms in HNSCC remains controversial. The literature is conflicting regarding the significance of the under- or overexpression of CD44 variant isoforms in HNSCC. Whereas some studies have found a correlation between increased CD44 variant expression and HNSCC progression, other studies have reported no correlation or negative correlation. Reategui et al18Reategui E.P. de Mayolo A.A. Das P.M. Astor F.C. Singal R. Hamilton K.L. Goodwin W.J. Carraway K.L. Franzmann E.J. Characterization of CD44v3-containing isoforms in head and neck cancer.Cancer Biol Ther. 2006; 5: 1163-1168Crossref PubMed Scopus (35) Google Scholar described a novel CD44 v3 isoform in both tissue and soluble form that correlated with HNSCC status. Wang et al19Wang S.J. Wreesmann V.B. Bourguignon L.Y. Association of CD44 V3 containing isoforms in tumor cell growth, migration, matrix metalloproteinase expression, and lymph node metastasis in head and neck cancer.Head Neck. 2007; 29: 550-558Crossref PubMed Scopus (74) Google Scholar, 20Wang S.J. Wong G. de Heer A.M. Xia W. Bourguignon L.Y. CD44 variant isoforms in head and neck squamous cell carcinoma progression.Laryngoscope. 2009; 119: 1518-1530Crossref PubMed Scopus (140) Google Scholar reported that CD44 v3-containing isoforms were associated with HNSCC lymph node metastasis and advanced T status, CD44 v6-containing isoforms were associated with perineural invasion and shorter survival, and CD44 v10-containing isoforms were associated with distant metastasis and failure of radiotherapy. Kawano et al3Kawano T. Nakamura Y. Yanoma S. Kubota A. Furukawa M. Miyagi Y. Tsukuda M. Expression of E-cadherin, and CD44s and CD44v6 and its association with prognosis in head and neck cancer.Auris Nasus Larynx. 2004; 31: 35-41Abstract Full Text Full Text PDF PubMed Scopus (54) Google Scholar found correlations between CD44 v6 expression in HNSCC and tumor volume, lymph node metastasis, and shorter survival. Others, however, have reported that down-regulation of various CD44 variant isoforms correlated with a worse prognosis. Kanke et al4Kanke M. Fujii M. Kameyama K. Kanzaki J. Tokumaru Y. Imanishi Y. Tomita T. Matsumura Y. Clinicopathological significance of expression of CD44 variants in head and neck squamous cell carcinoma.Jpn J Cancer Res. 2000; 91: 410-415Crossref PubMed Scopus (15) Google Scholar reported that down-regulation of CD44 v2 correlated with poorer differentiation and shorter overall survival, whereas down-regulation of CD44 v6 correlated with a higher rate of cervical metastasis. Other groups, including Van Hal et al6Van Hal N.L. van Dongen G.A. Stigter-Van Walsum M. Snow G.B. Brakenhoff R.H. Characterization of CD44v6 isoforms in head-and-neck squamous-cell carcinoma.Int J Cancer. 1999; 82: 837-845Crossref PubMed Scopus (37) Google Scholar and Herold-Mende et al,5Herold-Mende C. Seiter S. Born A.I. Patzelt E. Schupp M. Zöller J. Bosch F.X. Zöller M. Expression of CD44 splice variants in squamous epithelia and squamous cell carcinomas of the head and neck.J Pathol. 1996; 179: 66-73Crossref PubMed Scopus (91) Google Scholar found no correlation between CD44 splice variants and any clinicopathologic variables, and these authors concluded that CD44 variant isoforms do not play a role in HNSCC progression. There are several possible explanations for these discrepant results. First, different studies have used different antibodies, making comparisons across reports from different research groups difficult. Certain CD44 variant domain epitopes may become hidden and not recognized by some antibodies because of post-translational changes (eg, glycosylation) that alter the three-dimensional conformation of the protein. In addition, assessment of immunostaining positivity is dependent on what region of the tumor is examined, and it has been reported that there are often large areas within the tumor that do not stain for many CD44 isoforms.21Bánkfalvi A. Krassort M. Buchwalow I.B. Végh A. Felszeghy E. Piffkó J. Gains and losses of adhesion molecules (CD44, E-cadherin, and beta-catenin) during oral carcinogenesis and tumour progression.J Pathol. 2002; 198: 343-351Crossref PubMed Scopus (124) Google Scholar, 22Maula S.M. Luukkaa M. Grénman R. Jackson D. Jalkanen S. Ristamäki R. Intratumoral lymphatics are essential for the metastatic spread and prognosis in squamous cell carcinomas of the head and neck region.Cancer Res. 2003; 63: 1920-1926PubMed Google Scholar, 23Orian-Rousseau V. CD44, a therapeutic target for metastasising tumours.Eur J Cancer. 2010; 46: 1271-1277Abstract Full Text Full Text PDF PubMed Scopus (387) Google Scholar Tissue heterogeneity appears to be another important factor in the conflicting results, with the specific region of the tumor that is examined apparently having high importance in the determination of CD44 expression levels. CD44s and CD44 variant receptors appear to be concentrated at invasive fronts of HNSCC tumors, but have decreased expression in other parts of the tumor.21Bánkfalvi A. Krassort M. Buchwalow I.B. Végh A. Felszeghy E. Piffkó J. Gains and losses of adhesion molecules (CD44, E-cadherin, and beta-catenin) during oral carcinogenesis and tumour progression.J Pathol. 2002; 198: 343-351Crossref PubMed Scopus (124) Google Scholar It has been hypothesized that the major CD44 ligand HA, which is present at high levels in the ECM surrounding HNSCCs, is responsible for the stimulation of CD44 to promote migration, invasion, and metastasis. Hyaluronan has been reported to stimulate both CD44 and lymphatic vessel endothelial hyaluronan receptor (LYVE-1) to promote nodal metastasis in HNSCC.22Maula S.M. Luukkaa M. Grénman R. Jackson D. Jalkanen S. Ristamäki R. Intratumoral lymphatics are essential for the metastatic spread and prognosis in squamous cell carcinomas of the head and neck region.Cancer Res. 2003; 63: 1920-1926PubMed Google Scholar Although we acknowledge that the recent scientific literature is without broad consensus, support for a link between CD44 variant expression and HNSCC progression is bolstered by the recent description of three CD44 variants associated with HNSCC progression in both clinical specimens and in in vitro studies.20Wang S.J. Wong G. de Heer A.M. Xia W. Bourguignon L.Y. CD44 variant isoforms in head and neck squamous cell carcinoma progression.Laryngoscope. 2009; 119: 1518-1530Crossref PubMed Scopus (140) Google Scholar Furthermore, the identification of CD44 as a putative cancer stem cell marker, as well as a marker for chemoresistance, is also consistent with the notion that certain CD44 variant isoforms may be contributory to HNSCC progression.8Toole B.P. Slomiany M.G. Hyaluronan: a constitutive regulator of chemoresistance and malignancy in cancer cells.Semin Cancer Biol. 2008; 18: 244-250Crossref PubMed Scopus (181) Google Scholar, 24Prince M.E. Sivanandan R. Kaczorowski A. Wolf G.T. Kaplan M.J. Dalerba P. Weissman I.L. Clarke M.F. Ailles L.E. Identification of a subpopulation of cells with cancer stem cell properties in head and neck squamous cell carcinoma.Proc Natl Acad Sci USA. 2007; 104: 973-978Crossref PubMed Scopus (1789) Google Scholar The mechanism of action for most CD44 variant isoforms in solid malignancies is not well understood. Several CD44 variant exons are known to contain binding domains for various growth factor ligands. The v3 exon is known to contain important glycosaminoglycan (GAG) attachment sites, and it has been postulated that tumor cells with CD44 receptors exhibiting these GAG sequences are involved with heparin binding growth factors such as basic fibroblast growth factor, vascular endothelial growth factor (VEGF), and heparin binding epidermal growth factor.17Kalish E.D. Iida N. Moffat F.L. Bourguignon L.Y. A new CD44V3-containing isoform is involved in tumor cell growth and migration during human breast carcinoma progression.Front Biosci. 1999; 4: A1-A8Crossref PubMed Google Scholar Thus, CD44 v3-containing isoforms appear to be capable of promoting tumor cell proliferation in an HA-independent manner, through the presence of additional growth factor binding sites. The CD44 v3 isoform is expressed in the metastatic breast tumor cell line Met-1, in which it has been shown to bind VEGF, suggesting that this isoform may promote breast tumor-associated angiogenesis.17Kalish E.D. Iida N. Moffat F.L. Bourguignon L.Y. A new CD44V3-containing isoform is involved in tumor cell growth and migration during human breast carcinoma progression.Front Biosci. 1999; 4: A1-A8Crossref PubMed Google Scholar, 25Bourguignon L.Y. Gunja-Smith Z. Iida N. Zhu H.B. Young L.J. Muller W.J. Cardiff R.D. CD44v(3,8–10) is involved in cytoskeleton-mediated tumor cell migration and matrix metalloproteinase (MMP-9) association in metastatic breast cancer cells.J Cell Physiol. 1998; 176: 206-215Crossref PubMed Scopus (244) Google Scholar CD44 v3 also appears to be linked to several other tumorigenic molecules, promoting tumor cell migration and the invasive tumor cell phenotype. In particular, CD44 v3 colocalizes with the active form of matrix metalloproteinase-9 (MMP-9) in Met-1 cells, promoting degradation of the ECM to facilitate tumor cell invasion.25Bourguignon L.Y. Gunja-Smith Z. Iida N. Zhu H.B. Young L.J. Muller W.J. Cardiff R.D. CD44v(3,8–10) is involved in cytoskeleton-mediated tumor cell migration and matrix metalloproteinase (MMP-9) association in metastatic breast cancer cells.J Cell Physiol. 1998; 176: 206-215Crossref PubMed Scopus (244) Google Scholar This isoform also up-regulates cytoskeleton function, through ankyrin, to activate the membrane-associated actomyosin contractile system and mediate tumor cell migration.25Bourguignon L.Y. Gunja-Smith Z. Iida N. Zhu H.B. Young L.J. Muller W.J. Cardiff R.D. CD44v(3,8–10) is involved in cytoskeleton-mediated tumor cell migration and matrix metalloproteinase (MMP-9) association in metastatic breast cancer cells.J Cell Physiol. 1998; 176: 206-215Crossref PubMed Scopus (244) Google Scholar The role of CD44 v3 isoforms in HNSCC progression is highlighted by studies showing an association of v3-containing isoforms with HNSCC growth, migration, and MMP expression.11Franzmann E. Weed D.T. Civantos F. Goodwin W.J. Bourguignon L.Y. A novel CD44 v3 isoform is involved in head and neck squamous cell carcinoma progression.Otolaryngol Head Neck Surg. 2001; 124: 426-432Crossref PubMed Scopus (38) Google Scholar, 19Wang S.J. Wreesmann V.B. Bourguignon L.Y. Association of CD44 V3 containing isoforms in tumor cell growth, migration, matrix metalloproteinase expression, and lymph node metastasis in head and neck cancer.Head Neck. 2007; 29: 550-558Crossref PubMed Scopus (74) Google Scholar, 20Wang S.J. Wong G. de Heer A.M. Xia W. Bourguignon L.Y. CD44 variant isoforms in head and neck squamous cell carcinoma progression.Laryngoscope. 2009; 119: 1518-1530Crossref PubMed Scopus (140) Google Scholar Transfection of a CD44 v3 isoform into a nonexpressing HNSCC cell line also resulted in significantly increased tumor cell migration, but not proliferation.18Reategui E.P. de Mayolo A.A. Das P.M. Astor F.C. Singal R. Hamilton K.L. Goodwin W.J. Carraway K.L. Franzmann E.J. Characterization of CD44v3-containing isoforms in head and neck cancer.Cancer Biol Ther. 2006; 5: 1163-1168Crossref PubMed Scopus (35) Google Scholar Treatment of a CD44 v3 isoform expressing HNSCC cell line with anti-CD44 v3 antibody decreased in vitro proliferation and increased cisplatin sensitivity.20Wang S.J. Wong G. de Heer A.M. Xia W. Bourguignon L.Y. CD44 variant isoforms in head and neck squamous cell carcinoma progression.Laryngoscope. 2009; 119: 1518-1530Crossref PubMed Scopus (140) Google Scholar Using the same anti-CD44 v3 antibody, immunohistochemical tissue analysis revealed that CD44 v3 isoforms were preferentially expressed in metastatic lymph nodes. Additionally, strong CD44 v3 isoform expression in primary tumors was significantly associated with advanced T status and positive lymph nodes, but did not correlate with disease-free interval.20Wang S.J. Wong G. de Heer A.M. Xia W. Bourguignon L.Y. CD44 variant isoforms in head and neck squamous cell carcinoma progression.Laryngoscope. 2009; 119: 1518-1530Crossref PubMed Scopus (140) Google Scholar In summary, there are several in vitro and histopathological studies suggesting that CD44 v3 isoforms are involved in HNSCC progression behaviors. To verify these findings, further research is needed to elucidate the mechanisms of CD44 v3 signaling. CD44 v6-containing isoforms also appear to promote tumor progression. Transfection of CD44 v6 converted nonmetastatic rat carcinoma cells into metastatic cells, and co-injection of anti-CD44 v6 antibody into these same cells suppressed their metastatic behavior.12Günthert U. Hofmann M. Rudy W. Reber S. Zöller M. Haussmann I. Matzku S. Wenzel A. Ponta H. Herrlich P. A new variant of glycoprotein CD44 confers metastatic potential to rat carcinoma cells.Cell. 1991; 65: 13-24Abstract Full Text PDF PubMed Scopus (1598) Google Scholar, 26Seiter S. Arch R. Reber S. Komitowski D. Hofmann M. Ponta H. Herrlich P. Matzku S. Zöller M. Prevention of tumor metastasis formation by anti-variant CD44.J Exp Med. 1993; 177: 443-455Crossref PubMed Scopus (328) Google Scholar The CD44 v6 splice variant was also found to stimulate sustained increased mitogen activated protein kinase (MAPK) levels and subsequent downstream Ras signaling, resulting in increased tumor cell proliferation.12Günthert U. Hofmann M. Rudy W. Reber S. Zöller M. Haussmann I. Matzku S. Wenzel A. Ponta H. Herrlich P. A new variant of glycoprotein CD44 confers metastatic potential to rat carcinoma cells.Cell. 1991; 65: 13-24Abstract Full Text PDF PubMed Scopus (1598) Google Scholar Because of evidence linking CD44 v6 as a marker for HNSCC tumor proliferation and metastasis, a phase I clinical trial was conducted to evaluate anti-CD44 v6 antibody therapy for the treatment of incurable HNSCC, with a 10% response rate reported.23Orian-Rousseau V. CD44, a therapeutic target for metastasising tumours.Eur J Cancer. 2010; 46: 1271-1277Abstract Full Text Full Text PDF PubMed Scopus (387) Google Scholar Administration of anti-CD44 v6 antibody to a CD44 v6 isoform-expressing HNSCC cell line resulted in decreased cell proliferation and increased cisplatin sensitivity.20Wang S.J. Wong G. de Heer A.M. Xia W. Bourguignon L.Y. CD44 variant isoforms in head and neck squamous cell carcinoma progression.Laryngoscope. 2009; 119: 1518-1530Crossref PubMed Scopus (140) Google Scholar Using the same anti-CD44 v6 antibody, immunohistochemical analysis of HNSCC tissue specimens indicated that CD44 v6 isoforms were preferentially expressed in metastatic lymph nodes, and strong expression of CD44 v6 in primary tumors was significantly associated with advanced T status, perineural invasion, and shorter disease-free survival.20Wang S.J. Wong G. de Heer A.M. Xia W. Bourguignon L.Y. CD44 variant isoforms in head and neck squamous cell carcinoma progression.Laryngoscope. 2009; 119: 1518-1530Crossref PubMed Scopus (140) Google Scholar Although these studies are small, the association of CD44 v6 isoforms with clinically advanced HNSCC and the intriguing results of anti-CD44 v6 therapy in a phase I clinical trial suggest a need for further study of the role of this CD44 variant isoform in HNSCC. Although all CD44 isoforms share HA binding domains, certain CD44 variant isoforms, such as CD44 v10, exhibit significantly reduced affinity for HA binding.25Bourguignon L.Y. Gunja-Smith Z. Iida N. Zhu H.B. Young L.J. Muller W.J. Cardiff R.D. CD44v(3,8–10) is involved in cytoskeleton-mediated tumor cell migration and matrix metalloproteinase (MMP-9) association in metastatic breast cancer cells.J Cell Physiol. 1998; 176: 206-215Crossref PubMed Scopus (244) Google Scholar It is thought that the reduction in HA-mediated cell adhesion in tumor cells expressing CD44 v10 may be the earliest event in the onset of tumor migration and invasion. The unique structure of CD44 v10 may also cause constitutive activation of CD44-cytoskeleton interactions that induce tumor cell migration and invasion. CD44 v10-containing isoforms have been reported to promote tumor progression in breast and renal cell carcinoma.25Bourguignon L.Y. Gunja-Smith Z. Iida N. Zhu H.B. Young L.J. Muller W.J. Cardiff R.D. CD44v(3,8–10) is involved in cytoskeleton-mediated tumor cell migration and matrix metalloproteinase (MMP-9) association in metastatic breast cancer cells.J Cell Physiol. 1998; 176: 206-215Crossref PubMed Scopus (244) Google Scholar, 27Li N. Tsuji M. Kanda K. Murakami Y. Kanayama H. Kagawa S. Analysis of CD44 isoform v10 expression and its p

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