PMCCPMCCPMCC

Search tips
Search criteria 

Advanced

 
Logo of nihpaAbout Author manuscriptsSubmit a manuscriptHHS Public Access; Author Manuscript; Accepted for publication in peer reviewed journal;
 
Cancer Res. Author manuscript; available in PMC 2017 May 1.
Published in final edited form as:
PMCID: PMC4874571
NIHMSID: NIHMS778401

Carcinoma Cell Hyaluronan as a ‘Portable’ Cancerized Pro-Metastatic Microenvironment

Abstract

Hyaluronan (HA) is a structurally simple polysaccharide, but its ability to act as a template for organizing pericellular matrices and its regulated synthesis and degradation are key to initiating repair responses. Importantly, these HA functions are usurped by tumor cells to facilitate progression and metastasis. Recent advances have identified the functional complexities associated with the synthesis and degradation of HA rich matrices. Three enzymes synthesize large HA polymers while multiple hyaluronidases or tissue free radicals degrade these into smaller bioactive fragments. A family of extracellular and cell associated HA binding proteins/receptors translate the bioinformation encrypted in this complex polymer mixture to activate signaling networks required for cell survival, proliferation and migration in an actively remodeling microenvironment. Changes in HA metabolism within both the peritumor stroma and parenchyma are linked to tumor initiation, progression and poor clinical outcome. We review evidence that metastatic tumor cells must acquire the capability to autonomously synthesize, assemble and process their own ‘portable’ HA rich microenvironments in order to survive in the circulation, metastasize to ectopic sites and escape therapeutic intervention. Strategies to disrupt the HA machinery of primary tumor and circulating tumor cells may enhance the effectiveness of current conventional and targeted therapies.

Introduction

Tumor initiation and progression result not only from mutant signaling networks but also from key host microenvironmental factors. A host-derived stroma develops concomitantly with primary tumor initiation and provides a nurturing or “cancerized” microenvironment that supports tumor cell survival, growth and invasion [14]. Aggressive tumor cell subsets become increasingly autonomous and ‘stromal independent’ by establishing autocrine networks permitting them to produce essential microenvironmental factors in an absence of host primary peritumor stroma. This autonomy facilitates the survival of immigrant metastatic cells during their colonization of foreign microenvironments. The tissue polysaccharide, hyaluronan (HA) is one such microenvironmental factor. Its autocrine production, cell surface retention and processing/degradation by aggressive carcinoma cells are major and targetable factors in metastasis. Evidence from multiple model systems and clinical analyses support a key role for cancerized stromal HA in the initiation of malignant tumors. However, metastatic tumor cells appear to acquire the ability to synthesize and assemble their own pericellular HA rich matrices that function to maintain the activation of oncogenic driver and survival signaling pathways. These matrices also support adhesion and extravasation at ectopic sites of metastasis and they function to condition the microenvironment surrounding metastatic lesions. Here we propose that these carcinoma cell associated pericellular HA rich matrices represent a ‘portable cancerized microenvironment’ in circulating tumor cells that can be effectively targeted to limit metastasis and improve patient outcome.

HA Pericellular Matrices, Fragments and Metastasis

Native HA consists of repeating β (1–3) linked disaccharides of D-glucuronic acid and N-acetyl-D glucosamine, which are knitted together as large (107 daltons or higher) polymers by the formation of hexosaminidic β (1–4) linkages. HA synthesis results from the action of three plasma membrane associated HA synthases (HAS 1, 2 and 3), which are homologous but encoded by distinct genes and are differentially expressed [1, 5]. Growing HA polymers are thought to be extruded through pores in the plasma membrane (Figure 1) created by HAS oligomerization [1, 5]. HAS expression and synthesis of HA are regulated by cytokines and growth factors such as PDGF-BB, TGFβ-1 and bFGF [5]. Extruded high molecular weight HA polymers are initially captured by cellular HA receptors and are assembled and stabilized into pericellular coats by a family of extracellular HA binding proteins including tenascin, inter-alpha-trypsin inhibitor, versican, and TSG-6 [68]. These HA rich pericellular matrices are easily visualized in culture as pericellular coats [9] and are also clearly present in vivo [10, 11]. In primary tumors, the cancerized stroma is a rich source of growth factors and cytokines that both stimulate HA synthesis and enhance carcinoma survival and progression. Autonomous metastatic tumor cells have developed an autocrine ability to produce these factors, which also promote synthesis and assembly of HA-rich pericellular matrices coating these aggressive tumor cells. These HA pericellular matrices facilitate several steps required by circulating tumor cells in the metastatic cascade. Compelling data also suggest that the autocrine production of HA pericellular matrices by themselves is not sufficient for successful metastatic colonization. Rather, it appears that tumor cells must also acquire an ability to fragment and metabolize HA in order to form metastatic colonies.

Figure 1
Autocrine Synthesis and Retention of a Hyaluronan Pericellular Matrix

Synthesis of pericellular HA functions to organize and cluster HA receptors on the plasma membrane and sequester growth factors and cytokines near the cell membrane (Figure 1). Receptor clustering induced by pericellular HA organizes plasma membrane microdomains such as lipid rafts, which together with the sequestered growth factors and cytokines promote coupling and sustained activation of driver oncogenic anti-apoptotic, and pro-invasion/migration signal transduction networks [1214]. Thus, HA rich pericellular matrices facilitate intravasation and protect immigrant cells from anoikis during circulatory transit. They also contribute to the ectopic tissue colonization of foreign microenvironments [15]. For example, they can promote the adhesion of tumor cells to microvessel endothelium as has been demonstrated for metastatic prostate carcinoma cells in culture [9]. Furthermore, breast tumor cell subpopulations that bind high levels of HA adhere to vessels and extravasate ex ovo more rapidly than tumor cells that bind little or no HA [16]. Pericellular HA matrices may participate in the conditioning of foreign microenvironments by stimulating the release of microvesicles from HAS and HA-rich cell microvilli [17]. These microvesicles contain numerous proteins involved in organizing and remodeling extracellular matrices (e.g. CD44, MMPs and EMPPRIN) as well as other regulatory factors that are known to produce cancer friendly microenvironments. This model of HA pericellular matrices as portable microenvironments that protect and nurture trafficking and extravasated metastatic tumor cells is summarized in Figure 2. However, an excellent example for the requirement of both HA synthesis and metabolism in tumorigenesis is provided by the naked mole rat, which is resistant to tumors [18]. Fibroblasts isolated from the naked mole rat are resistant to transformation yet actively produce very high molecular weight HA produced by a mutant HAS. Cells can be rendered sensitive to transformation by oncogenes if fragmentation of HA is stimulated by introduction of hyaluronidases.

Figure 2
Hyaluronan Pericellular Matrices as a Portable Pro-Metastatic Cancerized Microenvironment

HA fragments appear to be required for further conditioning of the metastatic microenvironment acting in part to attract host cells that remodel the microenvironment of metastatic colonies. HA is fragmented by enzymatic attack from one or more of several hyaluronidases (e.g. Hyal 1, 2 or 3). It can also be chemically cleaved by oxygen and nitrogen free radicals that are elevated in tumor microenvironments [1921]. This two-pronged attack on HA polymers results in a complex mixture of oligosaccharides and larger fragments with a broad range in sizes (e.g. 4mer to 300,000 daltons). HA fragments perform a range of essential functions necessary for successful metastasis and include effects on both tumor cell and host cell functions. Evidence is emerging that specific size ranges of HA fragments exert differential effects on tumor cell migration and growth [4, 22]. In addition, HA fragmentation within ectopic sites promotes the influx of host pro-tumorigenic macrophages and activate endothelial cells to stimulate angiogenesis [2]. Thus, aggressive immigrant tumor cells that have developed the ability to autonomously synthesize HA, assemble it into pericellular matrices and fragment/process the HA polymers have a selective advantage in metastasis. HA fragmentation is associated with more aggressive disease and studies using prostate cancer cell lines demonstrate that metastasis requires both elevated HA synthesis and Hyal 1 mediated HA fragmentation. Furthermore, targeting hyaluronidase-1 effectively limits prostate carcinoma invasion and metastasis in xenograft models [19, 22, 23]. Analysis of the naked mole rat genome has identified candidate genomic adaptations in the HA receptor genes CD44 and RHAMM, which may modify signaling through HA and partially account for the extraordinary longevity of the naked mole rat and its resistance to tumors [24].

CD44 and RHAMM as Mediators of HA-Promoted Metastasis

One family of proteins that has been extensively studied for their role in metastasis are the CD44 isoforms, which are produced by alternative splicing as well as changes in glycosylation of the core protein.. In particular, the standard CD44 isoform (CD44s), which binds to HA and lacks alternatively spliced domains, is structurally and functionally well characterized [4, 13, 15, 25]. CD44s is a type I transmembrane protein with an HA binding amino terminal link module that is structurally homologous to link modules found in other HA receptors such as LYVE-1 and in extracellular HA binding proteins such as TSG-6, versican [26, 27]. X-ray crystallography and NMR of the CD44 link module has guided the development of specific small molecules to disrupt binding of HA within its long shallow binding groove, which accommodates 8mer regions of the HA polymer [28].

CD44 co-localizes with HAS enzymes in lipid rafts where it is clustered by high molecular weight HA polymers and functions as a co-receptor for growth factor receptors to lower the activation threshold of oncogenic driver signaling networks [5, 12, 13]. This organizing influence of HA on cell surface CD44 also promotes the plasma membrane localization of multidrug resistance proteins and monocarboxylate transporters. Membrane localized multidrug transporters promote the efflux of therapeutic drugs and xenobiotics [29] while monocarboxylate transporters lower intracellular lactate concentrations in tumor cells to favor their survival in hypoxic microenvironments [30]. Specific sizes of HA fragments (<20kDa) can disrupt HA-induced CD44 clusters to block these effects [3133]. For example, these small HA fragments limit oncogenic pathway activation and reverse drug resistance in CD133 positive highly tumorigenic subpopulations of ovarian carcinoma cells [31]. Disrupting HA-CD44 interactions may also be effective in promoting anoikis of circulating tumor cells and limiting HA mediated extravasation and ectopic colonization. Therefore, HA fragments, mimics and small molecules that target link module HA binding are likely have enormous potential for restricting tumor cell metastasis and restoring their sensitivity to currently used targeted- and chemotherapies.

Unlike CD44, RHAMM (HMMR) is an HA receptor that is poorly expressed in most homeostatic tissues but is generally upregulated as well as cell surface displayed during tissue repair [4]. It is consistently overexpressed in many tumors, and its high expression is linked to the progression of multiple carcinomas (e.g. lung, pancreatic, breast, prostate, glioblastoma and colorectal cancers), and mesenchymal tumors including fibromatoses and sarcomas [3443]. RHAMM is considered to be a tumor marker for leukemia [44] and colorectal subtypes [42]. Elevated RHAMM expression is associated with castration resistant disease in patients harboring prostatic metastases [36] and elevated levels of RHAMM and HA area associated with a likelihood of biochemical failure in at-risk (Gleason 7) prostatectomized patients [45]. RHAMM hyperexpression in breast primary tumor cell subpopulations is linked to increased peripheral metastases [46] while increased RHAMM expression in colorectal tumor budding cells at the invasive front of primary tumors is linked to frequent lymphatic invasion, high tumor grade and nodal metastasis [47]. RHAMM is also one of 4 genes elevated in circulating lung adenocarcinoma cells, and patients exhibiting an increase in these markers at 3 months after their first detection had a significantly shorter survival time than patients exhibiting a decrease in these markers [41]. These results predict that aggressive RHAMM positive subpopulations emerge early in the development of primary tumors and contribute to metastasis. Several clinical studies also suggest a role for RHAMM in drug resistance that may determine patient outcome. Thus, the therapeutic sensitivity of peripheral nerve sheath tumors to therapy targeting AURKA depends in part upon RHAMM expression [39], and multidrug resistance of some human leukemia cell lines is mediated by RHAMM [48]. These and other studies suggest RHAMM hyperexpression in aggressive tumor cell subsets has promise as a biomarker for assessing patient risk. These studies also indicate that RHAMM is an attractive target both for limiting spread of these cancers and for treating residual disease.

Both cell surface and intracellular RHAMM contribute to tumor cell aggression [4]. RHAMM was originally identified as an extracellular HA motility promoting receptor on the surface of RAS transformed fibroblasts [49]. Extracellular RHAMM binds to HA and functionally associates with CD44 and growth factor receptors such as EGFR, PDGFR and RON to coordinate activation kinetics of kinase signaling networks [4]. Subsequent studies demonstrated that RHAMM also has diverse and complex subcellular functions. The binding partners of intracellular RHAMM vary with cell and tissue background but include kinases/activators such as ERK1, 2/MEK1 [4] SRC [3] and AURKA/TPX2 [38] as well as nuclear proteins, microtubule and actin binding proteins such as spectrin alpha [50] and supervillin [51]. The functional association of intracellular RHAMM with AURKA/TPX2 is linked to breast cancer risk in BRCA1, 2 carriers predicting key functional roles for these intracellular RHAMM complexes in tumor susceptibility and aggression [38]. In experimental models, intracellular RHAMM and its binding partners regulate tumor cell extravasation, mitotic spindle integrity/chromosome segregation and cytokinesis. Proliferative responses mediated by cell surface CD44/EGFR can be induced via intracellular RHAMM/ERK dependent mechanisms, indicating that cell surface CD44 and intracellular RHAMM can also functionally integrate to promote mitosis [52]. Intracellular RHAMM may therefore contribute to tumor aggression by affecting genomic stability, and it may contribute to tumor cell intravasation and extravasation by regulating both gene expression [53] and cytoskeleton dynamics [53, 54].

Tumor cells also export RHAMM to the cell surface using not well-characterized secretion mechanisms stimulated by growth factors such as TGFβ-1 [55]. Cell surface RHAMM binds both fragmented and high molecular weight HA polymers [4], and it often acts as a co-receptor for CD44 to activate kinase cascades [4]. It is therefore tempting to speculate that cell surface RHAMM functions as an ‘early warning system’ for promoting cell migration during tissue damage including that resulting from tumor formation [4]. The HA binding domains of RHAMM contain key positively charged amino acids originally described as BX7B motifs. These are structurally distinct from HA binding CD44 link domain [4, 14]. Peptides mimicking the RHAMM BX7B motif and peptides mimicking the size of HA fragments, which specifically block cell surface RHAMM functions [56, 57] along with anti-RHAMM antibodies, inhibit early responses relevant to both wound repair and tumorigenesis. These responses include RHAMM stimulated mesenchymal cell motility, tumor cell invasion and angiogenesis [57, 58]. Early clinical studies also suggest that targeting cell surface RHAMM is a potential effective cancer therapy. Thus, immune responsiveness to cell surface RHAMM positively correlates with good clinical outcome and immunization with a RHAMM derived peptide evokes clinical responses in patients with acute myeloid leukemia and multiple myeloma [34, 59]. These studies demonstrate that cell surface RHAMM is both biologically functional and immunogenic, and predict that cell surface RHAMM-directed vaccines may be useful for treating RHAMM expressing malignancies.

Conclusions and Opportunities for Therapeutic Intervention

There is now substantial evidence that elevated HA synthesis, fragmentation and organization as pericellular coats are important steps in the development of tumor cell aggression and primary tumor stromal autonomy required for establishing distant colonies. We propose that autocrine HA matrices produced by circulating metastatic carcinoma cells are utilized as ‘portable cancerized microenvironments’. These matrices function to organize carcinoma cell plasma membrane microdomains and receptors, which through interactions with CD44 facilitate oncogenic pro-survival mechanisms, trap and sequester essential nutrients/cytokines/growth factors and promote functioning and cell surface localization of multidrug and monocarboxylate transporters. In the context of HA rich matrices, CD44 and RHAMM either act independently or as co-receptors to enhance pro-oncogenic signaling activity, promote motility and modify the transcriptome of these cells. The HA-induced functional integration of CD44 and cell surface and intracellular RHAMM is an area of active research that will lead to improved targeting of circulating metastatic tumor cells. Inhibiting HA synthesis by using 4-methylumbilliferone inhibits metastasis of melanoma and prostate carcinoma cells with no apparent side effects [60, 61]. Furthermore, synthetic peptides, antibodies or small HA oligomers that that inhibit CD44 and RHAMM function have also proven effective for inhibiting tumor metastasis in multiple model systems. Given recent studies identifying the importance of RHAMM (in contrast to CD44) in mediating HA binding by suspended mesenchymal cells [62], it is worth considering that agents which specifically interfere with RHAMM/HA functions may be particularly effective at disrupting metastasis of circulating tumor cells that overexpress RHAMM [41].These inhibitors have the potential to be adopted as either single or neoadjuvant therapies to improve patient outcome by limiting metastasis recurrence and relapse, which remain major clinical challenges in cancer treatment.

Acknowledgments

This work was supported by the Chairman’s Fund Professor in Cancer Research to JM, American Heart Association Scientist Development Grant 13SDG6450000 to DW, Prostate Cancer Canada, LRCP catalyst and Canadian Breast Cancer Foundation to ET.

References

1. Karousou E, D'Angelo ML, Kouvidi K, Vigetti D, Viola M, Nikitovic D, et al. Collagen VI and hyaluronan: the common role in breast cancer. Biomed Res Int. 2014;2014:606458. [PMC free article] [PubMed]
2. Schwertfeger KL, Cowman MK, Telmer PG, Turley EA, McCarthy JB. Hyaluronan, Inflammation, and Breast Cancer Progression. Front Immunol. 2015;6:236. [PMC free article] [PubMed]
3. Slevin M, Krupinski J, Gaffney J, Matou S, West D, Delisser H, et al. Hyaluronan-mediated angiogenesis in vascular disease: uncovering RHAMM and CD44 receptor signaling pathways. Matrix Biol. 2007;26:58–68. [PubMed]
4. Tolg C, McCarthy JB, Yazdani A, Turley EA. Hyaluronan and RHAMM in wound repair and the "cancerization" of stromal tissues. Biomed Res Int. 2014;2014:103923. [PMC free article] [PubMed]
5. Tammi RH, Passi AG, Rilla K, Karousou E, Vigetti D, Makkonen K, et al. Transcriptional and post-translational regulation of hyaluronan synthesis. FEBS J. 2011;278:1419–1428. [PubMed]
6. Evanko SP, Tammi MI, Tammi RH, Wight TN. Hyaluronan-dependent pericellular matrix. Adv Drug Deliv Rev. 2007;59:1351–1365. [PMC free article] [PubMed]
7. Kusumoto T, Kodama J, Seki N, Nakamura K, Hongo A, Hiramatsu Y. Clinical significance of syndecan-1 and versican expression in human epithelial ovarian cancer. Oncol Rep. 2010;23:917–925. [PubMed]
8. Voutilainen K, Anttila M, Sillanpaa S, Tammi R, Tammi M, Saarikoski S, et al. Versican in epithelial ovarian cancer: relation to hyaluronan, clinicopathologic factors and prognosis. Int J Cancer. 2003;107:359–364. [PubMed]
9. Simpson MA, Wilson CM, Furcht LT, Spicer AP, Oegema TR, Jr, McCarthy JB. Manipulation of hyaluronan synthase expression in prostate adenocarcinoma cells alters pericellular matrix retention and adhesion to bone marrow endothelial cells. J Biol Chem. 2002;277:10050–10057. [PubMed]
10. Pasonen-Seppanen S, Hyttinen JM, Rilla K, Jokela T, Noble PW, Tammi M, et al. Role of CD44 in the organization of keratinocyte pericellular hyaluronan. Histochem Cell Biol. 2012;137:107–120. [PubMed]
11. Symonette CJ, Kaur Mann A, Tan XC, Tolg C, Ma J, Perera F, et al. Hyaluronan-phosphatidylethanolamine polymers form pericellular coats on keratinocytes and promote basal keratinocyte proliferation. Biomed Res Int. 2014;2014:727459. [PMC free article] [PubMed]
12. Murai T. Lipid Raft-Mediated Regulation of Hyaluronan-CD44 Interactions in Inflammation and Cancer. Front Immunol. 2015;6:420. [PMC free article] [PubMed]
13. Toole BP. Hyaluronan: from extracellular glue to pericellular cue. Nat Rev Cancer. 2004;4:528–539. [PubMed]
14. Turley EA, Noble PW, Bourguignon LY. Signaling properties of hyaluronan receptors. J Biol Chem. 2002;277:4589–4592. [PubMed]
15. Cieply B, Koontz C, Frisch SM. CD44S-hyaluronan interactions protect cells resulting from EMT against anoikis. Matrix Biol. 2015 [PMC free article] [PubMed]
16. Veiseh M, Kwon DH, Borowsky AD, Tolg C, Leong HS, Lewis JD, et al. Cellular heterogeneity profiling by hyaluronan probes reveals an invasive but slow-growing breast tumor subset. Proc Natl Acad Sci U S A. 2014;111:E1731–E1739. [PubMed]
17. Rilla K, Pasonen-Seppanen S, Deen AJ, Koistinen VV, Wojciechowski S, Oikari S, et al. Hyaluronan production enhances shedding of plasma membrane-derived microvesicles. Exp Cell Res. 2013;319:2006–2018. [PubMed]
18. Tian X, Azpurua J, Hine C, Vaidya A, Myakishev-Rempel M, Ablaeva J, et al. High-molecular-mass hyaluronan mediates the cancer resistance of the naked mole rat. Nature. 2013;499:346–349. [PMC free article] [PubMed]
19. Benitez A, Yates TJ, Lopez LE, Cerwinka WH, Bakkar A, Lokeshwar VB. Targeting hyaluronidase for cancer therapy: antitumor activity of sulfated hyaluronic acid in prostate cancer cells. Cancer Res. 2011;71:4085–4095. [PMC free article] [PubMed]
20. Cowman MK, Lee HG, Schwertfeger KL, McCarthy JB, Turley EA. The Content and Size of Hyaluronan in Biological Fluids and Tissues. Front Immunol. 2015;6:261. [PMC free article] [PubMed]
21. McAtee CO, Barycki JJ, Simpson MA. Emerging roles for hyaluronidase in cancer metastasis and therapy. Adv Cancer Res. 2014;123:1–34. [PMC free article] [PubMed]
22. Simpson MA, Lokeshwar VB. Hyaluronan and hyaluronidase in genitourinary tumors. Front Biosci. 2008;13:5664–5680. [PMC free article] [PubMed]
23. Bharadwaj AG, Kovar JL, Loughman E, Elowsky C, Oakley GG, Simpson MA. Spontaneous metastasis of prostate cancer is promoted by excess hyaluronan synthesis and processing. Am J Pathol. 2009;174:1027–1036. [PubMed]
24. Keane M, Craig T, Alfoldi J, Berlin AM, Johnson J, Seluanov A, et al. The Naked Mole Rat Genome Resource: facilitating analyses of cancer and longevity-related adaptations. Bioinformatics. 2014;30:3558–3560. [PMC free article] [PubMed]
25. Toole BP, Slomiany MG. Hyaluronan, CD44 and Emmprin: partners in cancer cell chemoresistance. Drug Resist Updat. 2008;11:110–121. [PMC free article] [PubMed]
26. Banerji S, Ni J, Wang SX, Clasper S, Su J, Tammi R, et al. LYVE-1, a new homologue of the CD44 glycoprotein, is a lymph-specific receptor for hyaluronan. J Cell Biol. 1999;144:789–801. [PMC free article] [PubMed]
27. Day AJ, Prestwich GD. Hyaluronan-binding proteins: tying up the giant. J Biol Chem. 2002;277:4585–4588. [PubMed]
28. Liu LK, Finzel BC. Fragment-based identification of an inducible binding site on cell surface receptor CD44 for the design of protein-carbohydrate interaction inhibitors. J Med Chem. 2014;57:2714–2725. [PubMed]
29. Toole BP, Slomiany MG. Hyaluronan: a constitutive regulator of chemoresistance and malignancy in cancer cells. Semin Cancer Biol. 2008;18:244–250. [PMC free article] [PubMed]
30. Slomiany MG, Grass GD, Robertson AD, Yang XY, Maria BL, Beeson C, et al. Hyaluronan, CD44, and emmprin regulate lactate efflux and membrane localization of monocarboxylate transporters in human breast carcinoma cells. Cancer Res. 2009;69:1293–1301. [PMC free article] [PubMed]
31. Slomiany MG, Dai L, Tolliver LB, Grass GD, Zeng Y, Toole BP. Inhibition of Functional Hyaluronan-CD44 Interactions in CD133-positive Primary Human Ovarian Carcinoma Cells by Small Hyaluronan Oligosaccharides. Clin Cancer Res. 2009;15:7593–7601. [PMC free article] [PubMed]
32. Wakamatsu Y, Sakamoto N, Oo HZ, Naito Y, Uraoka N, Anami K, et al. Expression of cancer stem cell markers ALDH1, CD44 and CD133 in primary tumor and lymph node metastasis of gastric cancer. Pathol Int. 2012;62:112–119. [PubMed]
33. Yan Y, Zuo X, Wei D. Concise Review: Emerging Role of CD44 in Cancer Stem Cells: A Promising Biomarker and Therapeutic Target. Stem Cells Transl Med. 2015;4:1033–1043. [PMC free article] [PubMed]
34. Greiner J, Ringhoffer M, Taniguchi M, Schmitt A, Kirchner D, Krahn G, et al. Receptor for hyaluronan acid-mediated motility (RHAMM) is a new immunogenic leukemia-associated antigen in acute and chronic myeloid leukemia. Exp Hematol. 2002;30:1029–1035. [PubMed]
35. Gurski LA, Xu X, Labrada LN, Nguyen NT, Xiao L, van Golen KL, et al. Hyaluronan (HA) interacting proteins RHAMM and hyaluronidase impact prostate cancer cell behavior and invadopodia formation in 3D HA-based hydrogels. PLoS One. 2012;7:e50075. [PMC free article] [PubMed]
36. Korkes F, de Castro MG, de Cassio Zequi S, Nardi L, Del Giglio A, de Lima Pompeo AC. Hyaluronan-mediated motility receptor (RHAMM) immunohistochemical expression and androgen deprivation in normal peritumoral, hyperplasic and neoplastic prostate tissue. BJU Int. 2014;113:822–829. [PubMed]
37. Kouvidi K, Nikitovic D, Berdiaki A, Tzanakakis GN. Hyaluronan/RHAMM interactions in mesenchymal tumor pathogenesis: role of growth factors. Adv Cancer Res. 2014;123:319–349. [PubMed]
38. Maxwell CA, Benitez J, Gomez-Baldo L, Osorio A, Bonifaci N, Fernandez-Ramires R, et al. Interplay between BRCA1 and RHAMM regulates epithelial apicobasal polarization and may influence risk of breast cancer. PLoS Biol. 2011;9:e1001199. [PMC free article] [PubMed]
39. Mohan P, Castellsague J, Jiang J, Allen K, Chen H, Nemirovsky O, et al. Genomic imbalance of HMMR/RHAMM regulates the sensitivity and response of malignant peripheral nerve sheath tumour cells to aurora kinase inhibition. Oncotarget. 2013;4:80–93. [PMC free article] [PubMed]
40. Tolg C, Poon R, Fodde R, Turley EA, Alman BA. Genetic deletion of receptor for hyaluronan-mediated motility (Rhamm) attenuates the formation of aggressive fibromatosis (desmoid tumor) Oncogene. 2003;22:6873–6882. [PubMed]
41. Man Y, Cao J, Jin S, Xu G, Pan B, Shang L, et al. Newly identified biomarkers for detecting circulating tumor cells in lung adenocarcinoma. Tohoku J Exp Med. 2014;234:29–40. [PubMed]
42. Zlobec I, Terracciano L, Tornillo L, Gunthert U, Vuong T, Jass JR, et al. Role of RHAMM within the hierarchy of well-established prognostic factors in colorectal cancer. Gut. 2008;57:1413–1419. [PubMed]
43. Mantripragada KK, Spurlock G, Kluwe L, Chuzhanova N, Ferner RE, Frayling IM, et al. High-resolution DNA copy number profiling of malignant peripheral nerve sheath tumors using targeted microarray-based comparative genomic hybridization. Clin Cancer Res. 2008;14:1015–1024. [PubMed]
44. Gutjahr JC, Greil R, Hartmann TN. The Role of CD44 in the Pathophysiology of Chronic Lymphocytic Leukemia. Front Immunol. 2015;6:177. [PMC free article] [PubMed]
45. Rizzardi AE, Vogel RI, Koopmeiners JS, Forster CL, Marston LO, Rosener NK, et al. Elevated hyaluronan and hyaluronan-mediated motility receptor are associated with biochemical failure in patients with intermediate-grade prostate tumors. Cancer. 2014;120:1800–1809. [PMC free article] [PubMed]
46. Wang C, Thor AD, Moore DH, 2nd, Zhao Y, Kerschmann R, Stern R, et al. The overexpression of RHAMM, a hyaluronan-binding protein that regulates ras signaling, correlates with overexpression of mitogen-activated protein kinase and is a significant parameter in breast cancer progression. Clin Cancer Res. 1998;4:567–576. [PubMed]
47. Koelzer VH, Huber B, Mele V, Iezzi G, Trippel M, Karamitopoulou E, et al. Expression of the hyaluronan-mediated motility receptor RHAMM in tumor budding cells identifies aggressive colorectal cancers. Hum Pathol. 2015 [PubMed]
48. Lompardia SL, Papademetrio DL, Mascaro M, Alvarez EM, Hajos SE. Human leukemic cell lines synthesize hyaluronan to avoid senescence and resist chemotherapy. Glycobiology. 2013;23:1463–1476. [PubMed]
49. Turley EA, Austen L, Vandeligt K, Clary C. Hyaluronan and a cell-associated hyaluronan binding protein regulate the locomotion of ras-transformed cells. J Cell Biol. 1991;112:1041–1047. [PMC free article] [PubMed]
50. Silverman-Gavrila RV, Silverman-Gavrila LB, Bilal KH, Bendeck MP. Spectrin alpha is important for rear polarization of the microtubule organizing center during migration and spindle pole assembly during division of neointimal smooth muscle cells. Cytoskeleton (Hoboken) 2015;72:157–170. [PubMed]
51. Smith TC, Fang Z, Luna EJ. Novel interactors and a role for supervillin in early cytokinesis. Cytoskeleton (Hoboken) 2010;67:346–364. [PMC free article] [PubMed]
52. Hatano H, Shigeishi H, Kudo Y, Higashikawa K, Tobiume K, Takata T, et al. RHAMM/ERK interaction induces proliferative activities of cementifying fibroma cells through a mechanism based on the CD44-EGFR. Lab Invest. 2011;91:379–391. [PubMed]
53. Meier C, Spitschak A, Abshagen K, Gupta S, Mor JM, Wolkenhauer O, et al. Association of RHAMM with E2F1 promotes tumour cell extravasation by transcriptional up-regulation of fibronectin. J Pathol. 2014;234:351–364. [PubMed]
54. Stangeland B, Mughal AA, Grieg Z, Sandberg CJ, Joel M, Nygard S, et al. Combined expressional analysis, bioinformatics and targeted proteomics identify new potential therapeutic targets in glioblastoma stem cells. Oncotarget. 2015;6:26192–26215. [PMC free article] [PubMed]
55. Samuel SK, Hurta RA, Spearman MA, Wright JA, Turley EA, Greenberg AH. TGF-beta 1 stimulation of cell locomotion utilizes the hyaluronan receptor RHAMM and hyaluronan. J Cell Biol. 1993;123:749–758. [PMC free article] [PubMed]
56. Esguerra KV, Tolg C, Akentieva N, Price M, Cho CF, Lewis JD, et al. Identification, design and synthesis of tubulin-derived peptides as novel hyaluronan mimetic ligands for the receptor for hyaluronan-mediated motility (RHAMM/HMMR) Integr Biol (Camb) 2015 [PMC free article] [PubMed]
57. Tolg C, Hamilton SR, Zalinska E, McCulloch L, Amin R, Akentieva N, et al. A RHAMM mimetic peptide blocks hyaluronan signaling and reduces inflammation and fibrogenesis in excisional skin wounds. Am J Pathol. 2012;181:1250–1270. [PubMed]
58. Lokeshwar VB, Mirza S, Jordan A. Targeting hyaluronic acid family for cancer chemoprevention and therapy. Adv Cancer Res. 2014;123:35–65. [PMC free article] [PubMed]
59. Schmitt M, Schmitt A, Rojewski MT, Chen J, Giannopoulos K, Fei F, et al. RHAMM-R3 peptide vaccination in patients with acute myeloid leukemia, myelodysplastic syndrome, and multiple myeloma elicits immunologic and clinical responses. Blood. 2008;111:1357–1365. [PubMed]
60. Yates TJ, Lopez LE, Lokeshwar SD, Ortiz N, Kallifatidis G, Jordan A, et al. Dietary supplement 4-methylumbelliferone: an effective chemopreventive and therapeutic agent for prostate cancer. J Natl Cancer Inst. 2015;107 [PMC free article] [PubMed]
61. Yoshihara S, Kon A, Kudo D, Nakazawa H, Kakizaki I, Sasaki M, et al. A hyaluronan synthase suppressor, 4-methylumbelliferone, inhibits liver metastasis of melanoma cells. FEBS Lett. 2005;579:2722–2726. [PubMed]
62. Veiseh M, Leith SJ, Tolg C, Elhayek SS, Bahrami SB, Collis L, et al. Uncovering the dual role of RHAMM as an HA receptor and a regulator of CD44 expression in RHAMM-expressing mesenchymal progenitor cells. Front Cell Dev Biol. 2015;3:63. [PMC free article] [PubMed]