**10. References**


Clinical response was correlated with an increase in CD8+ T cell proliferation and in some cases a decrease in Treg population. Interestingly, in B-CLL patients with clinical response to vaccination with stimulated DC cells, the CD8+ cytotoxic T cell and IL-12 anti-tumour response was increased, whereas the Treg cell population was decreased (Hus *et al*., 2008). In a Phase I study of CLL patients vaccinated with RHAMM peptide, there was no correlation between clinical response and Treg population dynamics (Giannopoulos *et al*., 2010). This strategy has not yet been used for BCA, although, as RHAMM is a prognostic marker for BCA. and overexpressed in many cases which currently do not have a specific targeted therapeutic option (e.g. basal subtype) and also given the magnitude of the response, along with such low toxicity, it is an approach which merits further consideration.

In summary, HA is a glycosaminoglycan that exerts a critical role in BCA progression by interacting with other ECM components and the tumour cells themselves. HA fragmentation induces inflammation and signalling that results in cancer and immune cell proliferation and migration, which can lead to poor outcome. The links between HA and cancer progression, as well as HA and inflammation have in some aspects been well established. Given the similarities in their signalling cascades and cellular processes, the relationship between HA stimulated innate immunity and the BCA microenvironment

We would like to thank Kenneth Esguerra and the Translational Breast Cancer Research

Ambs S, Glynn SA. (2011). Candidate pathways linking inducible nitric oxide synthase to a

Barbera-Guillem E, Nyhus JK, Wolford CC, et al. (2002). Vascular endothelial growth factor

Bassi PF, Volpe A, D'Agostino D, et al. (2010). Paclitaxel-hyaluronic acid for intravesical

Ben-Baruch A. (2003). Host microenvironment in breast cancer development: inflammatory

basal-like transcription pattern and tumor progression in human breast cancer. *Cell cycle (Georgetown, Tex*, Vol.10, No.4, (Feb 15, 2011), pp. 619-24, lSSN 1551-4005 Banerji S, Ni J, Wang SX, et al. (1999). LYVE-1, a new homologue of the CD44 glycoprotein,

is a lymph-specific receptor for hyaluronan. *The Journal of cell biology*, Vol.144, No.4,

secretion by tumor-infiltrating macrophages essentially supports tumor angiogenesis, and IgG immune complexes potentiate the process. *Cancer research*,

therapy of bacillus Calmette-Guerin refractory carcinoma in situ of the bladder: results of a phase I study. *The Journal of urology*, Vol.185, No.2, (Feb, 2010), pp. 445-

cells, cytokines and chemokines in breast cancer progression: reciprocal tumor-

**8. Conclusion** 

should be further considered.

Unit for their support and assistance.

(Feb 22, 1999), pp. 789-801, lSSN 0021-9525

9, lSSN 1527-3792 (Electronic)

Vol.62, No.23, (Dec 1, 2002), pp. 7042-9, lSSN 0008-5472

**9. Acknowledgments** 

**10. References** 

microenvironment interactions. *Breast Cancer Res*, Vol.5, No.1, 2003), pp. 31-6, lSSN 1465-542X (Electronic)


Hyaluronan Associated Inflammation and Microenvironment

805, lSSN 1476-5551 (Electronic)

2006), pp. 347-54, lSSN 1470-8728 (Electronic)

(Nov 15, 2008), pp. 7161-6, lSSN 1078-0432 (Print)

(Mar, 2008), pp. 230-43, lSSN 1476-5586 (Electronic)

14, 1995), pp. 19-26, lSSN 0092-8674 (Print)

pp. 16667-80, lSSN 0021-9258 (Print)

pp. 215-8, lSSN 1607-8438 (Electronic)

No.1, (Apr, 1999), pp. 99-108, lSSN 0014-4800 (Print)

1551-4005 (Electronic)

lSSN 1538-7445 (Electronic)

1592-8721 (Electronic)

11, lSSN 0960-9822 (Print)

Remodelling Influences Breast Cancer Progression 227

Godar S, Weinberg RA. (2008). Filling the mosaic of p53 actions: p53 represses RHAMM

Goentzel BJ, Weigel PH, Steinberg RA. (2006). Recombinant human hyaluronan synthase 3

Golshani, R., Lopez L., Estrella V., Kramer M., Iida N., Lokeshwar V.B. (2008). Hyaluronic

Greiner J, Bullinger L, Guinn BA, et al. (2008). Leukemia-associated antigens are critical for

Greiner J, Schmitt A, Giannopoulos K, et al. (2010). High-dose RHAMM-R3 peptide

Groen, A.C., Cameron L.A., Coughlin M., Miyamoto D.T., Mitchison T.J., Ohi R. (2004).

Haim K, Weitzenfeld P, Meshel T, et al. (2008). Epidermal Growth Factor and Estrogen Act

Hall CL, Yang B, Yang X, et al. (1995). Overexpression of the hyaluronan receptor RHAMM

Hamilton SR, Fard SF, Paiwand FF, et al. (2007). The hyaluronan receptors CD44 and

He M, Zhao Z, Yin L, et al. (2009). Hyaluronic acid coated poly(butyl cyanoacrylate)

Herrera-Gayol A, Jothy S. (1999). CD44 modulates Hs578T human breast cancer cell

Vol.373, No.1-2, (May 21, 2009), pp. 165-73, lSSN 1873-3476 (Electronic) Heldin P, Karousou E, Bernert B, et al. (2008). Importance of hyaluronan-CD44 interactions

with chronic lymphocytic leukemia. *Leukemia*, Vol.24, No.4, (Apr, 2010), pp. 798-

expression. *Cell cycle (Georgetown, Tex*, Vol.7, No.22, (Nov 15, 2008), pp. 3479, lSSN

is phosphorylated in mammalian cells. *The Biochemical journal*, Vol.396, No.2, (Jun 1,

acid synthase-1 expression regulates bladder cancer growth, invasion, and angiogenesis through CD44. *Cancer research,* Vol. 68, No. 2, (Jan 15, 2008), pp.483-91,

the proliferation of acute myeloid leukemia cells. *Clin Cancer Res*, Vol.14, No.22,

vaccination for patients with acute myeloid leukemia, myelodysplastic syndrome and multiple myeloma. *Haematologica*, Vol.95, No.7, (Jul, 2010), pp. 1191-7, lSSN

XRHAMM functions in ran-dependent microtubule nucleation and pole formation during anastral spindle assembly. *Curr Biol,* Vol. 14, No. 20, (Oct 26, 2004), pp.1801-

by Independent Pathways to Additively Promote the Release of the Angiogenic Chemokine CXCL8 by Breast Tumor Cells. *Neoplasia (New York, NY*, Vol.13, No.3,

is transforming and is also required for H-ras transformation. *Cell*, Vol.82, No.1, (Jul

Rhamm (CD168) form complexes with ERK1,2 that sustain high basal motility in breast cancer cells. *The Journal of biological chemistry*, Vol.282, No.22, (Jun 1, 2007),

nanoparticles as anticancer drug carriers. *International journal of pharmaceutics*,

in inflammation and tumorigenesis. *Connective tissue research*, Vol.49, No.3, 2008),

adhesion, migration, and invasiveness. *Experimental and molecular pathology*, Vol.66,


Davidenko N, Campbell JJ, Thian ES, et al. (2010). Collagen-hyaluronic acid scaffolds for

del Fresno C, Otero K, Gomez-Garcia L, et al. (2005). Tumor cells deactivate human

progression. *Breast Cancer Res*, Vol.9, No.4, 2007), pp. 212, lSSN 1465-542X Diaz LK, Zhou X, Wright ET, et al. (2005). CD44 expression is associated with increased

Docherty R, Forrester JV, Lackie JM, et al. (1989). Glycosaminoglycans facilitate the

Du Y, Liu Y, Wang Y, et al. (2010). LYVE-1 enhances the adhesion of HS-578T cells to COS-7

Eck SM, Cote AL, Winkelman WD, et al. (2009). CXCR4 and matrix metalloproteinase-1 are

Ekici S, Cerwinka WH, Duncan R, et al. (2004). Comparison of the prognostic potential of

Fanning A, Volkov Y, Freeley M, et al. (2005). CD44 cross-linking induces protein kinase C-

Fernandez Madrid F. (2005). Autoantibodies in breast cancer sera: candidate biomarkers and

Fukui M, Whittlesey K, Metcalfe DD, et al. (2000). Human mast cells express the hyaluronic-

*(Orlando, Fla*, Vol.94, No.3, (Mar, 2000), pp. 173-8, lSSN 1521-6616 (Print) Fukui M, Ueno K, Suehiro Y, et al. (2006). Anti-tumor activity of dendritic cells transfected

Gale NW, Prevo R, Espinosa J, et al. (2007). Normal lymphatic development and function in

Giannopoulos K, Dmoszynska A, Kowal M, et al. (2010). Peptide vaccination elicits

*biology*, Vol.27, No.2, (Jan, 2007), pp. 595-604, lSSN 0270-7306 (Print)

*science*, Vol.92 ( Pt 2), (Feb, 1989), pp. 263-70, lSSN 0021-9533 (Print)

No.7, (Jul, 2009), pp. 1033-44, lSSN 1557-3125 (Electronic)

No.4, (Apr, 2005), pp. 449-58, lSSN 0953-8178 (Print)

(May 1, 2005), pp. 3309-14, lSSN 1078-0432 (Print)

lSSN 1878-7568 (Electronic)

54, lSSN 1488-2353 (Electronic)

9, lSSN 0020-7136 (Print)

lSSN 0304-3835 (Print)

7004 (Print)

adipose tissue engineering. *Acta biomaterialia*, Vol.6, No.10, (Oct, 2010), pp. 3957-68,

monocytes by up-regulating IL-1 receptor associated kinase-M expression via CD44 and TLR4. *J Immunol*, Vol.174, No.5, (Mar 1, 2005), pp. 3032-40, lSSN 0022-1767 DeNardo DG, Coussens LM. (2007). Inflammation and breast cancer. Balancing immune

response: crosstalk between adaptive and innate immune cells during breast cancer

survival in node-negative invasive breast carcinoma. *Clin Cancer Res*, Vol.11, No.9,

movement of fibroblasts through three-dimensional collagen matrices. *Journal of cell* 

cells via hyaluronan. *Clinical and investigative medicine*, Vol.34, No.1, 2010), pp. E45-

elevated in breast carcinoma-associated fibroblasts and in normal mammary fibroblasts exposed to factors secreted by breast cancer cells. *Mol Cancer Res*, Vol.7,

hyaluronic acid, hyaluronidase (HYAL-1), CD44v6 and microvessel density for prostate cancer. *International journal of cancer*, Vol.112, No.1, (Oct 20, 2004), pp. 121-

regulated migration of human T lymphocytes. *International immunology*, Vol.17,

reporters of tumorigenesis. *Cancer letters*, Vol.230, No.2, (Dec 18, 2005), pp. 187-98,

acid-binding isoform of CD44 and adhere to hyaluronic acid. *Clinical immunology* 

with mRNA for receptor for hyaluronan-mediated motility is mediated by CD4+ T cells. *Cancer Immunol Immunother*, Vol.55, No.5, (May, 2006), pp. 538-46, lSSN 0340-

mice deficient for the lymphatic hyaluronan receptor LYVE-1. *Molecular and cellular* 

leukemia-associated antigen-specific cytotoxic CD8+ T-cell responses in patients

with chronic lymphocytic leukemia. *Leukemia*, Vol.24, No.4, (Apr, 2010), pp. 798- 805, lSSN 1476-5551 (Electronic)


Hyaluronan Associated Inflammation and Microenvironment

Remodelling Influences Breast Cancer Progression 229

Kobayashi N, Miyoshi S, Mikami T, et al. (2010). Hyaluronan deficiency in tumor stroma

Kuang DM, Wu Y, Chen N, et al. (2007). Tumor-derived hyaluronan induces formation of

Kuo YC, Su CH, Liu CY, et al. (2009). Transforming growth factor-beta induces CD44

Lokeshwar, V.B., Obek C., Pham H.T., Wei D., Young M.J., Duncan R.C., Soloway M.S.,

Lokeshwar, V.B., Selzer M.G. (2008). Hyalurondiase: both a tumor promoter and suppressor. *Seminars in cancer biology,* Vol. 18, No. 4, (Aug, 2008), pp.281-7, lSSN 1096-3650 Lokeshwar, V.B., Lopez L.E., Munoz D., Chi A., Shirodkar S.P., Lokeshwar S.D., Escudero

Lopez JI, Camenisch TD, Stevens MV, et al. (2005). CD44 attenuates metastatic invasion

Ma, W., Deng Y., Zhou L. (2005). The prognostic value of adhesion molecule CD44v6 in

Mantovani A, Marchesi F, Porta C, et al. (2007). Inflammation and cancer: breast cancer as a

Vol.124, No.11, (Jun 1, 2009), pp. 2568-76, lSSN 1097-0215 (Electronic) Lin EY, Nguyen AV, Russell RG, et al. (2001). Colony-stimulating factor 1 promotes

Vol.193, No.6, (Mar 19, 2001), pp. 727-40, lSSN 0022-1007 (Print)

No. 7, (Apr 1, 2010), pp.2613-23, lSSN 1538-7445 (Electronic)

2000), pp.348-56, lSSN 0022-5347 (Print)

6755-63, lSSN 0008-5472 (Print)

lSSN 0936-6555 (Print)

0960-9776 (Print)

*Blood*, Vol.110, No.2, (Jul 15, 2007), pp. 587-95, lSSN 0006-4971 (Print) Kuang DM, Zhao Q, Xu J, et al. (2008). Tumor-educated tolerogenic dendritic cells induce

No.11, (Jul 1, 2009), pp. 1914-23, lSSN 1090-2422 (Electronic)

Vol.70, No.18, (Sep 15, 2010), pp. 7073-83, lSSN 1538-7445 (Electronic) Koyama H, Hibi T, Isogai Z, et al. (2007). Hyperproduction of hyaluronan in neu-induced

No.3, (Mar, 2007), pp. 1086-99, lSSN 0002-9440 (Print)

impairs macrophage trafficking and tumor neovascularization. *Cancer research*,

mammary tumor accelerates angiogenesis through stromal cell recruitment: possible involvement of versican/PG-M. *The American journal of pathology*, Vol.170,

immunosuppressive macrophages through transient early activation of monocytes.

CD3epsilon down-regulation and apoptosis of T cells through oxygen-dependent pathways. *J Immunol*, Vol.181, No.5, (Sep 1, 2008), pp. 3089-98, lSSN 1550-6606 Kultti A, Pasonen-Seppanen S, Jauhiainen M, et al. (2009). 4-Methylumbelliferone inhibits

hyaluronan synthesis by depletion of cellular UDP-glucuronic acid and downregulation of hyaluronan synthase 2 and 3. *Experimental cell research*, Vol.315,

cleavage that promotes migration of MDA-MB-435s cells through the up-regulation of membrane type 1-matrix metalloproteinase. *International journal of cancer*,

progression of mammary tumors to malignancy. *The Journal of experimental medicine*,

Block N.L. (2000). Urinary hyaluronic acid and hyaluronidase: markers for bladder cancer detection and evaluation of grade. *The Journal of urology,* Vol. 163, No. 1, (Jan,

D.O., Dhir N., Altman N. (2010). Antitumor activity of hyaluronic acid synthesis inhibitor 4-methylumbelliferone in prostate cancer cells. *Cancer research,* Vol. 70,

during breast cancer progression. *Cancer research*, Vol.65, No.15, (Aug 1, 2005), pp.

women with primary breast carcinoma: a clinicopathologic study. *Clinical oncology (Royal College of Radiologists (Great Britain)),* Vol. 17, No. 4, (Jun, 2005), pp.258-63,

prototype. *Breast (Edinburgh, Scotland)*, Vol.16 Suppl 2, (Dec, 2007), pp. S27-33, lSSN


Hus I, Schmitt M, Tabarkiewicz J, et al. (2008). Vaccination of B-CLL patients with

Hyung W, Ko H, Park J, et al. (2008). Novel hyaluronic acid (HA) coated drug carriers

Itano N, Sawai T, Yoshida M, et al. (1999). Three isoforms of mammalian hyaluronan

Itano N, Atsumi F, Sawai T, et al. (2002). Abnormal accumulation of hyaluronan matrix

Itano N, Sawai T, Atsumi F, et al. (2004). Selective expression and functional characteristics

Itano N, Kimata K. (2008). Altered hyaluronan biosynthesis in cancer progression. *Seminars in cancer biology*, Vol.18, No.4, (Aug, 2008), pp. 268-74, lSSN 1096-3650 (Electronic) Itano, N., Zhuo L., Kimata K. (2008). Impact of the hyaluronan-rich tumor

Jackson DG. (2009). Immunological functions of hyaluronan and its receptors in the

Jiang, D., Liang J., Noble P.W. (2007). Hyaluronan in tissue injury and repair. *Annual review* 

Insert 'Joukov V, Groen AC, et al. (2006). The BRCA1/BARD1 heterodimer modulates ran-

Kakizaki I, Kojima K, Takagaki K, et al. (2004). A novel mechanism for the inhibition of

*chemistry*, Vol.279, No.32, (Aug 6, 2004), pp. 33281-9, lSSN 0021-9258 (Print) Karihtala P, Soini Y, Auvinen P, et al. (2007). Hyaluronan in breast cancer: correlations with

Karousou E, Kamiryo M, Skandalis SS, et al. (2010). The activity of hyaluronan synthase 2 is

Vol.285, No.31, (Jul 30, 2010), pp. 23647-54, lSSN 1083-351X (Electronic) Khazaie K, Blatner NR, Khan MW, et al. (2011). The significant role of mast cells in cancer. *Cancer metastasis reviews*, Vol.30, No.1, (Mar, 2011), pp. 45-60, lSSN 1573-7233

Vol.99, No.2, (Feb 1, 2008), pp. 442-54, lSSN 1097-0290 (Electronic)

Vol.274, No.35, (Aug 27, 1999), pp. 25085-92, lSSN 0021-9258 (Print)

No.6, (Mar 19, 2002), pp. 3609-14, lSSN 0027-8424 (Print)

9, (Sep, 2008), pp.1720-5, lSSN 1349-7006 (Electronic)

No.12, (Dec, 2007), pp. 1191-8, lSSN 0022-1554 (Print)

5551 (Electronic)

0021-9258 (Print)

065X (Electronic)

ISSN 0092-8674 (Electronic)'

autologous dendritic cells can change the frequency of leukemia antigen-specific CD8+ T cells as well as CD4+CD25+FoxP3+ regulatory T cells toward an antileukemia response. *Leukemia*, Vol.22, No.5, (May, 2008), pp. 1007-17, lSSN 1476-

(HCDCs) for human breast cancer treatment. *Biotechnology and bioengineering*,

synthases have distinct enzymatic properties. *The Journal of biological chemistry*,

diminishes contact inhibition of cell growth and promotes cell migration. *Proceedings of the National Academy of Sciences of the United States of America*, Vol.99,

of three mammalian hyaluronan synthases in oncogenic malignant transformation. *The Journal of biological chemistry*, Vol.279, No.18, (Apr 30, 2004), pp. 18679-87, lSSN

microenvironment on cancer initiation and progression. *Cancer science,* Vol. 99, No.

lymphatics. *Immunological reviews*, Vol.230, No.1, (Jul, 2009), pp. 216-31, lSSN 1600-

*of cell and developmental biology,* Vol. 23, No. 2007), pp.435-61, lSSN 1081-0706 (Print)

dependent mitotic spindle assembly. *Cell*, Vol.127, No.3, (Nov, 2006), pp. 539-52,

hyaluronan biosynthesis by 4-methylumbelliferone. *The Journal of biological* 

nitric oxide synthases and tyrosine nitrosylation. *J Histochem Cytochem*, Vol.55,

regulated by dimerization and ubiquitination. *The Journal of biological chemistry*,


Hyaluronan Associated Inflammation and Microenvironment

1878-3686 (Electronic)

Remodelling Influences Breast Cancer Progression 231

Pedroza-Gonzalez A, Xu K, Wu TC, et al. (2011). Thymic stromal lymphopoietin fosters

Riechelmann H, Sauter A, Golze W, et al. (2008). Phase I trial with the CD44v6-targeting

Rockey DC, Chung JJ, McKee CM, et al. (1998). Stimulation of inducible nitric oxide

Rys J, Kruczak A, Lackowska B, et al. (2003). The role of CD44v3 expression in female breast carcinomas. *Pol J Pathol*, Vol.54, No.4, 2003), pp. 243-7, lSSN 1233-9687 (Print) Schmitt M, Schmitt A, Rojewski MT, et al. (2008). RHAMM-R3 peptide vaccination in

Simpson, M.A., Lokeshwar V.B. (2008). Hyaluronan and hyaluronidase in genitourinary tumors. *Front Biosci,* Vol. 13, No. 2008), pp.5664-80, lSSN 1093-4715 (Electronic) Slevin M., Krupinski J., Gaffney J., Matou S., West D., Delisser H., Savani R.C., Kumar S.

Sohr S, Engeland K. (2008). RHAMM is differentially expressed in the cell cycle and

Soria G, Ben-Baruch A. (2008). The inflammatory chemokines CCL2 and CCL5 in breast cancer. *Cancer letters*, Vol.267, No.2, (Aug 28 2008), pp.271-85, ISSN 1872-7980 Stern R. (2008). Hyaluronidases in cancer biology. *Seminars in cancer biology*, Vol.18, No.4,

Sugahara KN, Hirata T, Hayasaka H, et al. (2006). Tumor cells enhance their own CD44

*chemistry*, Vol.281, No.9, (Mar 3, 2006), pp. 5861-8, lSSN 0021-9258 (Print)

cleavage and motility by generating hyaluronan fragments. *The Journal of biological* 

No.1, (Jan, 1998), pp. 86-92, lSSN 0270-9139 (Print)

2008), pp. 1357-65, lSSN 0006-4971 (Print)

2007), pp.58-68, lSSN 0945-053X (Print)

(Aug, 2008), pp. 275-80, lSSN 1096-3650 (Electronic)

0282-0080 (Print)

human breast tumor growth by promoting type 2 inflammation. *The Journal of experimental medicine*, Vol.208, No.3, (Mar 14, 2011), pp. 479-90, lSSN 1540-9538 Rajput AB, Turbin DA, Cheang MC, et al. (2008). Stromal mast cells in invasive breast cancer

are a marker of favourable prognosis: a study of 4,444 cases. *Breast cancer research and treatment*, Vol.107, No.2, (Jan, 2008), pp. 249-57, lSSN 1573-7217 (Electronic) Rakhra K, Bachireddy P, Zabuawala T, et al. (2010). CD4(+) T cells contribute to the

remodeling of the microenvironment required for sustained tumor regression upon oncogene inactivation. *Cancer cell*, Vol.18, No.5, (Nov 16, 2010), pp. 485-98, lSSN

immunoconjugate bivatuzumab mertansine in head and neck squamous cell carcinoma. *Oral oncology*, Vol.44, No.9, (Sep, 2008), pp. 823-9, lSSN 1368-8375 (Print)

synthase in rat liver by hyaluronan fragments. *Hepatology (Baltimore, Md*, Vol.27,

patients with acute myeloid leukemia, myelodysplastic syndrome, and multiple myeloma elicits immunologic and clinical responses. *Blood*, Vol.111, No.3, (Feb 1,

(2007). Hyaluronan-mediated angiogenesis in vascular disease: uncovering RHAMM and CD44 receptor signaling pathways. *Matrix Biol,* Vol. 26, No. 1, (Jan,

downregulated by the tumor suppressor p53. *Cell cycle (Georgetown, Tex*, Vol.7, No.21, (Nov 1, 2008), pp. 3448-60, lSSN 1551-4005 Soria G, Ben-Baruch A. (2008). The inflammatory chemokines CCL2 and CCL5 in breast cancer. *Cancer letters*, Vol.267, No.2, (Aug 28, 2008), pp. 271-85, lSSN 1872-7980 Spicer AP, Tien JL, Joo A, et al. (2002). Investigation of hyaluronan function in the mouse through targeted mutagenesis. *Glycoconjugate journal*, Vol.19, No.4-5, (May-Jun, 2002), pp. 341-5, lSSN


Matsumoto N, Mukae S, Tsuda H, et al. (2010). Prognostic value of LYVE-1-positive

Maxwell, C.A., McCarthy J., Turley E. (2008). Cell-surface and mitotic-spindle RHAMM:

Micke P, Kappert K, Ohshima M, et al. (2007). In situ identification of genes regulated

*States of America*, Vol.72, No.9, (Sep, 1975), pp. 3585-9, lSSN 0027-8424 (Print) Mytar B, Siedlar M, Woloszyn M, et al. (2001). Cross-talk between human monocytes and

Mytar B, Woloszyn M, Szatanek R, et al. (2003). Tumor cell-induced deactivation of human

Nagano O, Saya H. (2004). Mechanism and biological significance of CD44 cleavage. *Cancer* 

Naor, D., Wallach-Dayan S.B., Zahalka M.A., Sionov R.V. (2008). Involvement of CD44, a

Noble, P.W., McKee C.M., et al. (1996). Hyaluronan fragments activate an NF-kappa B/I-

Paiva, P., Van Damme M.P., Tellbach M., Jones R.L., Jobling T., Salamonsen L.A. (2005).

*oncology,* Vol. 98, No. 2, (Aug, 2005), pp.193-202, lSSN 0090-8258 (Print)

Medicine, Vol.183, No.5, (May 1996), pp.2373-8, ISSN 0022-1007 (Print) Ouhtit, A., Abd Elmageed Z.Y., Abdraboh M.E., Lioe T.F., Raj M.H. (2007). In vivo evidence

kappa B alpha autoregulatory loop in murine macrophages. *Journal of Experimental* 

for the role of CD44s in promoting breast cancer metastasis to the liver. *The American journal of pathology,* Vol. 171, No. 6, (Dec, 2007), pp.2033-9, lSSN 0002-9440

Expression patterns of hyaluronan, hyaluronan synthases and hyaluronidases indicate a role for hyaluronan in the progression of endometrial cancer. *Gynecologic* 

*science*, Vol.95, No.12, (Dec, 2004), pp. 930-5, lSSN 1347-9032 (Print)

Vol.171, No.6, (Dec, 2007), pp. 2033-9, lSSN 0002-9440 (Print)

32, lSSN 0021-9533 (Print)

lSSN 0020-7136 (Print)

0741-5400 (Print)

(Apr 1, 2008), pp.925-32, ISSN 0021-9533 (print)

lymphatic vessel in tongue squamous cell carcinomas. *Anticancer research*, Vol.30, No.6, (Jun, 2010), pp. 1897-903, lSSN 1791-7530 Maxwell, C.A., Mccarthy J., Turley E. (2008). Cell-surface and mitotic-spindle RHAMM: moonlighting or dual oncogenic functions? *Journal of cell science,* Vol. 121, No. Pt 7, (Apr 1, 2008), pp.925-

moonlighting or dual oncogenic functions? *Journal of cell sciences*, Vol. 121, No. Pt 7,

specifically in fibroblasts of human basal cell carcinoma. *The Journal of investigative dermatology*, Vol.127, No.6, (Jun, 2007), pp. 1516-23, lSSN 1523-1747 (Electronic) Mintz B, Illmensee K. (1975). Normal genetically mosaic mice produced from malignant

teratocarcinoma cells. *Proceedings of the National Academy of Sciences of the United* 

cancer cells during reactive oxygen intermediates generation: the essential role of hyaluronan. *International journal of cancer*, Vol.94, No.5, (Dec 1, 2001), pp. 727-32,

monocytes. *Journal of leukocyte biology*, Vol.74, No.6, (Dec, 2003), pp. 1094-101, lSSN

molecule with a thousand faces, in cancer dissemination. *Seminars in cancer biology,*  Vol. 18, No. 4, (Aug, 2008), pp.260-7, lSSN 1096-3650 Noble PW, McKee CM, Cowman M, et al. (1996). Hyaluronan fragments activate an NF-kappa B/I-kappa B alpha autoregulatory loop in murine macrophages. *The Journal of experimental medicine*, Vol.183, No.5, (May 1, 1996), pp. 2373-8, lSSN 0022-1007 Ouhtit A, Abd Elmageed ZY, Abdraboh ME, et al. (2007). In vivo evidence for the role of CD44s in promoting breast cancer metastasis to the liver. *The American journal of pathology*,


Hyaluronan Associated Inflammation and Microenvironment

74, lSSN 1083-351X (Electronic)

2084 (Electronic)

6821 (Electronic)

45, ISSN 1083-351X (electronic)

0906

0366-6999 (Print)

Remodelling Influences Breast Cancer Progression 233

Toole, B.P. (2004). Hyaluronan: from extracellular glue to pericellular cue. *Nature reviews,* 

Toole BP, Slomiany MG. (2008). Hyaluronan, CD44 and Emmprin: partners in cancer cell

Toole, B.P., Slomiany M.G. (2008). Hyaluronan: a constitutive regulator of chemoresistance

Turley, E.A., Veiseh M., Radisky D.C., Bissell M.J. (2008). Mechanisms of disease: epithelial-

Vol. 4, No. 7, (Jul, 2004), pp.528-39, lSSN 1474-175X (Print)

2008), pp.244-50, lSSN 1096-3650 (Electronic)

activity. *The Journal of biological chemistry*, Vol.285, No.34, (Aug 20, 2010), pp. 26461-

chemoresistance. *Drug Resist Updat*, Vol.11, No.3, (Jun, 2008), pp. 110-21, lSSN 1532-

and malignancy in cancer cells. *Seminars in cancer biology,* Vol. 18, No. 4, (Aug,

mesenchymal transition--does cellular plasticity fuel neoplastic progression? *Nature clinical practice,* Vol. 5, No. 5, (May, 2008), pp.280-90, lSSN 1743-4262 (Electronic) Udabage L, Brownlee GR, Waltham M, et al. (2005). Antisense-mediated suppression of

hyaluronan synthase 2 inhibits the tumorigenesis and progression of breast cancer. *Cancer research*, Vol.65, No.14, (Jul 15, 2005), pp. 6139-50, lSSN 0008-5472 (Print) Unger K, Wienberg J, Riches A, et al. (2009). Novel gene rearrangements in transformed

breast cells identified by high-resolution breakpoint analysis of chromosomal aberrations. *Endocrine-related cancer*, Vol.17, No.1, (Mar, 2009), pp. 87-98, lSSN 1479-

probes for imaging and therapy of breast cancer. *Integr Biol (Camb),* Vol. 3, No. 4, (Apr 1, 2011), pp.304-15, lSSN 1757-9708 Vigetti D, Genasetti A, Karousou E, et al. (2010). Proinflammatory cytokines induce hyaluronan synthesis and monocyte adhesion in human endothelial cells through hyaluronan synthase 2 (HAS2) and the nuclear factor-kappaB (NF-kappaB) pathway. *The Journal of biological chemistry*,

 hyaluronan synthesis and monocyte adhesion in human endothelial cells through hyaluronan synthase 2 (HAS2) and the nuclear factor-kappaB (NF-kappaB) pathway. *The Journal of biological chemistry*, Vol.285, No.32, (Aug 6 2010), pp.24639-

Anderegg U., Simon J. (2008). Hyaluronan fragments induce cytokine and metalloprotease upregulation in human melanoma cells in part by signalling via TLR4. *Experimental dermatology,* Vol. 17, No. 2, (Feb, 2008), pp.100-7, lSSN 1600-0625

invasiveness and tubule formation promotion in ER (-) and ER (+) breast cancer cell lines in vitro. *Chinese medical journal*, Vol.122, No.11, (Jun 5, 2009), pp. 1300-4, lSSN

induced proliferation, tube formation and signal transduction in endothelial cells.

Veiseh, M., Turley E.A. (2011). Hyaluronan metabolism in remodeling extracellular matrix:

Vol.285, No.32, (Aug 6, 2010), pp. 24639-45, lSSN 1083-351X (Electronic) Vigetti, D., Genasetti A., Karousou E, et al. (2010). Proinflammatory cytokines induce

Voelcker, V., Gebhardt C., Averbeck M., Saalbach A., Wolf V., Weih F., Sleeman J.,

Wang XY, Tan JX, Vasse M, et al. (2009). Comparison of hyaluronidase expression,

Wang YZ, Cao ML, Liu YW, et al. (2011). CD44 mediates oligosaccharides of hyaluronan-


Szabo P, Kolar M, Dvorankova B, et al. (2011). Mouse 3T3 fibroblasts under the influence of

Tafani M, Russo A, Di Vito M, et al. (2010). Up-regulation of pro-inflammatory genes as

Tammi R, Rilla K, Pienimaki JP, et al. (2001). Hyaluronan enters keratinocytes by a novel

Tammi RH, Kultti A, Kosma VM, et al. (2008). Hyaluronan in human tumors:

Tan JX, Wang XY, Li HY, et al. (2010). HYAL1 overexpression is correlated with the

*J Immunol*, Vol.165, No.4, (Aug 15, 2000), pp. 1863-70, lSSN 0022-1767 (Print) Termeer CC, Hennies J, Voith U, et al. (2000). Oligosaccharides of hyaluronan are potent

Termeer C, Benedix F, Sleeman J, et al. (2002). Oligosaccharides of Hyaluronan activate

Theocharis, A.D., Skandalis S.S., Tzanakakis G.N., Karamanos N.K. (2010). Proteoglycans in

Thorne RF, Legg JW, Isacke CM. (2004). The role of the CD44 transmembrane and

*science*, Vol.117, No.Pt 3, (Jan 26, 2004), pp. 373-80, lSSN 0021-9533 (Print) Tijink BM, Buter J, de Bree R, et al. (2006). A phase I dose escalation study with anti-CD44v6

Tolg C, Hamilton SR, Nakrieko KA, et al. (2006). Rhamm-/- fibroblasts are defective in

Tolg C, Hamilton SR, Morningstar L, et al. (2010). RHAMM promotes interphase

*Biology Organization*, (Feb 28, 2011), pp. lSSN 1768-322X (Electronic)

1349-7006 (Electronic)

1096-3650 (Electronic)

pp.1863-70, ISSN 0022-1767 (Print)

23, lSSN 1742-4658 (Electronic)

6064-72, lSSN 1078-0432 (Print)

0021-9525 (Print)

No.1, (Jan 7, 2002), pp. 99-111, lSSN 0022-1007 (Print)

(Sep 14, 2001), pp. 35111-22, lSSN 0021-9258

fibroblasts isolated from stroma of human basal cell carcinoma acquire properties of multipotent stem cells. *Biology of the cell / under the auspices of the European Cell* 

adaptation to hypoxia in MCF-7 cells and in human mammary invasive carcinoma microenvironment. *Cancer science*, Vol.101, No.4, (Apr, 2010), pp. 1014-23, lSSN

endocytic route for catabolism. *The Journal of biological chemistry*, Vol.276, No.37,

pathobiological and prognostic messages from cell-associated and stromal hyaluronan. *Seminars in cancer biology*, Vol.18, No.4, (Aug, 2008), pp. 288-95, lSSN

malignant behavior of human breast cancer. *International journal of cancer*, Vol.128, No.6, (Mar 15, 2010), pp. 1303-15, lSSN 1097-0215 Termeer CC, Hennies J, Voith U, et al. (2000). Oligosaccharides of hyaluronan are potent activators of dendritic cells.

activators of dendritic cells. *Journal of Immunology*, Vol.165, No.4, (Aug 15 2000),

dendritic cells via toll-like receptor 4. *The Journal of experimental medicine*, Vol.195,

health and disease: novel roles for proteoglycans in malignancy and their pharmacological targeting. *The FEBS journal,* Vol. 277, No. 19, (Oct, 2010), pp.3904-

cytoplasmic domains in co-ordinating adhesive and signalling events. *Journal of cell* 

bivatuzumab mertansine in patients with incurable squamous cell carcinoma of the head and neck or esophagus. *Clin Cancer Res*, Vol.12, No.20 Pt 1, (Oct 15, 2006), pp.

CD44-mediated ERK1,2 motogenic signaling, leading to defective skin wound repair. *The Journal of cell biology*, Vol.175, No.6, (Dec 18, 2006), pp. 1017-28, lSSN

microtubule instability and mitotic spindle integrity through MEK1/ERK1/2

activity. *The Journal of biological chemistry*, Vol.285, No.34, (Aug 20, 2010), pp. 26461- 74, lSSN 1083-351X (Electronic)


**Part 3** 

**Breast Cancer Stem Cells** 

*Experimental biology and medicine (Maywood, NJ*, Vol.236, No.1, (Jan, 2011), pp. 84-90, lSSN 1535-3699 (Electronic)


**Part 3** 

**Breast Cancer Stem Cells** 

234 Breast Cancer – Focusing Tumor Microenvironment, Stem Cells and Metastasis

Weigel PH, DeAngelis PL., (2007) Hyaluronan syntheases: a decade-plus of novel

Weigelt, B., Bissell M.J. (2008). Unraveling the microenvironmental influences on the normal

Yang R, Yan Z, Chen F, et al. (2002). Hyaluronic acid and chondroitin sulphate A rapidly

Yang, H., Zhou H., Feng P., Zhou X., Wen H., Xie X., Shen H., Zhu X. (2010). Reduced

Yu H, Li Q, Zhou X, et al. (2011). Role of hyaluronan and CD44 in reactive oxygen species-

lSSN 1535-3699 (Electronic)

0300-9475 (Print)

2007), pp. 36777-81, lSSN 0021-9258 (Print)

2008), pp.311-21, lSSN 1096-3650 (Electronic)

pp.92, lSSN 1756-9966 (Electronic)

pp. lSSN 1573-4919 (Electronic)

*Experimental biology and medicine (Maywood, NJ*, Vol.236, No.1, (Jan, 2011), pp. 84-90,

glycosyltransferases. *The Journal of biological chemistry*, Vol.282, No.51, (Dec 21,

mammary gland and breast cancer. *Seminars in cancer biology,* Vol. 18, No. 5, (Oct,

promote differentiation of immature DC with upregulation of costimulatory and antigen-presenting molecules, and enhancement of NF-kappaB and protein kinase activity. *Scandinavian journal of immunology*, Vol.55, No.1, (Jan, 2002), pp. 2-13, lSSN

expression of Toll-like receptor 4 inhibits human breast cancer cells proliferation and inflammatory cytokines secretion. *J Exp Clin Cancer Res,* Vol. 29, No. 2010),

induced mucus hypersecretion. *Molecular and cellular biochemistry*, (Feb 10, 2011),

**11** 

*USA* 

**The Microenvironment of** 

**Breast Cancer Stem Cells** 

Ernst Haeckel first described the term "stem" as a concept for the evolution or organisms. For representation purpose he described the ancestor organism as a "stem" from which all the other organisms evolved. Arthur Pappenheim later adopted this concept in the context of cells, and he elegantly placed the "stem cell" in the centre in cartoon from which all the

The concept was carried forward and the term "cancer stem cell" was first coined in 1980 (Carney *et al.*, 1982) where the authors described the stem cell origin of lung cancer cells. The difficulty in isolation and the absence of specific markers of cancer stem cell stalled the research in this area. However a decade later Bonnet and Dick successfully isolated CSC in AML which then incited the development in the field of cancer stem cells (Bonnet and Dick, 1997). Their discovery was later supported by many groups, which also resulted in isolation

Now a large body of evidence suggests that cancer comprises of different population of cells with various tumorogenic potentials. The tumor cells follow a hierarchy, where the subset capable of self-renewal, generate the tumor heterogeneity and are called cancer stem cells (CSC). Very low number of these cancer stem cells generates tumors in immunocompromised mice whereas large number of non-CSCs fails to generate tumors. CSCs have been characterized based on their ability to form colonies in soft agar and their ability to form spheres in serum free media. The generation of tumors in immunocompromised mice however remains the gold standard. Another characteristic of CSC is their ability to resist the action of common chemotherapeutic drugs which is attributed to higher expression of ABC transporters and their slow cycling nature. Further it has also been documented that these CSCs have activated signaling pathways as in the case

of normal stem cells. Hence CSCs are distinct from other non-CSC in many respects.

Cancer stem cells have been isolated based on membrane markers. One of the characteristics is their ability to efflux the Hoechst dye. However this ability to efflux the dye is also attributed to membrane ABC transporter ABCG2. ABCG5 has been used as a cancer stem cell marker as it pumps out the drug doxorubicin. ALDH1 has the ability to convert retinol to retinoic acid, which has diverse role in cell physiology, and this activity is used as a marker for CSC. CD 44, CD 133, EpCAM and CD 90 are also abundantly expressed in CSCs and are used to isolate or enrich CSC (Visvader and Lindeman, 2008). A number of groups have isolated CSC based on these markers however a robust marker for CSC still remains to

blood cells arise describing hematopoiesis (Ramalho-Santos and Willenbring, 2007).

of CSC from a variety of malignancies including solid tumors.

**1. Introduction** 

be identified.

Deepak Kanojia and Hexin Chen

*University of South Carolina* 
