**Author details**

Marina Ferrarini1,2, Giovanna Mazzoleni3 , Nathalie Steimberg3 , Daniela Belloni1,2 and Elisabetta Ferrero1,2

1 Department of Oncology, San Raffaele Scientific Institute, Milan, Italy

2 Myeloma Unit, San Raffaele Scientific Institute, Milan, Italy

3 Laboratory of Tissue Engineering, Department of Clinical and Experimental Sciences, Fac‐ ulty of Medicine and Surgery, University of Brescia, Brescia, Italy

#### **References**

alloproteases activities, could be also assessed (M. Ferrarini *et al*., *submitted*). Overall, these observations suggest that the 3D culture model in Bioreactor can be exploited as a novel translational tool, allowing prospective pre-clinical toxicity and drug efficacy testing in indi‐

A major challenge in cancer biology and cancer therapy relies in the availability of suitable models that recapitulate the complex tumor-host interplay and responsiveness to drugs. This is especially true for MM, where the existence of tight links between MM cells and BM micro‐ environment has hampered for long the development of adequate animals and *in vitro* mod‐ els. Recently, innovative murine and chimeric *in vivo* models have been developed, which allowed both to investigate MM physiopathology and to perform drugs testing. On the other hand, the exploitation of novel technologies for *ex-vivo* 3D culturing of human MM samples is emerging as a tool to properly investigate its pathogenetic mechanisms (and interactions)

within a human context, and also to predict response to drugs in individual patients.

The availability of more and more sophisticated systems is expected to pave the way to a deeper understanding of pathogenetic events and also to development of novel patients-tail‐

This work was partially supported by the Italian Association for Cancer Research (AIRC)- Special Program Molecular Clinical Oncology AIRC 5x1000 project N° 9965 (to Prof. Federi‐ co Caligaris-Cappio) and by local funds of the University of Brescia (to GM). We wish to thank Prof. F. Caligaris-Cappio (Università Vita-Salute San Raffaele, Milano) for helpful dis‐ cussion and dr. Maurilio Ponzoni (Department of Pathology, San Raffaele Scientific Insti‐

, Nathalie Steimberg3

3 Laboratory of Tissue Engineering, Department of Clinical and Experimental Sciences, Fac‐

, Daniela Belloni1,2 and

tute, Milan) for the precious contribution to histochemical analyses.

1 Department of Oncology, San Raffaele Scientific Institute, Milan, Italy

2 Myeloma Unit, San Raffaele Scientific Institute, Milan, Italy

ulty of Medicine and Surgery, University of Brescia, Brescia, Italy

vidual patients.

52 Multiple Myeloma - A Quick Reflection on the Fast Progress

**6. Conclusions**

ored therapeutic strategies.

**Acknowledgements**

**Author details**

Elisabetta Ferrero1,2

Marina Ferrarini1,2, Giovanna Mazzoleni3


[15] Ramanujan S, Koenig GC, Padera TP, Stoll BR, Jain RK. Local imbalance of proangio‐ genic and antiangiogenic factors: a potential mechanism of focal necrosis and dor‐ mancy in tumors. Cancer Research 2000; 60:1442–1448.

[27] Roskelley CD, Desprez PY, Bissell MJ (1994) Extracellular matrix-dependent tissuespecific gene expression in mammary epithelial cells requires both physical and bio‐

Innovative Models to Assess Multiple Myeloma Biology and the Impact of Drugs

http://dx.doi.org/10.5772/54312

55

[28] Lee GY, Kenny PA, Lee EH, Bissel MJ, (2007) Three-dimensional culture models of

[29] Chang, TT. & Hughes-Fulford, M. (2009). Monolayer and Spheroid Culture of Hu‐ man Liver Hepatocellular Carcinoma Cell Line Cells Demonstrate Distinct Global Gene Expression Patterns and Functional Phenotypes. Tissue Engineering: Part A,

[30] Pickl M & CH Ries (2009) Comparison of 3D and 2D tumor models reveals enhanced HER2 activation in 3D associated with an increased response to trastuzumab. Onco‐

[31] Steimberg, N., Boniotti, J. & Mazzoleni, G. (2010). 3D culture of primary chondro‐ cytes, cartilage, and Bone/cartilage explants in simulated microgravity. In: Methods in Bioengineering: Alternative Technologies to Animal Testing, Maguire and Novak,

[32] Birgersdotter A, Sandberg R, Ernberg I (2005) Gene expression perturbation in vitro a growing case for three-dimensional (3D) culture systems. Semin Cancer Biol

[33] Fischbach C, Chen R, Matsumoto T, Schmelzle T, Brugge JS, Polverini PJ, Mooney DJ

[34] Yim EK, Darling EM, Kulangara K, Guilak F, Leong KW. Nanotopography-induced changes in focal adhesions, cytoskeletal organization, and mechanical properties of

[35] Bierwolf J, Lutgehetmann M, Feng K, Erbes J, Deichmann S, Toronyi E, Stieglitz C, Nashan B, Ma PX, Pollok JM. Primary rat hepatocyte culture on 3D nanofibrous pol‐ ymer scaffolds for toxicology and pharmaceutical research. Biotechnology and bioen‐

[36] Yoshii Y, Waki A, Yoshida K, Kakezuka A, Kobayashi M, Namiki H, Kuroda Y, Kiyo‐ no Y, Yoshii H, Furukawa T, Asai T, Okazawa H, Gelovani JG, Fujibayashi Y. The use of nanoimprinted scaffolds as 3D culture models to facilitate spontaneous tumor cell migration and well-regulated spheroid formation. Biomaterials. 2011; 32(26):

[37] Kuo SM, Chiang MY, Lan CW, Niu GC-C, Chang SJ. Evaluation of nanoarchitectured collagen type II molecules on cartilage engineering. 2012; Journal of biomedical mate‐

[38] Lo CM, Wang HB, Dembo M, Wang YL. Cell movement is guided by the rigidity of

(2007) Engineering tumors with 3D scaffolds. Nat Methods 4:855–860.

human mesenchymal stem cells. Biomaterials. 2010;31(6):1299-1306.

chemical signal transduction. Proc Natl Acad Sci USA 91:12378–12382.

normal and malignant breast epithelial cells. Nat Methods 4:359-365.

Vol. 15, No. 3, pp. 559-567, ISSN 1557-8690

pp. 205- 212, ISBN 978-1-60807-011-4, Boston, USA

gene 28:461-468.

15:405–412.

6052-6058.

gineering 2011;108(1):141-150.

rials research. Part A. 2012:00A:000–000.

the substrate. Biophysical journal. 2000; 79(1):144-152.


[27] Roskelley CD, Desprez PY, Bissell MJ (1994) Extracellular matrix-dependent tissuespecific gene expression in mammary epithelial cells requires both physical and bio‐ chemical signal transduction. Proc Natl Acad Sci USA 91:12378–12382.

[15] Ramanujan S, Koenig GC, Padera TP, Stoll BR, Jain RK. Local imbalance of proangio‐ genic and antiangiogenic factors: a potential mechanism of focal necrosis and dor‐

[16] Bergers G, Benjamin LE. Tumorigenesis and the angiogenic switch. Nature Reviews

[17] Di Raimondo F. Angiogenesis in hematology: a field of active research. Leukemia Re‐

[18] Vacca A, Ribatti D. Bone marrow angiogenesis in multiple myeloma. Leukemia

[19] Pour L, Svachova H, Adam Z, Almasi M, Buresova L, Buchler T, Kovarova L, Nemec P, Penka M, Vorlicek J, Hajek R. Levels of angiogenic factors in patients with multi‐ ple myeloma correlate with treatment response. Annals of Hematology 2010;

[20] Terpos E, Anargyrou K, Katodritou E, Kastritis E, Papatheodorou A, Christoulas D, Pouli A, Michalis E, Delimpasi S, Gkotzamanidou M, Nikitas N, Koumoustiotis V, Margaritis D, Tsionos K, Stefanoudaki E, Meletis J, Zervas K, Dimopoulos MA, Greek Myeloma Study Group, Greece. Circulating angiopoietin-1 to angiopoietin-2 ratio is an independent prognostic factor for survival in newly diagnosed patients with mul‐ tiple myeloma who received therapy with novel antimyeloma agents. International

[21] Ferrarini M, Ferrero E. Proteasome inhibitors and modulators of angiogenesis in

[22] Hideshima T, Richardson P, Chauhan D, Palombella VJ, Elliott PJ, Adams J, Ander‐ son KC. The proteasome inhibitor PS-341 inhibits growth, induces apoptosis, and overcomes drug resistance in human multiple myeloma cells. Cancer Research

[23] Roccaro AM, Hideshima T, Raje N, Kumar S, Ishitsuka K, Yasui H, Shiraishi N, Rib‐ atti D, Nico B, Vacca A, Dammacco F, Richardson PG, Anderson KC. Bortezomib me‐ diates antiangiogenesis in multiple myeloma via direct and indirect effects on

[24] Belloni D, Veschini L, Foglieni C, Dell'Antonio G, Caligaris-Cappio F, Ferrarini M, Ferrero E. Bortezomib induces autophagic death in proliferating human endothelial

[25] Pampaloni, F., Reynaud, EG. & Stelzer, EH. (2007). The third dimension bridges the gap between cell culture and live tissue. Nature Reviews. Molecular Cell Biology,

[26] Mazzoleni, G., Di Lorenzo, D. & Steimberg, N. (2009) Modelling tissues in 3D: the next future of pharmaco-toxicology and food research? Genes and Nutrition, Vol. 4,

multiple myeloma. Current Medicinal Chemistry 2011;18(34):5185-5195.

mancy in tumors. Cancer Research 2000; 60:1442–1448.

Cancer 2003;3:401-410.

54 Multiple Myeloma - A Quick Reflection on the Fast Progress

search 2003;27:571-573.

Journal of Cancer 2012;130(3):735-742.

endothelial cells. Cancer Research 2006;66(1):184-191.

cells. Experimental Cell Research 2010;316(6):1010-1018.

Vol. 8, No. 10, (October 2007), pp. 839-845, ISSN 1471-0080

No. 1 (March 2009), pp. 13-22, ISSN 1555-8932

2001;61(7):3071-3076.

2006;20:193-199.

89:385-389.


[39] Paszek MJ, Zahir N, Johnson KR, Lakins JN, Rozenberg GI, Gefen A, Reinhart-King CA, Margulies SS, Dembo M, Boettiger D, Hammer DA, Weaver VM. (2005) Tension‐ al homeostasis and the malignant phenotype. Cancer Cell 8: 241–254.

[52] Sandberg R, and Ernberg I. The molecular portrait of in vitro growth by meta-analy‐

Innovative Models to Assess Multiple Myeloma Biology and the Impact of Drugs

http://dx.doi.org/10.5772/54312

57

[53] Härmä V, Virtanen J, Mäkelä R, Happonen A, Mpindi J-P, Knuuttila M, Kohonen P, Lötjönen j, Kallioniemi O, Nees M. A Comprehensive Panel of Three-Dimensional Models for Studies of Prostate Cancer Growth, Invasion and Drug Responses. 2010,

[54] Petersen OW, R.nnov-Jessen L, Howlett AR, Bissell MJ: Interaction with basement membrane serves to rapidly distinguish growth and differentiation pattern of normal and malignant human breast epithelial cells. Proceedings of the National Academy

[55] Smalley KS, Lioni M, Herlyn M. Life isn't flat: taking cancer biology to the next di‐ mension In vitro Cellular & Developmental Biology 2006a; 42(8-9): 242-247.

[56] Fischbach C, Kong HJ, Hsiong SX, Evangelista MB, Yuen W, Mooney DJ. Cancer cell angiogenic capability is regulated by 3D culture and integrin engagement. Proc Natl

[57] Horning JL, Sahoo SK, Vijayaraghavalu S, Dimitrijevic S, Vasir JK, Jain TK, Panda AK, Labhasetwar V. 3-D tumor model for in vitro evaluation of anticancer drugs.

[58] Chitcholtan K, Sykes PH and Evans JJ. The resistance of intracellular mediators to doxorubicin and cisplatin are distinct in 3D and 2D endometrial cancer. Journal of

[59] Sasser AK, Mundy BL, Smith KM, Studebaker AW, Axel AE, Haidet AM, Fernandez SA, Hall BM. Human bone marrow stromal cells enhance breast cancer cell growth rates in a cell line-dependent manner when evaluated in 3D tumor environments.

[60] Yamada KM & Cukierman E (2007) Modeling tissue morphogenesis and cancer in

[61] Kim JB. Three-dimensional tissue culture models in cancer biology. Seminars in Can‐

[62] Hutmacher DW, Loessner D, Rizzi S, Kaplan DL, Mooney DJ, Clements JA (2010). Can tissue engineering concepts advance tumor biology research? Trends in Biotech‐

[63] Kirshner J, Thulien KJ, Martin LD, Debes Marun C, Reiman T, Belch AR, Pilarski LM. (2008) A unique three-dimensional model for evaluating the impact of therapy on

[64] Sausville EA, Burger AM. Contributions of human tumor xenografts to anticancer

sis of gene-expression profiles. Genome Biol. 2005; 6(8):R65

PLoS ONE 5(5): e10431

of Sciences USA 1992, 89:9064-9068.

Acad Sci U S A. 2009 Jan 13;106(2):399-404.

Mol Pharm. 2008;5:849-862

3D. Cell, 130:601-610.

cer Biology (2005)15: 365–377

nology, Vol.28 No.3, pp. 125-133

multiple myeloma. Blood Vol. 112(7):2935-2945.

drug development. Cancer Research 2006;66(7):3351-3354.

Translational Medicine 2012, 10:38

Cancer Lett. 2007 Sep 8;254(2):255-264.


[52] Sandberg R, and Ernberg I. The molecular portrait of in vitro growth by meta-analy‐ sis of gene-expression profiles. Genome Biol. 2005; 6(8):R65

[39] Paszek MJ, Zahir N, Johnson KR, Lakins JN, Rozenberg GI, Gefen A, Reinhart-King CA, Margulies SS, Dembo M, Boettiger D, Hammer DA, Weaver VM. (2005) Tension‐

[40] Schindler M, Nur-E-Kamal A, Ahmed I, Kamal J, Liu HY, Amor N, Ponery AS, Crockett DP, Grafe TH, Chung HY, Weik T, Jones E, Meiners S. Living in three di‐ mensions: 3D nanostructured environments for cell culture and regenerative medi‐

[41] Mazzoleni, G., Boukhechba, F., Steimberg, N., Boniotti, J., Bouler, JM. & Rochet, N. (2011). Impact of the dynamic culture condition in the RCCS™ bioreactor on a threedimensional model of bone formation. Procedia Engineering, Vol. 10, pp. 3662-3667,

[42] Gruber HE, Hanley EN Jr. Human disc cells in monolayer vs 3D culture: cell shape,

[43] Lin RZ, and Chang HY. Recent advances in three-dimensional multicellular spheroid

[44] Ortinau S, Schmich J, Block S, Liedmann A, Jonas L, Weiss DG, Helm CA, Rolfs A, Frech MJ. Effect of 3D-scaffold formation on differentiation and survival in human

[45] Campbell JJ, and Watson CJ. Three-dimensional culture models of mammary gland.

[46] Ross AM, Jiang Z, Bastmeyer M, Lahann J. Physical aspects of cell culture substrates:

[47] Mazzoleni, G. & Steimberg, N. (2012) New models for the in vitro study of liver tox‐ icity: 3D culture systems and the role of bioreactors. In"The continuum of Health Risk Assessment", edited by Dr. M.G. Tyshenko; Intech Open Access Publisher, Rije‐

[48] Ulrich TA, de Juan Pardo EM, Kumar S. The mechanical rigidity of the extracellular matrix regulates the structure, motility, and proliferation of glioma cells. Cancer Re‐

[49] Pathak A. and Kumar S. Independent regulation of tumor cell migration by matrix stiffness and confinement. Proceedings of the National Academy of Sciences (PNAS)

[50] Bissell MJ, Radisky DC, Rizki A, Weaver VM, Petersen OW. The organizing princi‐ ple: microenvironmental influences in the normal and malignant breast. Differentia‐

[51] Debnath J, and Brugge JS. Modelling glandular epithelial cancers in three-dimension‐

division and matrix formation. BMC musculoskeletal disorders. 2000;1:1.

culture for biomedical research. Biotechnol J. 2008;3(9-10):1172-1184.

neural progenitor cells. Biomed Eng Online. 2010 Nov 11;9:70.

topography, roughness, and elasticity. Small. 2012;8(3):336-355.

ka, Croatia; chapter 8, pp. 161-194; ISBN 978-953-51-0212-0.

al cultures. Nature Review Cancer. 2005;5(9):675-688

al homeostasis and the malignant phenotype. Cancer Cell 8: 241–254.

cine. Cell Biochemistry and Biophysics. 2006;45(2):215-227.

ISSN 1877-7058

56 Multiple Myeloma - A Quick Reflection on the Fast Progress

Organogenesis. 2009; 5(2): 43-49.

search; 2009; 69: 4167–4174.

(2012); 109 (26): 10334-10339

tion. 2002;70(9-10):537-546.


[65] Teicher BA. Tumor models for efficacy determination. Molecular Cancer Therapeu‐ tics 2006;5(10):2435-2443.

[77] Deleu S, Lemaire M, Arts J, Menu E, Van Valckenborgh E, King P, Vande Broek I, De Raeve H, Van Camp B, Croucher P, Vanderkerken K. The effects of JNJ-26481585, a novel hydroxamate-based histone deacetylase inhibitor, on the development of mul‐ tiple myeloma in the 5T2MM and 5T33MM murine models. Leukemia 2009;23(10):

Innovative Models to Assess Multiple Myeloma Biology and the Impact of Drugs

http://dx.doi.org/10.5772/54312

59

[78] Urashima M, Chen BP, Chen S, Pinkus GS, Bronson RT, Dedera DA, Hoshi Y, Teoh G, Ogata A, Treon SP, Chauhan D, Anderson KC. The development of a model for the homing of multiple myeloma cells to human bone marrow. Blood 1997;90(2):

[79] Yaccoby S, Barlogie B, Epstein J. Primary myeloma cells growing in SCID-hu mice: a model for studying the biology and treatment of myeloma and its manifestations.

[80] Yaccoby S, Johnson CL, Mahaffey SC, Wezeman MJ, Barlogie B, Epstein J. Antimye‐ loma efficacy of thalidomide in the SCID-hu model. Blood 2002;100(12):4162-4168. [81] Tassone P, Neri P, Carrasco DR, Burger R, Goldmacher VS, Fram R, Munshi V, Shammas MA, Catley L, Jacob GS, Venuta S, Anderson KC, Munshi NC. A clinically relevant SCID-hu in vivo model of human multiple myeloma. Blood 2005;106(2):

[82] Calimeri T, Battista E, Conforti F, Neri P, Di Martino MT, Rossi M, Foresta U, Piro E, Ferrara F, Amorosi A, Bahlis N, Anderson KC, Munshi N, Tagliaferri P, Causa F, Tas‐ sone P. A unique three-dimensional SCID-polymeric scaffold (SCID-synth-hu) model for in vivo expansion of human primary multiple myeloma cells. Leukemia

[83] DeWeerdt S. Animal models: Towards a myeloma mouse. Nature

[84] Carrasco DR, Sukhdeo K, Protopopova M, Sinha R, Enos M, Carrasco DE, Zheng M, Mani M, Henderson J, Pinkus GS, Munshi N, Horner J, Ivanova EV, Protopopov A, Anderson KC, Tonon G, DePinho RA. The differentiation and stress response factor

XBP-1 drives multiple myeloma pathogenesis. Cancer Cell 2007;11(4):349-360

[85] Zhan F, Tian E, Bumm K, Smith R, Barlogie B, Shaughnessy J Jr. Gene expression profiling of human plasma cell differentiation and classification of multiple myeloma based on similarities to distinct stages of late-stage B-cell development. Blood

[86] Robbiani DF, Colon K, Affer M, Chesi M, Bergsagel PL. Maintained rules of develop‐

[87] Chesi M, Robbiani DF, Sebag M, Chng WJ, Affer M, Tiedemann R, Valdez R, Palmer SE, Haas SS, Stewart AK, Fonseca R, Kremer R, Cattoretti G, Bergsagel PL. AID-de‐ pendent activation of a MYC transgene induces multiple myeloma in a conditional mouse model of post-germinal center malignancies. Cancer Cell 2008;13(2):167-180.

ment in a mouse B-cell tumor. Leukemia 2005;19(7):1278-1280

1894-1903.

754-765

713-716.

2011;25(4):707-711.

2011;480(7377):S38-9

2003;101(3):1128-1140

Blood 1998;92(8):2908-2913.


[77] Deleu S, Lemaire M, Arts J, Menu E, Van Valckenborgh E, King P, Vande Broek I, De Raeve H, Van Camp B, Croucher P, Vanderkerken K. The effects of JNJ-26481585, a novel hydroxamate-based histone deacetylase inhibitor, on the development of mul‐ tiple myeloma in the 5T2MM and 5T33MM murine models. Leukemia 2009;23(10): 1894-1903.

[65] Teicher BA. Tumor models for efficacy determination. Molecular Cancer Therapeu‐

[66] Tong AW, Huang YW, Zhang BQ, Netto G, Vitetta ES, Stone MJ. Heterotransplanta‐ tion of human multiple myeloma cell lines in severe combined immunodeficiency

[67] Mitsiades CS, Anderson KC, Carrasco DR. Mouse models of human myeloma. Hem‐

[68] Wu KD, Zhou L, Burtrum D, Ludwig DL, Moore MA. Antibody targeting of the insu‐ lin-like growth factor I receptor enhances the anti-tumor response of multiple myelo‐ ma to chemotherapy through inhibition of tumor proliferation and angiogenesis.

[69] Frost P, Moatamed F, Hoang B, Shi Y, Gera J, Yan H, Frost P, Gibbons J, Lichtenstein A. In vivo antitumor effects of the mTOR inhibitor CCI-779 against human multiple

[70] Beider K, Begin M, Abraham M, Wald H, Weiss ID, Wald O, Pikarsky E, Zeira E, Ei‐ zenberg O, Galun E, Hardan I, Engelhard D, Nagler A, Peled A. CXCR4 antagonist 4F-benzoyl-TN14003 inhibits leukemia and multiple myeloma tumor growth. Experi‐

[71] Miki H, Ozaki S, Nakamura S, Oda A, Amou H, Ikegame A, Watanabe K, Hiasa M, Cui Q, Harada T, Fujii S, Nakano A, Kagawa K, Takeuchi K, Yata K, Sakai A, Abe M, Matsumoto T. KRN5500, a spicamycin derivative, exerts anti-myeloma effects through impairing both myeloma cells and osteoclasts. British Journal of Haematolo‐

[72] Mirandola L, Yu Y, Chui K, Jenkins MR, Cabos E, John CM, Chiriva-Internati M. Ga‐ lectin-3C inhibits tumor growth and increases the anticancer activity of bortezomib

[73] Radl J, Hollander CF, Van den Berg P, De Glopper E. Idiopathic paraproteinaemia I. Studies in an animal model--the ageing C57BL/KaLwRij mouse. Clinical & Experi‐

[74] Radl J. Age-related monoclonal gammapathies: clinical lessons from the aging C57BL

[75] Menu E, Asosingh K, Van Riet I, Croucher P, Van Camp B, Vanderkerken K. Myelo‐ ma cells (5TMM) and their interactions with the marrow microenvironment. Blood

[76] Croucher PI, De Hendrik R, Perry MJ, Hijzen A, Shipman CM, Lippitt J, Green J, Van Marck E, Van Camp B, Vanderkerken K. Zoledronic acid treatment of 5T2MM-bear‐ ing mice inhibits the development of myeloma bone disease: evidence for decreased osteolysis, tumor burden and angiogenesis, and increased survival, Journal of Bone

in a murine model of human multiple myeloma. PLoS One 2011;6(7):e21811.

(SCID) mice. Anticancer Research 1993;13(3):593-597.

Cancer Immunology, Immunotherapy 2007;56(3):343-57

mental Hematology 2011;39(3):282-292.

mental Immunology 1978;33(3):395-402.

mouse. Immunology Today 1990;11(7):234-236.

Cells, Molecule and Disease 2004;33(2):111-119.

and Mineral Research 2003;18(3):482–492.

gy 2011;155(3):328-39.

atology/Oncology Clinics of North America 2007;21(6):1051-1069.

myeloma cells in a xenograft model. Blood 2004;104(13):4181-4187.

tics 2006;5(10):2435-2443.

58 Multiple Myeloma - A Quick Reflection on the Fast Progress


[88] Chesi M, Matthews GM, Garbitt VM, Palmer SE, Shortt J, Lefebure M, Stewart AK, Johnston RW, Bergsagel PL. Drug response in a genetically engineered mouse model of multiple myeloma is predictive of clinical efficacy. Blood. 2012;120(2):376-85.

**Chapter 4**

**Heterogeneity and**

http://dx.doi.org/10.5772/55365

**1. Introduction**

**Plasticity of Multiple Myeloma**

Additional information is available at the end of the chapter

inconsistencies among myeloma stem cell concepts.

Hana Šváchová, Sabina Sevcikova and Roman Hájek

Modern molecular and cytogenetic approaches have furthered progress in our understanding of MM biology and have led to the development of targeted therapy that has improved management of this incurable disease. Novel agents such as bortezomib, lenalidomide or thalidomide, have increased median survival rates and improved prospects for MM patients resistant to conventional therapy [1, 2]. Despite these therapeutic advances, MM remains a very difficult disease to treat still accompanied by the threat of repeated relapses with a fatal ending. These observations indicate that at least some of the MM cells are not targeted efficiently by current drug therapies. The existence of such persistent populations, called myeloma stem cells (MSC) or myeloma-initiating cells (MIC) has been suspected for more than two decades. However, the cells of origin remain elusive [3-9]. Timeline of growing knowledge about putative MSC is displayed in **Figure 1**. Discrepancies among myeloma stem cell concepts have arisen in parallel with the high phenotypic heterogeneity of clonal PCs that might be another factor contributing to the failure of therapies and identification of the population responsible for relapse. Myeloma PCs strongly depends on the supportive role of the bone marrow (BM) microenvironment (MEV) – it is a source of essential growth factors, supports survival and dissemination of pathological PCs [10-14]. Furthermore, hypoxic conditions of tumor microenvironments support tumor progression by inducing angiogenesis, maintaining the malignant phenotype and stimulating osteoclastogenesis [15-18]. There is growing evidence that signals from pathological microenvironments can (reversibly) alter the pheno‐ type of PCs. Such plasticity of PCs might result in obvious heterogeneity of MM and generate

> © 2013 Šváchová et al.; licensee InTech. This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

and reproduction in any medium, provided the original work is properly cited.

© 2013 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution,

