**1. Introduction**

Tumor and its embedding microenvironment form a unique, dynamic system, largely orch‐ estrated by cellular players, including fibroblasts and endothelial cells (EC), and surround‐ ing extracellular matrix (ECM) with its distinctive physical, biochemical, and biomechanical properties. There is a general consensus that, beyond genetic mutations and epigenetic mod‐ ifications, the dialogue that occurs between tumor and its microenvironment, through solu‐ ble factors and molecular interactions, may affect tumor cells survival, growth, proliferation, response to chemical/physical factors, and lies the basis for metastatization to distant, specif‐ ic organs. This theory was proposed by Paget in the 1880s [1], who underlined the need, for investigating and targeting tumor, to focus not only on the cancer cell, "the seed", but also on the "soil" where tumor homes and in which it derives its nutrients, oxygen and signals [2, 3]. Accordingly, tight links between tumor and surrounding microenvironment could de‐ termine the overall sensitivity to anti-cancer drugs and therefore represent an attractive therapeutic target [4].

Tumor microenvironment plays a critical role also in development and progression of hae‐ matological malignancies [5,6]. In this regard, Multiple Myeloma (MM) represents a para‐ digmatic condition [5,6]. Indeed, MM plasma cells almost exclusively home and thrive inside Bone Marrow (BM) microenvironment, which confers anti-apoptotic and pro-survival signals and resistance to drugs. In turn, tumor cell interactions with BM cells and matrix re‐

© 2013 Ferrarini 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. © 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, and reproduction in any medium, provided the original work is properly cited.

sult in re-shaping of microenvironment, and architectural changes involve in particular the vascular compartment [7].

molecules, including integrins. The complex interplay between MM cells and BM milieu, to‐

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

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

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1: erithrocytes; 2: megacaryocytes; 3: basophils; 4: adipocytes; 5: osteocytes; 6: B lymphocytes; 7: monocytes; 8: lining osteoblasts; 9: osteoblasts; 10: osteoclasts; 11: hematopoietic stem cells "niche"; 12: T lymphocytes; 13: NK cells; 14: eosinophils; 15: neutrophils; 16: monocytes; 17: stromal cells; 18: mesenchymal stem cells "niche"; 19: dendritic cells;

**Figure 1. Bone Marrow microenvironment.** Bone homeostasis is the result of a complex network of stimuli, includ‐ ing hormones, vitamins and physico-mechanical forces. In addition to osteoblats and osteoclasts, which are responsi‐ ble for bone deposition/resorption, BM microenvironment encompasses several cell types, like hematopoietic cells,

Interactions between MM cells and ECM and cellular components (Fig. 2, lower panel) trig‐ ger the release of soluble factors, which, in turn, determine autocrine/paracrine loops of MM survival/proliferation and also promote osteoclastogenesis, defective immune functions and the "angiogenic switch", overall leading to MM cells growth, survival, and resistance to che‐ motherapeutic agents [10]. In particular, adhesion of MM cells to BMSC and to ECM compo‐ nents triggers anti-apoptotic signals and also the release of the pro-survival factor Interleukin (IL)-6. Moreover, MM plasma cells and BM stroma release osteoclast-acivating factors, including IL-1, IL-6, tumor necrosis factor (TNF)-α, RANK-L(Ligand) and Macro‐ phage Inflammatory Protein (MIP)-1α. MM cells have also a unique ability to evade im‐ mune surveillance through several mechanisms, including impairment of cytotoxic activity

endothelial cells and mesenchimal cells, all embedded in a complex extra-cellular-matrix (ECM).

and induction of dendritic cells dysfunction (Fig. 2).

20: thrombocytes (platelets).

gether with the ensuing pathogenetic events, are depicted in Fig. 2 (upper panel).

The establishment of tight links between MM plasma cells and their microenvironment un‐ derlines the need for appropriate models for studying MM biology and predicting the im‐ pact of drugs.

In the present paper, we briefly summarize the role of BM microenvironment and, particularly, of MM associated angiogenesis, in MM pathogenesis, progression and prognosis. We then provide an overview of the currently available MM models, in‐ cluding animal models and a new three-dimensional (3D), gel-based, *in vitro* model of human MM microenvironment. Finally, we discuss the potential of RCCSTM bioreactorbased, dynamic 3D model systems (cell and tissue culture) to investigate critical as‐ pects of human MM pathobiology and possible clinical applications. Advantages and limitations of each model, relative to MM investigation and assessment of drug sensi‐ tivity, are also considered.
