Multiple myeloma: A prototypic disease model for the characterization and therapeutic targeting of interactions between tumor cells and their local microenvironment

Abstract

The interaction between tumor cells and the local milieu where are homing has recently become the focus of extensive research in a broad range of malignancies. Among them, multiple myeloma (MM) is now recognized as a prototypical tumor model for the characterization of these interactions. This is due not only to the propensity of MM cells to target the skeleton and form lytic bone lesions, but because interactions of MM cells with normal cells of the bone milieu can attenuate the anti-tumor activity of conventional therapies, such as glucocorticoids and standard cytotoxic agents, including alkylators. Herein, we highlight the recent advances in our understanding of cellular and molecular mechanisms of interactions between MM cells and their milieu. Particular emphasis is placed on the interface between MM cells and normal cell compartments of the BM, especially bone marrow stromal cells (BMSCs), and on the development of a series of new classes of therapeutic agents, including the proteasome inhibitor bortezomib, thalidomide and lenalidomide, which counteract specific aspects of those MM-BM interactions. The significant clinical activity of these novel therapies has not only led to a new era in the therapeutic management of this disease, but also underscored the importance of comprehensively characterizing the role of the local microenvironment in the pathophysiology of human neoplasias.

Concomitant downregulation of proliferation/survival pathways dependent on FGF-R3, JAK2 and BCMA in human multiple myeloma cells by multi-kinase targeting

“…In cooperation with the driving tumorigenic effects of genetic lesions within MM cells, the BM microenvironment provides essential support to the propagation and expansion of malignant clones and promotes drug resistance [8,26,32]. However, the RPI-1 ability to abrogate KMS18 cell growth enhancement provided by aFGF, suggests a potential benefit extended to t(4;14) MM not expressing a constitutively active FGFR3.…”

“…The potential therapeutic relevance of JAK2 in the treatment of MM is well recognized and related to its role as an effector of the signaling cascade induced by IL-6, a major growth and anti-apoptotic factor implicated in both autocrine and paracrine MM cell stimulation within the BM milieu [8,12,41]. It has been reported that IL-6 also participate to the regulation of BCMA expression [42], thus the early and stable downregulation of this receptor detected in KMS11 cells after RPI- 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 18 even in untreated cells, the expression of alternatively spliced forms of Mcl-1 cannot be ruled out [48].…”

“…In addition to the tumor genetic background, the BM microenvironment is well recognized as a crucial determinant of the biological and clinical behavior of MM [8].…”

“…A better understanding of the profile of signaling pathways involved in the pathophysiology of the disease now provides a framework for the identification of novel targets [1,11]. Accordingly, novel agents recently approved in clinical protocols for MM, 5 such as bortezomib, thalidomide and analogs, share the ability of targeting tumormicroenvironment interactions as an essential part of their mechanism of action [8,12].…”

“…The complex signaling network activated by oncogenic mutations and by the BM microenvironment sustains growth, survival and migration of MM cells contributing to tumor progression as well as to resistance to conventional chemotherapy [1,8]. Since failure to undergo apoptosis has been suggested to play a main role in MM cell accumulation within the BM as well as in drug resistance [9], blocking both intrinsic and BM microenvironment-driven signaling could be required to induce tumor cell death.…”