Multiple Myeloma as a Bone Disease? The Tissue Disruption-Induced Cell Stochasticity (TiDiS) Theory

Abstract

The standard model of multiple myeloma (MM) relies on genetic instability in the normal counterparts of MM cells. MM-induced lytic bone lesions are considered as end organ damages. However, bone is a tissue of significance in MM and bone changes could be at the origin/facilitate the emergence of MM. We propose the tissue disruption-induced cell stochasticity (TiDiS) theory for MM oncogenesis that integrates disruption of the microenvironment, differentiation, and genetic alterations. It starts with the observation that the bone marrow endosteal niche controls differentiation. As decrease in cellular stochasticity occurs thanks to cellular interactions in differentiating cells, the initiating role of bone disruption would be in the increase of cellular stochasticity. Thus, in the context of polyclonal activation of B cells, memory B cells and plasmablasts would compete for localizing in endosteal niches with the risk that some cells cannot fully differentiate if they cannot reside in the niche because of a disrupted microenvironment. Therefore, they would remain in an unstable state with residual proliferation, with the risk that subclones may transform into malignant cells. Finally, diagnostic and therapeutic perspectives are provided.

Tissue‐disruption‐induced cellular stochasticity and epigenetic drift: Common origins of aging and cancer?

“…Considering these results, it was proposed that cancer could be initiated by disrupting these constraints via cell–cell interactions that stabilize phenotypes and homogenize gene expression. [ 60–64 ] This disruption would produce cancer stem cells (CSC), defined as cells with increased gene expression variability that are no longer controlled by the cellular microenvironment. [ 25,60 ] Because cancer is supposed to originate from normal stem cells, this phenomenon could take place if cells fail to set up cellular interactions during the differentiation process.…”

“…It was already proposed that this would produce “non‐controlled” stem‐like cells that are different from normal stem cells in the sense that they are no longer “canalized” towards differentiation by the cellular environment and stabilizing constraints that normally canalize cells in the tissue and avoid pathological phenotypes. [ 60–64 ] These stem‐like cells would harbor increased cellular stochasticity and the required phenotypic plasticity to produce tumors. Genetic alterations are not initially required in this framework, [ 62 ] even though their preexistence could accelerate neoplastic transformation, but they would then necessarily appear because of global cellular destabilization, and allow tumor progression.…”

“…Based on this literature, we propose that the TiDiS theory of aging, in which increased cell‐to‐cell expression variability and epigenetic drift observed in aging tissues are primarily due to defects in short‐ or long‐range cellular interactions. Without excluding a promoting role for the inherent imperfection of cellular replication and repair processes that enhance expression variability; however, one can propose that endogenous factors altering the cellular microenvironment or exogenous compounds able to disrupt cellular interactions primarily induce accelerated aging in the same way that they could induce cancer [ 60–64 ] (Figure 1). Thus, the alteration of cellular membranes, cellular junctions, adhesion molecules, or soluble molecules like hormones or growth factors is among the possible mechanisms at the origin of the aging process.…”

“…For instance, factors that alter the bone micro‐environment and induce bone loss—which is a sign of aging—could play a role in the initiation and promotion of multiple myeloma by favoring phenotypic and genetic instability within myeloma cells and their precursors. [ 64 ] Non‐mutagenic chemicals able to modulate gap junctional intercellular communication are also expected to alter normal functioning of tissue stem cell pools and affect both aging and diseases of aging. [ 88 ] More generally, many other types of cellular interactions could be the target of exogenous compounds and environmental toxicants, including endocrine disruptors that are known to strongly alter epigenetic patterns [ 89 ] in addition to their primary action at the cell surface.…”

Treatment Strategies Considering Micro-Environment and Clonal Evolution in Multiple Myeloma

“…The endosteal niche is constituted by osteoclasts and osteoblasts, and is a reasonable environment to enable the survival of myeloma cells [ 100 ]. Osteoclasts contribute to the survival and proliferation of myeloma cells by releasing the receptor activator of nuclear factor kappa-B ligand (RANKL), which is secreted by myeloma cells [ 101 ], osteoclasts [ 102 ], and BMSCs [ 103 ], and the abnormality of RANΚL-osteoprotegerin (OPG) pathway [ 104 , 105 , 106 ].…”