Adipose, Bone, and Myeloma: Contributions from the Microenvironment

Abstract

Researchers globally are working towards finding a cure for multiple myeloma (MM), a destructive blood cancer diagnosed yearly in ~750,000 people worldwide [1]. Although MM targets multiple organ systems, it is the devastating skeletal destruction experienced by over 90% of patients that often most severely impacts patient morbidity, pain, and quality of life. Preventing bone disease is therefore a priority in MM treatment, and understanding how and why myeloma cells target the bone marrow (BM) is fundamental to this process. This review focuses on a key area of MM research: the contributions of the bone microenvironment to disease origins, progression, and drug resistance. We describe some of the key cell types in the BM niche: osteoclasts, osteoblasts, osteocytes, adipocytes and mesenchymal stem cells. We then focus on how these key cellular players are, or could be, regulating a range of disease-related processes spanning MM growth, drug resistance, and bone disease (including osteolysis, fracture, and hypercalcemia). We summarize the literature regarding MM-bone cell and MM-adipocyte relationships and subsequent phenotypic changes or adaptations in MM cells, with the aim of providing a deeper understanding of how myeloma cells grow in the skeleton to cause bone destruction. We identify avenues and therapies that intervene in these networks to stop tumor growth and/or induce bone regeneration. Overall, we aim to illustrate how novel therapeutic target molecules, proteins, and cellular mediators may offer new avenues to attack this disease while reviewing currently utilized therapies.

Epigenetic‐Based Mechanisms of Osteoblast Suppression in Multiple Myeloma Bone Disease

“…Although the more predominant white adipose tissue partakes in energy storage, insulation, mechanical support for internal organs, and endocrine and immune modulation, brown adipocytes have extensive thermogenic properties . Bone marrow adipose tissue residing on the endosteal surface and throughout the bone marrow cavities has a complex set of regulatory functions directly impacting the osteogenic, angiogenic, and immunogenic properties of the bone marrow niche . Increased marrow adiposity can have multiple effects on the marrow and bone because adipocytes express and secrete multiple factors, such as adepsin, leptin, adiponectin, TNF, and angiotensinogen with significant pleiotropic effects on the local microenvironment of bone marrow cells.…”

MicroRNA Transfer Between Bone Marrow Adipose and Multiple Myeloma Cells

“…BMAT volume increases with age and occupies a significant portion of the BM, as well as composing over 10% of the average person's total adipose tissue mass [21]. Of significance to this review is the finding that elevated regulated BMAT volume, which is located in close proximity to the trabecular bone and hematopoietic elements and increases with age, is directly correlated with bone loss and resultant osteoporosis [22]. A mutually incompatible relationship arises between adipose components of the BM and bone-forming components, as osteoblastogenesis and the factors that support it often inhibit adipogenesis, and vice versa.…”

Reflections on Cancer in the Bone Marrow: Adverse Roles of Adipocytes

“…A handful of studies in myeloma have found that MAT produces factors that support myeloma disease progression, although certain adipokines, such as adiponectin [16], have been found to inhibit myeloma, confounding the roles of MAT in myeloma [17,18]. Cell-derived factors (molecules, lipids, small metabolites, or microRNAs) may be free or embedded in exosomes or other microvesicles and transferred between BMAs and myeloma cells as one method of communication [19].…”