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 (Podar et al. in Expert Opin Emerg Drugs 14:99-127, 2009). 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.

Keywords: Adipocyte; BMAT; Bone marrow; Bone marrow adipose; Bone microenvironment; MGUS; Multiple myeloma (MM).

Figure 1. Endosteal and Perivascular Niches in the Healthy State

A) A simplified view of the bone marrow niche. In normal bone marrow environment, multiple niches exist to create a habitat supportive of multiple cell types. The perivascular niche supports cells actively migrating to and away from bone marrow and the endosteal niche supports cells at the bone surface. Within the bone remodeling compartment reside bone-forming osteoblasts and bone-resorbing osteoclasts, communicating with embedded osteocytes to maintain bone homeostasis. Other cells in the bone marrow include progenitors and immune cells. Bone marrow adipocytes, coined osteo-adipocytes by Dr. Clifford Rosen can be found throughout the bone marrow. B) Localization of MM cells with the bone marrow niche components. When MM cells infiltrate the bone marrow, they dysregulate the homeostasis of cells in the marrow. MM cells express proteins to help them home specifically to bone marrow vasculature, disrupting their structure and organization upon growth. Moreover, MM cells arrive at the endosteal niche where they interact with niche components to either survive in a dormant state or activate to form bone destructive tumors, depending on the activity of the surface they engage with. Osteoblasts are inhibited, osteoclasts are supported, and effects on adipocytes are largely unknown. Hematopoiesis is also disrupted as the tumor grows, and the immune system’s normal anti-tumor function is inhibited.

Figure 2. Osteoclast-Myeloma Interactions

Myeloma cells induce a vicious cycle in the bone marrow where osteoclasts are activated by myeloma cells through molecules such as RANKL, MIP1α, TNF-α, IL-3 and IL-6. In turn, osteoclasts support MM cells through secretion of molecules such as IL-6, OPN, and TGF-β and release of growth factors, collagens, and other proteins stored in the bone matrix. By resorbing matrix, osteoclasts may also release dormant MM cells, transforming them into activated tumor cells which lead to micrometastases.

Figure 3. Osteoblast/Osteocyte- Myeloma Interactions

Myeloma cells inhibit osteoblastogenesis and osteoblastic activity through secretion of molecules such as Dkk-1, SFRP-2/3, and TNF-α. MM cells also induce apoptosis in osteocytes, and increase their secretion of sclerostin, through Notch signaling. Bone lining cells of the endosteal niche are able to induce dormancy and potentially apoptosis in MM tumor cells.

Figure 4. Bone Marrow Adipocyte-Myeloma Interactions

Correlative and preliminary data suggest that bone marrow adipose tissue supports myeloma tumor cells through various mechanisms. Excessive bone marrow adiposity has been linked to decreased osteoblast and immune cell function, which may indirectly accelerate MM cell proliferation. BM adipocytes also directly support tumor growth via secretion of adipokines (leptin and resistin) and potentially lipids as a high-caloric energy source for tumor cells. Obesity and elevated BMAT may also lead to hypertrophy or apoptosis in BM adipocytes, which could cause local inflammation and may accelerate tumor growth through enhanced COX-2 or CCL-2 signaling in tumor cells. Influences of MM cells on BMAT are essentially unknown and under investigation.