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

Falank, Carolyne; Fairfield, Heather; Reagan, Michaela R.

doi:10.1007/s40610-017-0074-6

Cited by 8 publications

(6 citation statements)

References 70 publications

(101 reference statements)

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“…Sclerostin has anti-osteoblastic properties and anti-sclerostin therapeutics are currently being investigated for use in MM-associated bone loss pre-clinically (153, 154). Anti-sclerostin antibodies also reduce BM adiposity, and hence more research into their effects on bone or cancer though modulating BM adiposity is warranted (155, 156). DKK1 is another Wnt inhibitor involved in MM-mediated bone loss and disease progression that has been investigated as a target in MM bone loss (157).…”

Section: Il-6 and Bone-metastatic Cancermentioning

confidence: 99%

Interleukin-6 Interweaves the Bone Marrow Microenvironment, Bone Loss, and Multiple Myeloma

2019

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The immune system is strongly linked to the maintenance of healthy bone. Inflammatory cytokines, specifically, are crucial to skeletal homeostasis and any dysregulation can result in detrimental health complications. Interleukins, such as interleukin 6 (IL-6), act as osteoclast differentiation modulators and as such, must be carefully monitored and regulated. IL-6 encourages osteoclastogenesis when bound to progenitors and can cause excessive osteoclastic activity and osteolysis when overly abundant. Numerous bone diseases are tied to IL-6 overexpression, including rheumatoid arthritis, osteoporosis, and bone-metastatic cancers. In the latter, IL-6 can be released with growth factors into the bone marrow microenvironment (BMM) during osteolysis from bone matrix or from cancer cells and osteoblasts in an inflammatory response to cancer cells. Thus, IL-6 helps create an ideal microenvironment for oncogenesis and metastasis. Multiple myeloma (MM) is a blood cancer that homes to the BMM and is strongly tied to overexpression of IL-6 and bone loss. The roles of IL-6 in the progression of MM are discussed in this review, including roles in bone homing, cancer-associated bone loss, disease progression and drug resistance. MM disease progression often includes the development of drug-resistant clones, and patients commonly struggle with reoccurrence. As such, therapeutics that specifically target the microenvironment, rather than the cancer itself, are ideal and IL-6, and its myriad of downstream signaling partners, are model targets. Lastly, current and potential therapeutic interventions involving IL-6 and connected signaling molecules are discussed in this review.

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Section: Il-6 and Bone-metastatic Cancermentioning

confidence: 99%

Interleukin-6 Interweaves the Bone Marrow Microenvironment, Bone Loss, and Multiple Myeloma

2019

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“…Once differentiated, pre-adipocytes and mature adipocytes seem to play a causative role in the pathology of MM and may affect MBD. BM adipocytes secrete several adipokines and growth factors (e.g., MCP-1, SDF-1α, leptin, TNFα, insulin, resistin) which recruit myeloma cells and promote myeloma growth and protection from chemotherapy [ 187 , 188 , 189 ]. Adipocytes also secrete adiponectin, which has anti-myeloma properties, and its diminished expression in MM creates a permissive microenvironment for myeloma growth and the development of MBD [ 190 ].…”

Section: Biological Roles Of Mscs In MM Pathologymentioning

confidence: 99%

Bone Marrow Mesenchymal Stromal Cells in Multiple Myeloma: Their Role as Active Contributors to Myeloma Progression

Maiso

Mogollón

Ocio

et al. 2021

Cancers

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Multiple myeloma (MM) is a hematological malignancy of plasma cells that proliferate and accumulate within the bone marrow (BM). Work from many groups has made evident that the complex microenvironment of the BM plays a crucial role in myeloma progression and response to therapeutic agents. Within the cellular components of the BM, we will specifically focus on mesenchymal stromal cells (MSCs), which are known to interact with myeloma cells and the other components of the BM through cell to cell, soluble factors and, as more recently evidenced, through extracellular vesicles. Multiple structural and functional abnormalities have been found when characterizing MSCs derived from myeloma patients (MM-MSCs) and comparing them to those from healthy donors (HD-MSCs). Other studies have identified differences in genomic, mRNA, microRNA, histone modification, and DNA methylation profiles. We discuss these distinctive features shaping MM-MSCs and propose a model for the transition from HD-MSCs to MM-MSCs as a consequence of the interaction with myeloma cells. Finally, we review the contribution of MM-MSCs to several aspects of myeloma pathology, specifically to myeloma growth and survival, drug resistance, dissemination and homing, myeloma bone disease, and the induction of a pro-inflammatory and immunosuppressive microenvironment.

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“…However, these adipokines also promote the growths of some solid tumors, such as breast cancer and prostate cancer [ 116 , 117 ]. The role of these adipokines in hematologic cancers is not well known, but co-culture of MM cell lines with adipocyte-containing media revealed soluble factors that could promote proliferation and migration of MM cells, while inhibiting apoptosis via leptin [ 118 , 119 ]. In addition, adipocytes also secrete high levels of IL-6 [ 120 ].…”

Section: Bone Marrow Stromal Cells and Resistancementioning

confidence: 99%

NRF2 Is One of the Players Involved in Bone Marrow Mediated Drug Resistance in Multiple Myeloma

Yen

Hsiao

2018

IJMS

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Multiple myeloma with clonal plasma expansion in bone marrow is the second most common hematologic malignancy in the world. Though the improvement of outcomes from the achievement of novel agents in recent decades, the disease progresses and leads to death eventually due to the elusive nature of myeloma cells and resistance mechanisms to therapeutic agents. In addition to the molecular and genetic basis of resistance pathomechanisms, the bone marrow microenvironment also contributes to disease progression and confers drug resistance in myeloma cells. In this review, we focus on the current state of the literature in terms of critical bone marrow microenvironment components, including soluble factors, cell adhesion mechanisms, and other cellular components. Transcriptional factor nuclear factor erythroid-derived-2-like 2 (NRF2), a central regulator for anti-oxidative stresses and detoxification, is implicated in chemoresistance in several cancers. The functional roles of NRF2 in myeloid-derived suppressor cells and multiple myeloma cells, and the potential of targeting NRF2 for overcoming microenvironment-mediated drug resistance in multiple myeloma are also discussed.

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

Cited by 8 publications

References 70 publications

Interleukin-6 Interweaves the Bone Marrow Microenvironment, Bone Loss, and Multiple Myeloma

Interleukin-6 Interweaves the Bone Marrow Microenvironment, Bone Loss, and Multiple Myeloma

Bone Marrow Mesenchymal Stromal Cells in Multiple Myeloma: Their Role as Active Contributors to Myeloma Progression

NRF2 Is One of the Players Involved in Bone Marrow Mediated Drug Resistance in Multiple Myeloma

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