New Bone Cell Type Identified as Driver of Drug Resistance in Multiple Myeloma: The Bone Marrow Adipocyte

Multiple myeloma (MM) is a hematological malignancy that is characterized by clonal proliferation of transformed plasma cells within the bone marrow (BM) and severe bone disease. Although MM cells are initially sensitive to many therapies, patients eventually relapse with refractory disease. Because MM cells show a dependency on the BM microenvironment for survival and proliferation, and BM adipocytes (BMAs) demonstrate a unique, endocrine signaling capacity and lipid composition, it is likely that there is cross-talk between MM cells and BMAs that leads to tumor support. Unlike the influences of osteoblasts and osteoclasts, the effect of BMAs on MM cells is poorly understood and few studies have investigated the relationship between bone marrow adipose tissue (BMAT) and cancer. We predict there to be a strong link between MAT and MM, as obesity is a risk factor for MM and also correlates with increased MAT in humans. Moreover, MAT has been shown to support other tumors and correlates with bone diseases such as osteoporosis, anorexia, and aging. Thus, we explored here the novel hypothesis that BMAs induce drug resistance in MM cells through direct cell-cell contact signaling and/or secreted signaling molecules

Inhibiting Fatty Acid Binding Protein Family Members Decreases Multiple Myeloma Cell Proliferation Through Effecting the myc Pathway

FABP inhibition leads to increased survival of myeloma bearing mice and decreased cell growth by inhibiting MYC signaling.https://knowledgeconnection.mainehealth.org/lambrew-retreat-2021/1016/thumbnail.jp

Multiple myeloma cells Graphs and Figures inhibit adipogenesis, increase senescencerelated and inflammatory gene transcript expression, and alter metabolism in preadipocytes

Myeloma cells alter metabolism & induce senescence in adipocyte-lineage cells, suggesting that senescence-associated proteins are involved in multiple myeloma.https://knowledgeconnection.mainehealth.org/lambrew-retreat-2021/1032/thumbnail.jp

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

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

Sister Chromatid Cohesion Disruption: A Potential Role in Particulate Hexavalent Chromium-Induced Carcinogenesis

Hexavalent chromium (Cr(VI)) compounds are well-known human lung carcinogens. Solubility plays an essential role in Cr(VI)-induced carcinogenesis, with the particulate form being the most potent. The carcinogenic mechanism of particulate Cr(VI) is poorly understood. The most plausible mechanistic model for particulate Cr(VI)- induced lung cancer appears to be one that involves genomic instability. We found that chronic exposure to two different particulate Cr(VI) compounds induced a concentration- and time-dependent increase in numerical chromosome instability in the form of aneuploidy. Furthermore, we found that aneuploidy is a permanent phenotypic change. Defects in sister chromatid cohesion is a mechanism that leads to chromosome instability. Consistent with this mechanism, chronic exposure to two different particulate Cr(VI) compounds induced a concentration-dependent increase in sister chromatid cohesion defect that correlates with aneuploidy. Additionally, we found that the cohesion defect phenotype is also a permanent phenotypic change after chromate exposure. This suggests that defects in sister chromatid cohesion may play a role in particulate Cr(VI)- induced carcinogenesis.Additionally for this study, we focused on investigating the potential mechanism of particulate Cr(VI)-induced cohesion defect phenotype. We found that exposure to particulate Cr(VI) disrupted vital proteins that are involved in maintaining sister chromatid cohesion and a decrease in histone methylation. In particular we found that chronic exposure to chromate disrupted the protein levels and localization of Shugoshin1 (Sgo1) in G2 cells, and that this disruption is a permanent change in human lung fibroblast cells. We propose that chronic exposure to particulate Cr(VI) decreases histone methylation which facilitates in disrupting Sgo1 localization, which prompts premature sister chromatid separation, leading to a cohesion defect phenotype and numerical chromosome instability

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

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

MicroRNA transfer between bone marrow adipose and multiple myeloma cells.

PURPOSE OF REVIEW: Multiple myeloma remains an incurable disease, largely due to the tumor-supportive role of the bone marrow microenvironment. Bone marrow adipose tissue (BMAT) is one component of the fertile microenvironment which is believed to contribute to myeloma progression and drug resistance, as well as participate in a vicious cycle of osteolysis and tumor growth. RECENT FINDINGS: MicroRNAs (miRNAs) have recently emerged as instrumental regulators of cellular processes that enable the development and dissemination of cancer. This review highlights the intersection between two emerging research fields and pursues the scientific and clinical implications of miRNA transfer between BMAT and myeloma cells. This review provides a concise and provocative summary of the evidence to support exosome-mediated transfer of tumor-supportive miRNAs. The work may prompt researchers to better elucidate the mechanisms by which this novel means of genetic communication between tumor cells and their environment could someday yield targeted therapeutics

3d Tissue Engineered In Vitro Models Of Cancer In Bone.

Biological models are necessary tools for gaining insight into underlying mechanisms governing complex pathologies such as cancer in the bone. Models range fro

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

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

Assessing the Need for Transfer to a Trauma Center for Isolated Craniofacial Injury in a Rural State

Management of craniofacial injuries typically defaults to plastic, ophthalmology, and oral maxillofacial surgeons which can challenge these surgical subspecialists\u27 capacity to care for both trauma victims and non-trauma patients. Evaluating the need to transfer patients to a higher level of trauma care for isolated craniofacial injuries warrants investigation. Our 5-year retrospective study measured the frequency of craniofacial injuries and subsequent surgical interventions in elderly trauma patients\u27 ≥65 years old. Eighty-one percent of patients consulted with plastic surgeons and 28% with ophthalmology. Twenty percent had craniofacial surgery with the majority of surgical interventions were in soft tissue (97%), mandible (48%), and Le Fort III (29%) injuries. A patient\u27s ISS, GCS, head and face AIS, and presents of spinal or brain injury had no statistically significant impact on injury repair. Elderly patients with isolated craniofacial trauma may be better served by pretransfer consultation with a surgical subspecialist to determine the necessity