Serum High Expression of Micorna-214 Is a Novel Predictor for Myeloma Bone Disease and Poor Prognosis

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 4186-4186
Author(s):  
Mu Hao ◽  
Meirong Zang ◽  
Yan Xu ◽  
Yu Qin ◽  
Lei Zhao ◽  
...  
Keyword(s):  
Bone Disease ◽  
Operating Characteristic ◽  
Area Under The Curve ◽  
Serum Levels ◽  
Bone Lesions ◽  
Myeloma Bone Disease ◽  
Serum Mirna ◽  
Normal Bone ◽  
Healthy Donors ◽  
Lytic Bone Lesions

Abstract Background: Multiple myeloma (MM) originates from clonal expansion of malignant plasma cells in bone marrow, leading to multiple destructive lytic bone lesions that occur in more than 80% of MM patients. MicroRNAs (miRNAs), such as miR-214, miR-34a and Mir-135 are reported to be involved in maintaining normal bone formation and development of metastatic bone lesions in cancers. Recent studies have demonstrated that miRNAs are stably expressed in human plasma and serum samples. And serum miRNAs have been used as biomarkers in diagnosis and prognosis of multiple cancers, including MM. However, the functional roles of miRNA in myeloma bone disease have not been elucidated yet. Materials and methods: In the present study, the serum miRNA expression was assessed from 152 samples including 108 MM samples and 44 healthy donors (HD) of serum. Microarray-based assay and real-time PCR was used to determine differentially expressed miRNAs. The correlation of miRNA expression and bone disease detected by whole body X-ray scanning was evaluated by the receiver operating characteristic (ROC) curve and the area under the curve (AUC). Survival analysis was performed using the Kaplan-Meier method with a log-rank test and the generalized Wilcoxon procedure. Results: We performed serum miRNA profiles from 7 newly diagnosed MMs and 5 normal donors using a microarray-based assay. Our results identified that twenty-seven miRNAs which were reported to be involved in maintaining normal bone formation and development of bone lesions were significantly dysregulated, 4 miRNAs were significantly up-regulated and 23 miRNAs were significantly down-regulated in patient serum. We further performed real-time PCR to verify the expression of miR-214, miR-135, miR-132 and miR-92a in a large cohort of 108 MM patients and 44 healthy donors. We found that miR-214 (0.43±0.17 vs. 2.3±0.14, p<0.0001) and miR-135 (-0.13±0.08 vs. 1.84±0.13, p=0.0022) levels were significantly increased, while serum levels of miR-92a (-0.19±0.20 vs. -1.03±0.11, p=0.0023) were significantly decreased in MM patients. However, we did not found that miR-132 was obviously altered between normal and patient serum. Furthermore, serum levels of miR-214 and miR-135 were notably increased in the patients with lytic bone lesions compared to those without bone disease (both p<0.0001), and a positive correlation was observed between the expression levels of miR-214 (r=0.455, p<0.0001) and miR-135 (r=0.404, p<0.001) with grades of lytic bone lesions. Receiver operating characteristic (ROC) analysis revealed that serum levels of miR-214 and miR-135 can be used to distinguish bone disease in myeloma patients with area under the curve (AUC) > 0.7. Moreover, patients had a significantly shortened OS with high levels of circulating miR-214 (50.0 months vs. NR (not reached); p=0.039) or miR-135 (34.0 months vs.NR; p=0.041) versus those patients with down-regulated levels of miR-214 and miR-135. Patients with higher serum levels of miR-214 were responsible to bisphosphonates with extended OS (NR comparing to 26.0 months, p=0.029), suggesting that bisphosphonates is suitable to treat patients with high expression of circulating miR-214. Conclusion: Our findings reveal that the circulating miR-214 level is a biomarker for prediction of bone disease and prognosis in multiple myeloma. The detail mechanism how miR-214 involves in disease progression will be further explored. The result of this study also set the foundation for searching more circulating miRNA as biomarkers for metastatic bone lesions. Disclosures No relevant conflicts of interest to declare.

Serum Concentrations of DKK-1 Correlate with the Extent of Bone Disease in Multiple Myeloma.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 3518-3518
Author(s):  
Martin Kaiser ◽  
Maren Mieth ◽  
Peter Liebisch ◽  
Susanne Rötzer ◽  
Christian Jakob ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Disease ◽  
Serum Levels ◽  
Conventional Radiography ◽  
Bone Lesions ◽  
X Rays ◽  
Myeloma Bone Disease ◽  
Lytic Lesions ◽  
Significant Difference ◽  
First Time

Abstract Objectives: Lytic bone disease is a hallmark of multiple myeloma (MM) and is caused by osteoclast activation and osteoblast inhibition. Secretion of Dickkopf (DKK)-1 by myeloma cells was reported to cause inhibition of osteoblast precursors. DKK-1 is an inhibitor of the Wnt/β-catenin signaling, which is a critical signaling pathway for the differentiation of mesenchymal stem cells into osteoblasts. So far there is no study showing a significant difference in serum DKK-1 levels in MM patients with or without lytic bone lesions. Methods: DKK-1 serum levels were quantified in 184 previously untreated MM patients and 33 MGUS patients by ELISA, using a monoclonal anti-DKK-1 antibody. For the evaluation of bone disease, skeletal X-rays were performed. Results: Serum DKK-1 was elevated in MM as compared to MGUS (mean 11,963 pg/mL versus 1993 pg/mL, P < 0.05). Serum DKK-1 levels significantly correlated with myeloma stage according to Durie and Salmon (mean 2223 pg/mL versus 15,209 pg/mL in stage I and II/III, respectively; P = 0.005). Importantly, myeloma patients without lytic lesions in conventional radiography had significantly lower DKK-1 levels than patients with lytic bone disease (mean 3114 pg/mL versus 17,915 pg/mL; P = 0.003). Of interest, serum DKK-1 correlated with the number of bone lesions (0 vs. 1–3 vs. >3 lesions: mean 3114 pg/mL vs. 3559 pg/mL vs. 24,068 pg/mL; P = 0.002). Conclusion: This is the largest study of DKK-1 serum levels in multiple myeloma patients and data show for the first time a correlation between DKK-1 serum concentration and the amount of lytic bone disease, suggesting that DKK1 is an important factor for the extent of bone disease and supporting the hypothesis of DKK-1 as a therapeutic target in myeloma bone disease.

scholarly journals Circulating microRNAs Correlate with Multiple Myeloma and Skeletal Osteolytic Lesions

Cancers ◽  
2021 ◽  
Vol 13 (21) ◽  
pp. 5258
Author(s):  
Sara Reis Moura ◽  
Hugo Abreu ◽  
Carla Cunha ◽  
Cláudia Ribeiro-Machado ◽  
Carla Oliveira ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Bone Disease ◽  
Area Under The Curve ◽  
Genetic Alterations ◽  
Disease Stage ◽  
Bone Lesions ◽  
Healthy Controls ◽  
Osteolytic Lesions ◽  
Circulating Micrornas ◽  
Myeloma Bone Disease

Multiple myeloma (MM) is the second most frequent hematological disease and can cause skeletal osteolytic lesions. This study aims to evaluate the expression of circulating microRNAs (miRNAs) in MM patients and to correlate those levels with clinicopathological features, including bone lesions. A panel of miRNAs associated with MM onset and progression, or with bone remodeling, was analyzed in the plasma of 82 subjects (47 MM patients; 35 healthy controls). Results show that miR-16-5p, miR-20a-5p, and miR-21-5p are differently expressed between MM patients and healthy controls. Receiver operating characteristic analyses indicate that their combined expression has potential as a molecular marker (Area Under the Curve, AUC of 0.8249). Furthermore, significant correlations were found between the analyzed miRNAs and disease stage, treatment, β2 microglobulin, serum albumin and creatinine levels, but not with calcium levels or genetic alterations. In this cohort, 65.96% of MM patients had bone lesions, the majority of which were in the vertebrae. Additionally, miR-29c-3p was decreased in patients with osteolytic lesions compared with patients without bone disease. Interestingly, circulating levels of miR-29b-3p correlated with cervical and thoracic vertebral lesions, while miR-195-5p correlated with thoracic lesions. Our findings suggest circulating miRNAs can be promising biomarkers for MM diagnosis and that their levels correlate with myeloma bone disease and osteolytic lesions.

The EphrinB2/EphB4 Axis Is Dysregulated in Osteoprogenitors from Myeloma Patients and Its Activation by EphrinB2-Fc or EhpB4-Fc Affects Myeloma Bone Disease and Tumor Growth in Vivo

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 844-844
Author(s):  
Angela Pennisi ◽  
Wen Ling ◽  
Xin Li ◽  
Jianmei Chen ◽  
Sharmin Khan ◽  
...  
Keyword(s):  
Tumor Growth ◽  
Osteogenic Differentiation ◽  
Bone Disease ◽  
Plasma Cells ◽  
Bone Lesions ◽  
Reverse Signaling ◽  
Myeloma Bone Disease ◽  
Bidirectional Signaling ◽  
Healthy Donors

Abstract Induction of osteolytic bone lesions in myeloma (MM) is caused by an uncoupling of osteoclastic bone resorption and osteoblastic bone formation. Recent studies indicate that in addition to role in cell adhesion, repulsion and neovascularization, bidirectional signaling between the cell surface molecules EphrinB2 and EphB4 also mediates the coupling between osteoblasts and osteoblasts. While mesenchymal stem cells (MSCs) and osteoblasts express the ligand EphrinB2 land its receptor, EphB4, osteoclasts and their precursors mainly express EphrinB2. Forward signaling in MSCs promotes osteogenic differentiation and reverse signaling in osteoclast precursors inhibits their differentiation. The aims of the study were to investigate whether the EphrinB2/Eph4 axis is dysregulated in MM osteoprogenitors and whether activation of this axis in myelomatous bone by EphrinB2-Fc or EphB4-Fc affects MM bone disease, angiogenesis and tumor growth. MSCs were generated from bone marrow of healthy donors (n=5) and patients with MM (n=13). Gene expression was determined by qRT-PCR. MSCs from MM patients had reduced expression of EphrinB2 (EFNB2) by 61±6% (p<0.02) and EphB4 by 60±10% (p<0.02) than expression levels of these molecules in MSCs from healthy donors. Expression of other EFN and EPH B genes were detected and similarly expressed in patients and donors MSCs. Differentiation of MSCs from MM patients into osteoblasts resulted in upregulation of EFNB2 and downregulation of EPHB4. MM cell lines and primary MM plasma cells expressed low to undetectable levels of this family of genes. We exploited our SCID-hu system for primary MM to study the consequences of activation of forward signaling by EphrinB2-Fc or reverse signaling by EphB4-Fc on MM-induced bone disease and MM growth. Twelve SCID-hu mice were engrafted with MM cells from a patient with active MM. Upon detection of MM growth (by human Ig ELISA) and bone disease (radiographically), hosts were locally treated with Fc (control), EphrinB2-Fc or EPHB4 (4 mice/group) for 4 weeks using Alzet pump that continually released 0.11 μg/hour of each compound. While in Fc-treated hosts BMD of the implanted bone was reduced by 8±3% from pretreatment levels, it was increased by EphrinB2-Fc and EPhB4-Fc by 15±8% (p<0.03 vs. Fc) and 2±1% (p<0.02 vs. Fc) from pretreatment levels, respectively. At experiment’s end levels of human Ig in mice sera were increased by 308±99% and 244±86% from pretreatment levels in Fc- and EphrinB2- Fc groups, respectively, while were reduced by 92±1% (p<0.02 vs. Fc) from pretreatment levels in EphB4-Fc group. In myelomatous bones, EphB4-Fc and EphrinB2-Fc increased the numbers of osteoblasts by >3 folds (p<0.004) while EphB4-Fc, but not EphrinB2-Fc, reduced osteoclast numbers by 5 folds (p<0.01 vs. Fc group). The numbers of CD34-reactive neovessels were reduced by 2 folds following treatment with EphB4-Fc (p<0.03) and were increased by 2.5 folds following treatment with EphrinB2-Fc (p<0.05). Our study suggests that downregulation of EphrinB2 and EhpB4 in MSCs from MM patients contributes to their impaired osteogenic differentiation and that treatment with EphrinB2-Fc or EphB4-Fc helps restore coupling of bone remodeling in myelomatous bones. The results also indicate that EphB4-Fc treatment is an effective approach to simultaneously inhibit MM and its associated bone disease.

scholarly journals Serum levels of Trimethylamine-N-oxide in patients with ischemic stroke

2019 ◽  
Vol 39 (6) ◽  
Author(s):  
Maimaiti Rexidamu ◽  
Hongmei Li ◽  
Haiyan Jin ◽  
Jiankang Huang
Keyword(s):  
Ischemic Stroke ◽  
Operating Characteristic ◽  
Area Under The Curve ◽  
Serum Levels ◽  
Clinical Severity ◽  
Chinese Patients ◽  
Stroke Severity ◽  
Increased Risk ◽  
Median Level ◽  
And Gender

Abstract Objective: Accumulating evidence suggests that Trimethylamine-N-oxide (TMAO), a gut microbial metabolite, is implicated in the pathogenesis of many cardiovascular diseases. The aim of the present study was to investigate the serum levels of TMAO in Chinese patients with ischemic stroke. Method: In the present study, 255 consecutive patients with first-ever acute ischemic stroke and 255 age and gender-matched healthy volunteers were included for testing serum TMAO. Stroke severity was determined by the NIH Stroke Scale (NIHSS). The stroke severity was dichotomized as minor (NIHSS ≤ 5) and moderate-to-high clinical severity (NIHSS > 6). Results: The serum levels of TMAO in stroke ranged from 0.5 to 18.3 μM, with a median value of 5.8 (interquartile range (IQR), 3.3–10.0) μM, which was higher than in those controls (3.9; IQR, 2.6–6.1 μM). The median level of TMAO in those patients was significantly lower than in those moderate-to-high stroke patients (4.1 μM [IQR, 2.8–6.2] vs. 9.1 μM [5.1–11.0]; P<0.001). In univariate and multivariable models, the unadjusted risk of moderate-to-high stroke was increased by 31% (odds ratio (OR) = 1.31 [95% confidence interval (CI): 1.21–1.42], P<0.001) and 22% (OR = 1.22; 95% CI = 1.08–1.32; P<0.001), when TMAO was increased each by 1 μM. Based on the receiver operating characteristic (ROC) curve, the optimal cut-off value of serum level of TMAO as an indicator for screening of moderate-to-high stroke was estimated to be 6.6 μM, which yielded a sensitivity of 69.3 % and a specificity of 79.0%, with the area under the curve at 0.750 (95% CI, 0.687–0.812). Conclusions: Higher TMAO levels were associated with increased risk of first ischemic stroke and worse neurological deficit in Chinese patients.

Serum Levels of OPG and MIP-1α in Untreated Multiple Myeloma Patients. Correlations with Staging, Survival and Bone Disease.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 5074-5074
Author(s):  
Argyro Papadogiannis ◽  
Marie-Cristine Kyrtsonis ◽  
Theodoros P. Vassilakopoulos ◽  
Tatiana Tzenou ◽  
Antonios G. Antoniadis ◽  
...  
Keyword(s):  
Bone Disease ◽  
Staging System ◽  
Serum Levels ◽  
High Serum ◽  
Stage I ◽  
Stage Ii ◽  
Stage Iii ◽  
Bone Lesions ◽  
Disease Biology ◽  
Significant Difference

Abstract Cytokines, such as MIP-1a (macrophage inhibiting factor) and OPG (osteoprotegerin) are assumed to play a role in MM disease biology and bone disease, by mechanisms that are still under investigation. MIP-1a is constitutively secreted by myeloma cells, plays a possible role in the development of MM bone lesions, enhance MM cell adhesion to stromal cells and its serum levels have been recently related to survival in MM. OPG is a soluble decoy receptor which acts as a soluble receptor antagonist that prevents osteoclasts activation and the development of bone disease. Reported findings on serum OPG levels in MM patients are controversial as well as its possible role in the biology of the disease. In order to investigate the possible relationship of MIP-1a and OPG levels in MM patients with prognosis and bone disease, we determined by ELISA serum MIP-1a and OPG levels in 20 MGUS, 82 MM patients and 27 healthy individuals (HI). Both cytokines were determined by ELISA (R&D, Quantikine, USA) in frozen sera collected at dignosis, before treatment. The median age of MM patients was 69 years (44–84) and 50% were males. MM patients’ stage was as follows: 23 stage I, 28 stage II, 31 stage III according to Durie-Salmon staging system and 27 stage I, 17 stage II, 35 stage III according to the International Scoring System (ISS). In HI median MIP-1a was 28 pg/ml (15–54) and median OPG 1600 pg/ml (450–4600). In subjects with MGUS, median MIP-1a was 34 pg/ml (17–58) and median OPG 2300 pg/ml (820–6200). In MM patients, median pretreatment serum MIP-1a was 32 pg/ml (16–100) and OPG 3000 pg/ml (820–25000). No statistical significant difference was observed between HI, MGUS and MM patients with regard to MIP-1a levels but for OPG levels differences between HI and MM patients and between MGUS and MM patients were both significant (0.01 and 0.05 respectively). No relationship was found between MIP-1a or OPG levels and bone disease. However, there was a trend for longer survival in patients with MIP-1a or OPG levels lower than median (5-year overall survival 60 ± 12 vs 38 ± 14, p=0.08 and 66 ± 13 vs 29 ± 13, p=0.07 respectively). In addition MIP-1a levels were correlated with ISS stage: MIP-1a levels were 28.3±11.3 in ISS stage 1, 29.8±11.1 in ISS stage 2, 39±19.2 in ISS stage 3 (p=0.02). In conclusion, in our experience serum OPG levels are higher in MM patients than in MGUS or HI, MIP-1a levels are correlated with the ISS stage and both high serum MIP-1a and OPG levels at diagnosis are related with a shorter survival.

Inhibition of p38α MAPK Reduces Tumor Burden, Prevents the Development of Myeloma Bone Disease, and Increases Survival in the 5T2 and 5T33 Murine Models of Myeloma.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 3436-3436 ◽  
Author(s):  
Karin Vanderkerken ◽  
Satya Medicherla ◽  
Les Coulton ◽  
Benjamin Van Camp ◽  
Andy Protter ◽  
...  
Keyword(s):  
Bone Disease ◽  
Critical Role ◽  
Disease Free Survival ◽  
Myeloma Cell ◽  
Bone Lesions ◽  
Myeloma Cells ◽  
Growth And Survival ◽  
Myeloma Bone Disease ◽  
Osteolytic Bone Disease

Abstract The bone microenvironment plays a critical role in supporting the growth and survival of myeloma cells and the development of osteolytic bone disease. Signalling through p38 α MAPK mediates synthesis of myeloma cell survival factors by stromal cells; whereas, inhibiting p38 α MAPK reduces myeloma cell proliferation and inhibits osteoclast formation in vitro. However, it is unclear whether p38 α MAPK inhibition will prevent the growth and survival of myeloma cells and the bone disease in vivo. The aim of this study was to determine whether SCIO-469, a selective p38 α MAPK inhibitor, would inhibit myeloma growth and prevent the development of bone disease in the 5TMM syngeneic models of myeloma. Treatment of 5TMM cells, in vitro, with SCIO-469 resulted in a clear inhibition of p38 phosphorylation, as assessed by Western blotting and an inhibition up to 35% of stromal cell induced 5T33MM proliferation. Injection of 5T2MM murine myeloma cells into C57Bl/KaLwRij mice resulted in the growth of myeloma in bone and the development of bone disease characterized by increased osteoclast surface (p<0.05), a reduction in cancellous bone (p<0.01) and the presence of osteolytic bone lesions on x-ray (p<0.01). Treatment of 5T2MM-bearing mice with SCIO-469 (150mg/kg in the diet, therapeutical treatment from paraprotein detection) resulted in a 42% decrease in serum paraprotein and prevented development of osteolytic lesions (p<0.01). Injection of 5T33MM cells into C57Bl/KaLwRij mice also resulted in the development of myeloma but not associated bone disease. Treatment of 5T33MM-bearing mice from the time of tumor cell injection with SCIO-469 resulted in a decrease in serum paraprotein (8.8+/−1.4g/dl to 0.04+/− 0.03g/dl, p<0.001) and a reduction in the proportion of tumor cells in the bone marrow (67 +/− 8.1% to 1.09 +/− 0.58%, p<0.001). Kaplan-Meier analysis demonstrated an increase in disease-free survival (veh=27.5 days vs 96 days, p<0.001) after treatment of the mice with SCIO-469. These data demonstrate that targeting p38 α MAPK with SCIO-469 is associated with an anti-myeloma effect, which indirectly prevents the development of myeloma bone disease.

Ibandronate Reduces Osteolytic Lesions but not Tumor Burden in a Murine Model of Myeloma Bone Disease

Blood ◽  
1999 ◽  
Vol 93 (5) ◽  
pp. 1697-1706 ◽  
Author(s):  
Sarah L. Dallas ◽  
I. Ross Garrett ◽  
Babatunde O. Oyajobi ◽  
Mark R. Dallas ◽  
Brendan F. Boyce ◽  
...  
Keyword(s):  
Murine Model ◽  
Bone Disease ◽  
Bone Destruction ◽  
Myeloma Cell ◽  
Tumor Burden ◽  
Clinical Findings ◽  
Bone Lesions ◽  
Detectable Effect ◽  
Myeloma Cells ◽  
Myeloma Bone Disease

We determined the effects of the potent bisphosphonate ibandronate in a murine model of human myeloma bone disease. In this model, bone lesions typical of the human disease develop in mice following inoculation of myeloma cells via the tail vein. Treatment with ibandronate (4 μg per mouse per day) significantly reduced the occurrence of osteolytic bone lesions in myeloma-bearing mice. However, ibandronate did not prevent the mice from developing hindlimb paralysis and did not produce a detectable effect on survival. There was no significant effect of ibandronate on total myeloma cell burden, as assessed by morphometric measurements of myeloma cells in the bone marrow, liver, and spleen, or by measurement of serum IgG2b levels. These results support clinical findings that bisphosphonates may be useful for the treatment of myeloma-associated bone destruction, but suggest that other therapies are also required to reduce tumor growth.

scholarly journals An Improved Animal Model of Multiple Myeloma Bone Disease

Cancers ◽  
2021 ◽  
Vol 13 (17) ◽  
pp. 4277
Author(s):  
Syed Hassan Mehdi ◽  
Carol A Morris ◽  
Jung Ae Lee ◽  
Donghoon Yoon
Keyword(s):  
Multiple Myeloma ◽  
Bone Disease ◽  
Plasma Cells ◽  
Bone Lesions ◽  
Myeloma Bone Disease ◽  
Nsg Mice ◽  
Morphometric Analyses ◽  
Imaging Results ◽  
Nsg Mouse

Multiple myeloma (MM) is a plasma cell malignancy that causes an accumulation of terminally differentiated monoclonal plasma cells in the bone marrow, accompanied by multiple myeloma bone disease (MMBD). MM animal models have been developed and enable to interrogate the mechanism of MM tumorigenesis. However, these models demonstrate little or no evidence of MMBD. We try to establish the MMBD model with severe bone lesions and easily accessible MM progression. 1 × 106 luciferase-expressing 5TGM1 cells were injected into 8–12 week-old NOD SCID gamma mouse (NSG) and C57BL/KaLwRij mouse via the tail vein. Myeloma progression was assessed weekly via in vivo bioluminescence (BL) imaging using IVIS-200. The spine and femur/tibia were extracted and scanned by the micro-computer tomography for bone histo-morphometric analyses at the postmortem. The median survivals were 56 days in NSG while 44.5 days in C57BL/KaLwRij agreed with the BL imaging results. Histomorphic and DEXA analyses demonstrated that NSG mice have severe bone resorption that occurred at the lumbar spine but no significance at the femur compared to C57BL/KaLwRij mice. Based on these, we conclude that the systemic 5TGM1 injected NSG mouse slowly progresses myeloma and develops more severe MMBD than the C57BL/KaLwRij model.

scholarly journals Targeting the BMP Pathway in Prostate Cancer Induced Bone Disease

2021 ◽  
Vol 12 ◽  
Author(s):  
Desiree M. Straign ◽  
Claire L. Ihle ◽  
Meredith D. Provera ◽  
Philip Owens
Keyword(s):  
Prostate Cancer ◽  
Bone Metastasis ◽  
Bone Metastases ◽  
Bone Disease ◽  
Bone Health ◽  
Metastatic Prostate Cancer ◽  
Bone Lesions ◽  
Prostate Cell ◽  
Prostate Cell Line ◽  
Lytic Bone Lesions

From the 33,000 men in the U.S. who die from prostate cancer each year, the majority of these patients exhibit metastatic disease with bone being the most common site of metastasis. Prostate cancer bone metastases are commonly blastic, exhibiting new growth of unhealthy sclerotic bone, which can cause painful skeletal related events. Patient’s current care entails androgen deprivation therapy, anti-resorptive agents, radiation, and chemotherapy to help control the spread of the cancer but little intervention is available to treat blastic bone disease. The transforming growth factor beta (TGFβ) and bone morphogenetic protein (BMP) pathways are known to regulate bone growth and resorption of destructive lytic bone lesions, yet the role of TGFβ/BMP signaling in prostate cancer blastic vs lytic bone lesions are not fully understood. We hypothesized that to target the BMP/TGFβ pathway, a useful biomarker of bone lytic or blastic pathology would have superior response. We show distinct BMP vs. TGFβ signaling in clinical samples of human prostate cancer bone metastases with either lytic or blastic pathologies. BMPs exhibit distinct effects on bone homeostasis, so to examine the effect of BMP inhibition on healthy bone, we treated mice with the BMP receptor small molecule antagonist DMH1 and saw a modest temporary improvement in bone health, with increased trabecular bone. We next sought to use the BMP inhibitor DMH1 to treat bone metastasis engraftment seeded by a caudal artery injection of the lytic human prostate cell line PC3 in immunodeficient mice. The colonization by PC3 cells to the bone were restricted with DMH1 treatment and bone health was importantly preserved. We next proceeded to test BMP inhibition in an injury model of established bone metastasis via intratibial injection of the MYC-CaP mouse prostate cell line into FVBN syngeneic mice. DMH1 treated mice had a modest decrease in trabecular bone and reduced lymphocytes in circulation without affecting tumor growth. Taken together we show unique responses to BMP inhibition in metastatic prostate cancer in the bone. These studies suggest that profiling bone lesions in metastatic prostate cancer can help identify therapeutic targets that not only treat the metastatic tumor but also address the need to better treat the distinct tumor induced bone disease.

scholarly journals Electrochemotherapy and Simultaneous Photodynamic Bone Stabilization of Upper Limbs in Metastatic Renal Cancer Disease: Case Report and Literature Review

2020 ◽  
Vol 2020 ◽  
pp. 1-7
Author(s):  
Ugo Albertini ◽  
Andrea Conti ◽  
Nicola Ratto ◽  
Pietro Pellegrino ◽  
Michele Boffano ◽  
...  
Keyword(s):  
Quality Of Life ◽  
Minimally Invasive ◽  
Bone Disease ◽  
Metastatic Bone Disease ◽  
Invasive Technique ◽  
Bone Lesions ◽  
Disease Case ◽  
Lytic Bone Lesions

Introduction. Metastatic bone disease represents a systemic pathology that heavily affects the quality of life of oncologic patients causing pain and functional disability. Methodology. We present the case of a patient with a history of renal cell cancer presenting pathologic fractures of both humeri and proximal right radius. Results. After a careful multidisciplinary approach, an adjuvant anticancer therapy and a photodynamic bone stabilization procedure were performed with a minimally invasive technique aiming to minimize pain and local disease progression, while restoring functional autonomy and improving the patient’s quality of life. Electrochemotherapy was delivered on the lytic bone lesions with extraskeletal involvement of the proximal left humerus and the proximal right radius, and then polymeric bone stabilization was performed on both humeri. At two months of follow-up, the patient presented satisfactory functional scores (MSTS score: 12/30 bilaterally; DASH scores: 46.7/100 for the right side and 48.3/100 for the left one), and pain was well controlled with opioid analgesics. Radiographs showed good results in terms of ossification of lytic bone lesions and durability of polymeric stabilization. At four months of follow-up, the patient reported a stable clinical scenario. Six months after surgery, due to extremely poor prognosis after the progression of primary disease, the patient was referred to palliative care and died shortly thereafter. Conclusion. Over the last decade, the management of metastatic bone disease has changed. Low-toxicity and minimally invasive procedures such as electrochemotherapy and polymeric bone stabilization might be performed concomitantly in selected patients, as an alternative to radiation therapy and to more demanding surgical procedures such as plating and adjuvant cementing.

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