Radiographical efficacy of systemic treatment for bone metastasis from renal cell carcinoma
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ABSTRACT:
SUBMITTER: Negishi T
PROVIDER: S-EPMC7517538 | biostudies-literature | 2020 Sep
REPOSITORIES: biostudies-literature
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Project description:Bone is one of the common sites of metastases from renal cell carcinoma (RCC), however the mechanism by which RCC preferentially metastasize to bone is poorly understood. Homing/retention of RCC cells to bone and subsequent proliferation are necessary steps for RCC cells to colonize bone. To explore possible mechanisms by which these processes occur, we used an in vivo metastasis model in which 786-O RCC cells were injected into SCID mice intracardially, and organotropic cell lines from bone, liver, and lymph node were selected. The expression of molecules affecting cell adhesion, angiogenesis, and osteolysis were then examined in these selected cells. Cadherin-11, a mesenchymal cadherin mainly expressed in osteoblasts, was significantly increased on the cell surface in bone metastasis-derived 786-O cells (Bo-786-O) compared to parental, liver, or lymph node-derived cells. In contrast, the homing receptor CXCR4 was equivalently expressed in cells derived from all organs. No significant difference was observed in the expression of angiogenic factors, including HIF-1α, VEGF, angiopoeitin-1, Tie2, c-MET, and osteolytic factors, including PTHrP, IL-6 and RANKL. While the parental and Bo-786-O cells have similar proliferation rates, Bo-786-O cells showed an increase in migration compared to the parental 786-O cells. Knockdown of Cadherin-11 using shRNA reduced the rate of migration in Bo-786-O cells, suggesting that Cadherin-11 contributes to the increased migration observed in bone-derived cells. Immunohistochemical analysis of cadherin-11 expression in a human renal carcinoma tissue array showed that the number of human specimens with positive cadherin-11 activity was significantly higher in tumors that metastasized to bone than that in primary tumors. Together, these results suggest that Cadherin-11 may play a role in RCC bone metastasis.
| S-EPMC3933681 | biostudies-literature
Project description:Kidney cancers including clear cell carcinoma (RCC) are identified with very vulnerable mitochondria DNA (mtDNA) and frequent epigenetic aberrations. Bone metastasis from RCC is prevalent and destructive. Bone marrow contains a quite hypoxic microenvironment that usually insitigate 50% of hypermethylation events in conferring a selective advantage for tumor growth. We hypothesized that hypermethylation of mtDNA in RCC cells would significantly contribute to bone metastatic tumor progression. Methylation-specific polymerase chain reaction assay (MSP) was adopted to measure the methylation status of D-loop region of mtDNA in 15 pairs of bone metastatic and primary RCC as well as tumor adjescent normal kidney tissues. mtDNA copy number was examined by the real-time quantitative polymerase chain reaction (qPCR). Western blotting analysis was used to measure the accumulation of several DNA methyltransferases (DNMTs) in the mitochondria and nucleus fractions of bone metastatic RCC cells. mRNA expression of mitochondria encoded genes was examined by RT-PCR. Reactive oxygen species (ROS), mitochondrial membrane potential and ATP content were measured using in vitro cells treated with de-methylation drug 5-Azacytidine (5-Aza). Non-invasive bioluminescent imaging was performed to monitor tumor occurrence in skeleton in mice. Our results showed that the D-loop region in bone metastatic tumor cells was markedly hypermethylated than those in primary RCC tumor cells, that is associated with a decreased mtDNA copy number and accumulation of DNMT1 in the mitochondria. The bone-tropism tumor colonization and progression of RCC cells was significantly suppressed by demethylating the D-loop region of mtDNA and reducing the intracellular level of ROS and ATP by 5-Aza treatment. In conclusion, our study provided a direct association between hypermethylation of mtDNA in RCC with bone metastastic tumor growth.
| S-EPMC8692697 | biostudies-literature
Project description:Bone metastases are responsible for some of the most devastating complications of renal cell carcinoma (RCC). However, pro-metastatic factors leading to the highly osteolytic characteristics of RCC bone metastasis have barely been explored. We previously developed novel bone-seeking RCC cell lines by the in vivo selection strategy and performed a comparative proteome analysis on their total cell lysate. Here, we focused on STIP1 (stress-induced phosphoprotein 1), the high up-regulated protein in the bone-seeking cells, and explored its clinical relevance and functions in RCC bone metastasis. We observed high levels of both intracellular and extracellular STIP1 protein in bone metastatic tissue samples. Elevated STIP1 mRNA in the primary RCC tumors remarkably correlated with worse clinical outcomes. Furthermore, both human recombinant STIP1 protein and anti-STIP1 neutralizing antibody were used in the functional studies. We found that 1) STIP1 protein on the extracellular surface of tumor cells promoted the proliferation and migration/invasion of RCC tumor cells through the autocrine STIP1-ALK2-SMAD1/5 pathway; and 2) STIP1 protein secreted into the extracellular tumor stromal area, promoted the differentiation of osteoclasts through the paracrine STIP1-PrPc-ERK1/2 pathway. Increased cathepsin K (CTSK), the key enzyme secreted by osteoclasts to degrade collagen and other matrix proteins during bone resorption was further detected in the differentiated osteoclasts. These results provide evidence of the great potential of STIP1 as a novel biomarker and therapeutic target in RCC bone metastasis.
| S-EPMC5370018 | biostudies-literature
Project description:Bone metastasis is an important prognostic factor in renal cell carcinoma (RCC). The calcium-sensing receptor (CaSR) has been associated with bone metastasis in several different malignancies. We analyzed the impact of CaSR in bone metastasis in RCC in vitro and in vivo. The RCC cell line 786-O was stably transfected with the CaSR gene and treated with calcium alone or in combination with the CaSR antagonist NPS2143. Afterwards migration, adhesion, proliferation and prominent signaling molecules were analyzed. Calcium treated CaSR-transfected 768-O cells showed an increased adhesion to endothelial cells and the extracellular matrix components fibronectin and collagen I, but not to collagen IV. The chemotactic cell migration and proliferation was also induced by calcium. The activity of SHC, AKT, ERK, P90RSK and JNK were enhanced after calcium treatment of CaSR-transfected cells. These effects were abolished by NPS2143. Development of bone metastasis was evaluated in vivo in a mouse model. Intracardiac injection of CaSR-transfected 768-O cells showed an increased rate of bone metastasis. The results indicate CaSR as an important component in the mechanism of bone metastasis in RCC. Therefore, targeting CaSR might be beneficial in patients with bone metastatic RCC with a high CaSR expression.
| S-EPMC5884663 | biostudies-literature
Project description:Bone metastasis in clear-cell renal cell carcinoma (ccRCC) leads to substantial morbidity through skeletal related adverse events and implicates worse clinical outcomes. MicroRNAs (miRNA) are small non-protein coding RNA molecules with important regulatory functions in cancer development and metastasis. In this retrospective analysis we present dysregulated miRNA in ccRCC, which are associated with bone metastasis. In particular, miR-23a-3p, miR-27a-3p, miR-20a-5p, and miR-335-3p specifically correlated with the earlier appearance of bone metastasis, compared to metastasis in other organs. In contrast, miR-30b-3p and miR-139-3p were correlated with less occurrence of bone metastasis. These miRNAs are potential biomarkers and attractive targets for miRNA inhibitors or mimics, which could lead to novel therapeutic possibilities for bone targeted treatment in metastatic ccRCC.
| S-EPMC8036650 | biostudies-literature
Project description:About one-third of patients with advanced renal cell carcinoma (RCC) have bone metastases. The incidence of RCC is increasing and bone metastatic RCC merits greater focus. Realistic preclinical bone metastasis models of RCC are lacking, hampering the development of effective therapies. We developed a realistic in vivo bone metastasis model of human RCC by implanting precision-cut tissue slices under the renal capsule of immunodeficient mice. The presence of disseminated cells in bone marrow of tissue slice graft (TSG)-bearing mice was screened by human-specific polymerase chain reaction and confirmed by immunohistology using human-specific antibody. Disseminated tumor cells in bone marrow of TSG-bearing mice derived from three of seven RCC patients were detected as early as 1 month after tissue implantation at a high frequency with close resemblance to parent tumors (e.g., CAIX expression and high vascularity). The metastatic patterns of TSGs correlated with disease progression in patients. In addition, TSGs retained capacity to metastasize to bone at high frequency after serial passaging and cryopreservation. Moreover, bone metastases in mice responded to Temsirolimus treatment. Intratibial injections of single cells generated from TSGs showed 100 % engraftment and produced X-ray-visible tumors as early as 3 weeks after cancer cell inoculation. Micro-computed tomography (?CT) and histological analysis revealed osteolytic characteristics of these lesions. Our results demonstrated that orthotopic RCC TSGs have potential to develop bone metastases that respond to standard therapy. This first reported primary RCC bone metastasis model provides a realistic setting to test therapeutics to prevent or treat bone metastases in RCC.
| S-EPMC4351963 | biostudies-literature
Project description:BACKGROUND:Bone metastasis is common in renal cell carcinoma (RCC), and the lesions are mainly osteolytic. The mechanism of bone destruction in RCC bone metastasis is unknown. METHODS:We used a direct intrafemur injection of mice with bone-derived 786-O RCC cells (Bo-786) as an in vivo model to study if inhibition of osteoblast differentiation is involved in osteolytic bone lesions in RCC bone metastasis. RESULTS:We showed that bone-derived Bo-786 cells induced osteolytic bone lesions in the femur of mice. We examined the effect of conditioned medium of Bo-786 cells (Bo-786 CM) on both primary mouse osteoblasts and MC3T3-E1 preosteoblasts and found that Bo-786 CM inhibited osteoblast differentiation. Secretome analysis of Bo-786 CM revealed that BIGH3 (Beta ig h3 protein), also known as TGFBI (transforming growth factor beta-induced protein), is highly expressed. We generated recombinant BIGH3 and found that BIGH3 inhibited osteoblast differentiation in vitro. In addition, CM from Bo-786 BIGH3 knockdown cells (786-BIGH3 KD) reduced the inhibition of osteoblast differentiation compared to CM from vector control. Intrafemural injection of mice with 786-BIGH3 KD cells showed a reduction in osteolytic bone lesions compared to vector control. Immunohistochemical staining of 18 bone metastasis specimens from human RCC showed strong BIGH3 expression in 11/18 (61%) and moderate BIGH3 expression in 7/18 (39%) of the specimens. CONCLUSIONS:These results suggest that suppression of osteoblast differentiation by BIGH3 is one of the mechanisms that enhance osteolytic lesions in RCC bone metastasis, and raise the possibilty that treatments that increase bone formation may improve therapy outcomes.
| S-EPMC5711998 | biostudies-literature
Project description:Renal cell carcinoma (RCC) is one of the ten most frequent solid tumors worldwide. Recent innovations in the treatment of metastatic disease have led to new therapeutic approaches being investigated in the adjuvant setting. Observation is the only current standard of care after radical nephrectomy, although there is evidence of efficacy of adjuvant use of vaccine among all the strategies used. This article aims to collect published experiences with systemic adjuvant approaches in RCC and to describe the results of past and ongoing phase III clinical trials in this field. We explored all the systemic treatments, including chemotherapy, immunotherapy and targeted drugs while alternative approaches have also been described. Appropriate selection of patients who would benefit from adjuvant therapies remains a crucial dilemma. Although the international guidelines do not actually recommend any adjuvant treatment after radical surgery for RCC, no conclusions have yet been drawn pending the results of the promising ongoing clinical trials with the target therapies. The significant changes that these new drugs have made on advanced disease outcome could represent the key to innovation in terms of preventing recurrence, delaying relapse and prolonging survival after radical surgery for RCC.
| S-EPMC4419621 | biostudies-other
Project description:IntroductionThere have been a number of recent advances in the management of advanced clear cell renal cell carcinoma (ccRCC). However, the majority of these studies excluded patients with non-clear cell RCC (nccRCC), and optimal management of nccRCC remains unknown.Materials and methodsA systematic review of the literature was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines to evaluate systemic treatment options in locally advanced or metastatic nccRCC between 2000-2019. Randomized controlled trials, single-arm phase II-IV trials, and prospective analyses of medication access programs were included. The primary outcome measures were progression free survival (PFS), overall survival (OS), and objective response rate (ORR).ResultsA total of 31 studies were included in the final analysis. There was the highest level of evidence to support first-line treatment of nccRCC with sunitinib. Additional single-arm trials support the use of other vascular endothelial growth factor (VEGF) inhibitors with axitinib and pazopanib, as well as mammalian target of rapamycin (mTOR) inhibition with temsirolimus or everolimus +/- bevacizumab. Immune checkpoint inhibition has an emerging role in nccRCC, but optimal sequencing of available options is not clear. Prospective data to support the use of newer immunotherapy combinations are lacking. Treatment for collecting duct carcinoma remains platinum-based chemotherapy.ConclusionsThe availability of randomized trials in nccRCC is limited, and most studies include outcomes for nccRCC as a group, making conclusions about efficacy by subtype difficult. This systematic review supports consensus guidelines recommending sunitinib or clinical trial enrollment as preferred first-line treatment options for nccRCC, but also suggests a more nuanced approach to management and new options for therapy such as immune checkpoint inhibition.
| S-EPMC8384265 | biostudies-literature
Project description:BackgroundThe efficacy of systemic therapy regimens, such as immune checkpoint inhibitors and tyrosine kinase inhibitors (IO-TKI) and targeted therapy, for metastatic clear cell renal cell carcinoma (ccRCC) remains unpredictable due to the lack of effective biomarkers. Neutrophil extracellular trap (NET) plays an important role in promoting ccRCC. This study explores the NET predictive value of the efficacy in metastatic ccRCC.MethodsIn this retrospective study, patients with metastatic ccRCC who received targeted drugs and IO-TKI were included. Immunofluorescence staining was utilized to quantify the levels of tissue NETs through cell counts of H3Cit(+) and MPO(+) cells.ResultsA total of 183 patients with metastatic ccRCC were enrolled, including 150 patients who received TKIs and 33 patients who received IO-TKI. The levels of NETs in tumor tissue were significantly higher than in para-tumor tissue (p < 0.001). In terms of predicting drug efficacy, a correlation between NET levels and progression-free survival (PFS) was observed in the TKI with metachronous metastasis group (HR 1.73 [95% CI 1.02-2.91], log-rank p = 0.037), while no correlation was observed in the TKI with synchronous metastasis group and IO-TKI group. Regarding overall survival (OS), activated NET levels were associated with poor OS in both TKI (HR 1.60 [95% CI 1.05-2.43], log-rank p = 0.017) and IO-TKI group (HR 4.35 [95% CI 1.06-17.82], log-rank p =0.047). IMDC score (HR 1.462 [95% CI 1.030-2.075], p = 0.033) and tumor tissue NET levels (HR 1.733 [95% CI 1.165-2.579], p = 0.007) were independent prognostic risk factors for OS in patients with metastatic ccRCC.NET level was associated with poor OS in both TKI (HR 1.60 [95% CI 1.05-2.43], log-rank p = 0.017).ConclusionsThe active NET levels in tumor tissue can predict drug efficacy in patients with metastatic ccRCC who received systemic therapy. Elevated levels of NETs in tumor tissue were also associated with poor efficacy in OS.
| S-EPMC10757093 | biostudies-literature