A prognostic model of clear cell renal cell carcinoma based on telomere-related lncRNAs

AUTHORS

Hao Chen, Li Li, Longkun Mao, Jianfeng Zeng

ABSTRACT

Background

Telomeres have been demonstrated to be critical in the development of multiple tumors. However, the association of telomere-related lncRNAs with clear cell renal cell carcinoma (ccRCC) and their prognostic roles in ccRCC patients remain unknown.

METHODS

Expression matrix and clinicopathological data of ccRCC patients were extracted from The Cancer Genome Altas and UCSC Xena browser. The differentially expressed genes were identified and intersected with the telomere-related genes downloaded from the Telnet database. Telomere-related lncRNAs were screened by the univariate Cox regression analysis. Each patient's risk score was calculated to establish a nomogram based on eight telomere-related lncRNAs screened by the least absolute shrinkage and selection operator (LASSO) algorithm and multivariate Cox regression analysis. The correlation between telomere-related lncRNAs and immune cells was assessed by the CIBEERSORT algorithm. The immune and stromal infiltrations were quantified by the ESTIMATE algorithm. Gene set enrichment analysis (GSEA) was performed to explore the selected lncRNA functions.

Result

We screened eight telomere-related lncRNAs and established a risk score model for predicting survival in ccRCC patients. A nomogram was developed to predict the survival outcomes of postoperative patients by integrating several clinical factors, and a well-predictive effect was observed. The correlation between selected lncRNAs and immune function was explored by the CIBEERSORT and ESTIMATE algorithms. Besides, GSEA showed that telomere-related lncRNAs could affect ccRCC prognosis through multiple pathways.

Efficacy of zoledronic acid for the elimination of disseminated tumor cells in a clinically relevant, spontaneously metastatic prostate cancer xenograft model

AUTHORS

Lukas Clemens Böckelmann, Vera Freytag, Ann-Kristin Ahlers, Hanna Maar, Tobias Gosau, Anke Baranowsky, Rüdiger Schmitz, Klaus Pantel, Udo Schumacher, Marie-Therese Haider, Tobias Lange

ABSTRACT

Bone metastases develop in >90 % of patients with castration-resistant prostate cancer (PCa) through complex interactions between the bone microenvironment and tumor cells. Previous androgen-deprivation therapy (ADT), which is known to cause bone loss, as well as anti-resorptive agents such as zoledronic acid (ZA), used to prevent skeletal complications, may influence these interactions and thereby the growth of disseminated tumor cells (DTC) in the bone marrow (BM). Here, a spontaneously metastatic xenograft tumor model of human PCa was further optimized to mimic the common clinical situation of ADT (castration) combined with primary tumor resection in vivo. The effects of these interventions, alone or in combination with ZA treatment, on tumor cell dissemination to the BM and other distant sites were analyzed. Metastatic burden was quantified by human-specific Alu-qPCR, bioluminescence imaging (BLI), and immunohistochemistry. Further, bone remodeling was assessed by static histomorphometry and serum parameters. Initial comparative analysis between NSG and SCID mice showed that spontaneous systemic dissemination of subcutaneous PC-3 xenograft tumors was considerably enhanced in NSG mice. Primary tumor resection and thereby prolonged observational periods resulted in a higher overall metastatic cell load at necropsy and tumor growth alone caused significant bone loss, which was further augmented by surgical castration. In addition, castrated mice showed a strong trend towards higher bone metastasis loads. Weekly treatment of mice with ZA completely prevented castration- and tumor-induced bone loss but had no effect on bone metastasis burden. Conversely, the total lung metastasis load as determined by BLI was significantly decreased upon ZA treatment. These findings provide a basis for future research on the role of ZA not only in preventing skeletal complications but also in reducing metastasis to other organs.

MiR-214-3p targets Ras-related protein 14 (RAB14) to inhibit cellular migration and invasion in esophageal Cancer cells

AUTHORS

Pornima Phatak, Whitney M. Burrows, Timothy Michael Creed, Mariam Youssef, Goo Lee & James M. Donahue

ABSTRACT

Background

MicroRNA (miR)-214-3p is emerging as an important tumor suppressor in esophageal cancer. In this study, we examined the interaction between miR-214-3p and RAB14, a membrane trafficking protein shown to exert oncogenic functions in other malignancies, in esophageal cancer cells.

Methods

Studies were performed in a human esophageal epithelial cell line and a panel of esophageal cancer cell lines, as well in human specimens. MiR-214-3p expression was measured by digital PCR. Biotinylated RNA pull-down and luciferase reporter assays assessed binding. The xCELLigence RTCA system measured cell migration and invasion in real time. A lentiviral expression vector was used to create an esophageal cancer cell line stably expressing miR-214-3p.

Results

MiR-214-3p expression was decreased in esophageal cancer cell lines and human specimens compared to non-malignant controls. RAB14 mRNA stability and protein expression were decreased following miR-214-3p overexpression. Binding between miR-214-3p and RAB14 mRNA was observed. Either forced expression of miR-214-3p or RAB14 silencing led to a marked decrease in cellular migration and invasion. Esophageal cancer cells stably expressing miR-214-3p demonstrated decreased growth in a subcutaneous murine model.

Conclusions

These results further support the tumor-suppressive role of miR-214-3p in esophageal cancer cells by demonstrating its ability to regulate RAB14 expression.

Inhibition of myeloid PD-L1 suppresses osteoclastogenesis and cancer bone metastasis

AUTHORS

Hao Zuo & Yihong Wan

ABSTRACT

Programmed death-ligand 1 (PD-L1) is predominantly expressed in the antigen-presenting cells (APCs) that are originated and are abundant in the bone marrow. The roles of PD-L1 in bone cell differentiation and cancer bone metastasis remain unclear. Here we show that PD-L1 antibody or PD-L1 conditional knockout in the hematopoietic or myeloid lineage suppresses osteoclast differentiation in vitro and in vivo. Bone metastases of breast cancer and melanoma are diminished by PD-L1 antibody or PD-L1 deletion in the myeloid lineage. Transcriptional profiling of bone marrow cells reveals that PD-L1 deletion in the myeloid cells upregulates immune-stimulatory genes, leading to increased macrophage M1 polarization, decreased M2 polarization, enhanced IFNγ signaling, and elevated T cell recruitment and activation. All these alterations result in heightened anti-tumor immunity in the cancer microenvironment. Our findings support PD-L1 antibody as a potent therapy for bone metastasis of breast cancer and melanoma by simultaneously suppressing osteoclast and enhancing immunity.

Bacterial infections exacerbate myeloma bone disease

AUTHORS

Rui Liu, Yuping Zhong, Rui Chen, Shiyi Chen, Yazhu Huang & Huan Liu

ABSTRACT

Multiple myeloma is characterized by osteolytic lesions caused by reduced bone formation and activated bone resorption. An important feature of myeloma is a failure of bone healing after successful treatment. In this work, clinical studies indicated a highly positive correlation between bone marrow bacteria abundance and bone lesion numbers of myeloma patients in complete remission. Coculture experiments demonstrated that marrow Escherichia coli (E. coli) promotes osteoclast differentiation and inhibits osteoblast differentiation. Mechanism studies showed that E. coli lipopolysaccharides (LPS) activated NF-κB p65 signaling and reduced phosphorylated smad1/5/9 binding ability with RUNX2 promoter, leading to decreased RUNX2 expression in osteoblast progenitors. Additionally, LPS enhanced phosphorylated NF-κB p65 binding ability with NFATc1 promoter, leading to increased NFATc1 expression in osteoclast progenitors. In vivo studies revealed E. coli contributes to osteolytic bone lesion, and elimination of E. coli infection assists healing of bone lesion in mouse model of myeloma in complete remission. These findings establish a heretofore unrecognized effect for E. coli in the genesis of myeloma bone disease and suggest a new treatment strategy.

Fibroblast Growth Factor Receptor 1 Drives the Metastatic Progression of Prostate Cancer

AUTHORS

Estefania Labanca, Jun Yang, Peter D.A. Shepherd, Xinhai Wan, Michael W. Starbuck, Leah D. Guerra, Nicolas Anselmino, Juan A. Bizzotto, Jiabin Dong, Arul M. Chinnaiyan, Murali K. Ravoori, Vikas Kundra, Bradley M. Broom, Paul G. Corn, Patricia Troncoso, Geraldine Gueron, Christopher J. Logothethis, Nora M. Navone

ABSTRACT

Background

No curative therapy is currently available for metastatic prostate cancer (PCa). The diverse mechanisms of progression include fibroblast growth factor (FGF) axis activation.

Objective

To investigate the molecular and clinical implications of fibroblast growth factor receptor 1 (FGFR1) and its isoforms (α/β) in the pathogenesis of PCa bone metastases.

Design, setting, and participants

In silico, in vitro, and in vivo preclinical approaches were used. RNA-sequencing and immunohistochemical (IHC) studies in human samples were conducted.

Outcome measurements and statistical analysis

In mice, bone metastases (chi-square/Fisher’s test) and survival (Mantel-Cox) were assessed. In human samples, FGFR1 and ladinin 1 (LAD1) analysis associated with PCa progression were evaluated (IHC studies, Fisher’s test).

Results and limitations

FGFR1 isoform expression varied among PCa subtypes. Intracardiac injection of mice with FGFR1-expressing PC3 cells reduced mouse survival (α, p < 0.0001; β, p = 0.032) and increased the incidence of bone metastases (α, p < 0.0001; β, p = 0.02). Accordingly, IHC studies of human castration-resistant PCa (CRPC) bone metastases revealed significant enrichment of FGFR1 expression compared with treatment-naïve, nonmetastatic primary tumors (p = 0.0007). Expression of anchoring filament protein LAD1 increased in FGFR1-expressing PC3 cells and was enriched in human CRPC bone metastases (p = 0.005).

Conclusions

FGFR1 expression induces bone metastases experimentally and is significantly enriched in human CRPC bone metastases, supporting its prometastatic effect in PCa. LAD1 expression, found in the prometastatic PCa cells expressing FGFR1, was also enriched in CRPC bone metastases. Our studies support and provide a roadmap for the development of FGFR blockade for advanced PCa.

Patient summary

We studied the role of fibroblast growth factor receptor 1 (FGFR1) in prostate cancer (PCa) progression. We found that PCa cells with high FGFR1 expression increase metastases and that FGFR1 expression is increased in human PCa bone metastases, and identified genes that could participate in the metastases induced by FGFR1. These studies will help pinpoint PCa patients who use fibroblast growth factor to progress and will benefit by the inhibition of this pathway.